JPH01135778A - Production of acetic acid derivative - Google Patents
Production of acetic acid derivativeInfo
- Publication number
- JPH01135778A JPH01135778A JP62292815A JP29281587A JPH01135778A JP H01135778 A JPH01135778 A JP H01135778A JP 62292815 A JP62292815 A JP 62292815A JP 29281587 A JP29281587 A JP 29281587A JP H01135778 A JPH01135778 A JP H01135778A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ester
- salt
- acid
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001242 acetic acid derivatives Chemical class 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 28
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 67
- 238000006243 chemical reaction Methods 0.000 abstract description 50
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 24
- 239000002904 solvent Substances 0.000 abstract description 23
- 239000002994 raw material Substances 0.000 abstract description 8
- 229930186147 Cephalosporin Natural products 0.000 abstract description 4
- 229940124587 cephalosporin Drugs 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 abstract 1
- 125000004181 carboxyalkyl group Chemical group 0.000 abstract 1
- 150000001780 cephalosporins Chemical class 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 150000003567 thiocyanates Chemical class 0.000 abstract 1
- -1 cephalosporin compound Chemical class 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 238000001816 cooling Methods 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 13
- 235000011054 acetic acid Nutrition 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000002411 adverse Effects 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 150000002148 esters Chemical group 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 6
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 6
- 229910052697 platinum Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 125000005907 alkyl ester group Chemical group 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- LBWKJGADVUPZFR-UHFFFAOYSA-N 2-[[(5-amino-1,2,4-thiadiazol-3-yl)-carboxymethylidene]amino]oxy-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)ON=C(C(O)=O)C1=NSC(N)=N1 LBWKJGADVUPZFR-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 229910017052 cobalt Inorganic materials 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- YOSFGDLBDAFZMZ-UHFFFAOYSA-N 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]iminoacetic acid Chemical compound CC(C)(C)OC(=O)CON=C(C(O)=O)C1=NSC(N)=N1 YOSFGDLBDAFZMZ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000388 Polyphosphate Polymers 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 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 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 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
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 239000001205 polyphosphate Substances 0.000 description 2
- 235000011176 polyphosphates Nutrition 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- VGRXAHXMIDCTNV-UHFFFAOYSA-N (6-chlorobenzotriazol-1-yl) 4-chlorobenzenesulfonate Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)ON1C2=CC(Cl)=CC=C2N=N1 VGRXAHXMIDCTNV-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YZLSXKIVGNQGPR-UHFFFAOYSA-N 1,2-oxazole;hydrate Chemical compound O.C=1C=NOC=1 YZLSXKIVGNQGPR-UHFFFAOYSA-N 0.000 description 1
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-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
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical compound ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- BYAXHIDIDCTTGN-UHFFFAOYSA-N 2-(2-butoxy-2-oxoethoxy)iminoacetic acid Chemical group C(CCC)OC(=O)CON=CC(=O)O BYAXHIDIDCTTGN-UHFFFAOYSA-N 0.000 description 1
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 description 1
- MMWUUQAJVKBBGJ-UHFFFAOYSA-N 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(carboxymethoxyimino)acetic acid Chemical compound NC1=NC(C(=NOCC(O)=O)C(O)=O)=NS1 MMWUUQAJVKBBGJ-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- AVZBOAGCVKEESJ-UHFFFAOYSA-O 2-ethyl-1,2-benzoxazol-2-ium-7-ol Chemical class C1=CC(O)=C2O[N+](CC)=CC2=C1 AVZBOAGCVKEESJ-UHFFFAOYSA-O 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- IGIJSFNBEUBMGB-UHFFFAOYSA-N 4-(cyclohexyliminomethylideneamino)-n,n-diethylcyclohexan-1-amine Chemical compound C1CC(N(CC)CC)CCC1N=C=NC1CCCCC1 IGIJSFNBEUBMGB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- 108010000916 Fimbriae Proteins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 241000047703 Nonion Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WGPAQYSVWYWZKT-UHFFFAOYSA-N [C].[Ra] Chemical compound [C].[Ra] WGPAQYSVWYWZKT-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- WYYQVWLEPYFFLP-UHFFFAOYSA-K chromium(3+);triacetate Chemical compound [Cr+3].CC([O-])=O.CC([O-])=O.CC([O-])=O WYYQVWLEPYFFLP-UHFFFAOYSA-K 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- WMYNMYVRWWCRPS-UHFFFAOYSA-N ethynoxyethane Chemical group CCOC#C WMYNMYVRWWCRPS-UHFFFAOYSA-N 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 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
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- JVHPKYBRJQNPAT-UHFFFAOYSA-N n-cyclohexyl-2,2-diphenylethenimine Chemical compound C1CCCCC1N=C=C(C=1C=CC=CC=1)C1=CC=CC=C1 JVHPKYBRJQNPAT-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- OCDPVICYFFZSFE-UHFFFAOYSA-N prop-1-enoxybenzene Chemical group CC=COC1=CC=CC=C1 OCDPVICYFFZSFE-UHFFFAOYSA-N 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-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
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- IGVNJALYNQVQIT-UHFFFAOYSA-N tert-butyl 2-bromo-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)Br IGVNJALYNQVQIT-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical compound O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は、優れた抗菌活性を有するセラフ0スポリン化
合物を製造するための原料化合物として有用な、下記酢
酸誘導体(I)の新規製造法に関する。Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a new method for producing the following acetic acid derivative (I), which is useful as a raw material compound for producing Seraph 0 sporin compound having excellent antibacterial activity. .
(従来の技術)
酢酸誘導体(1)の製造法は例えば、特開昭55−10
5689号公報に記載されているが、下記化合物(rl
)を原料化合物きして使用した酢酸誘導体(I)の製造
法は知られていない。(Prior art) A method for producing the acetic acid derivative (1) is disclosed in, for example, Japanese Patent Application Laid-Open No. 55-10
Although it is described in Publication No. 5689, the following compound (rl
) is used as a raw material compound to produce an acetic acid derivative (I).
(本発明の目的)
本発明は、酢酸誘導体(I)の新規な工業的製造法を提
供するものである。(Objective of the present invention) The present invention provides a novel industrial method for producing acetic acid derivative (I).
(発明の構成)
本発明は一般式:
[式中 R1はカルボキシ(低級)アルキル基または保
護きれたカルボキシ(低級)アルキル基、R2はカルボ
キシ基または保護されたカルボキシ基をそれぞれ意味す
るコ
で示される酢酸誘導体(I)またはその塩の製造法に関
する。(Structure of the Invention) The present invention relates to the general formula: [In the formula, R1 is a carboxy(lower) alkyl group or a unprotected carboxy(lower) alkyl group, and R2 is a carboxy group or a protected carboxy group, respectively] The present invention relates to a method for producing an acetic acid derivative (I) or a salt thereof.
本発明の発明者等は、酢酸誘導体(I)またはその塩の
新規製造法についての種々の研究の結果、下記化合物(
I[)またはその塩にチオシアン酸(85CN)の塩を
反応させると、安全簡便に、しかも高収率で酢酸誘導体
(I)またはその塩が得られることを見いだし本発明を
完成した。The inventors of the present invention discovered the following compound (
The present invention was completed by discovering that acetic acid derivative (I) or a salt thereof can be obtained safely and easily and in high yield by reacting I[) or a salt thereof with a salt of thiocyanic acid (85CN).
本発明による酢酸誘導体(I)またはその塩の製造法は
下記の通りである。The method for producing acetic acid derivative (I) or a salt thereof according to the present invention is as follows.
1産迭二
晩
−R
(II)
またはその塩
[式中、RおよびR2はそれぞれ前と同じ意味、xlは
ハロゲンを意味する]
本発明の原料化合物(1)は新規化合物であり、下記の
製造法により製造することができる。One Birth Two Nights-R (II) or a salt thereof [In the formula, R and R2 each have the same meaning as before, xl means halogen] The raw material compound (1) of the present invention is a new compound, and the following It can be manufactured by a manufacturing method.
製造法A:
R−0−C−C−R2
製11虹亀上
xl
家
[式中、R、RおよびXlは前と同じ意味、Rは低級ア
ルキル基、X2はハロゲン R2は保護されたカルボキ
シ基をそれぞれ意味する]本発明で得られる酢酸誘導体
(I)およびその塩は、抗菌剤として有用なセファロス
ポリン化合物、例えば下記−数式(X)で示される新規
セフェム化合物またはその塩の原料として有用である。Production method A: R-0-C-C-R2 Product 11 Nijigami xl [wherein, R, R and Xl have the same meanings as before, R is a lower alkyl group, X2 is a halogen, R2 is a protected carboxy The acetic acid derivative (I) and its salt obtained in the present invention can be used as a raw material for a cephalosporin compound useful as an antibacterial agent, such as a new cephalosporin compound represented by the following formula (X) or a salt thereof. Useful.
C式中、R1は前と同じ意味、R4は低級アルキル基、
R5はアミン基または保護されたアミノ基をそれぞれ意
味する]
この新規セフェム化合物(X)またはその塩は、以下に
示す製法で製造することができる。In formula C, R1 has the same meaning as before, R4 is a lower alkyl group,
R5 means an amine group or a protected amino group, respectively] This novel cephem compound (X) or a salt thereof can be produced by the production method shown below.
1抹
またはアミ7基における
その反応性誘導体または
その塩
またはカルボキシ基におCする
その反応性誘導体またはその塩
(X)
またはその塩
[式中、R1、R4およびR5は前と同じ意味]本願目
的化合物(I)のR2が保護されたカルボキシ基の場合
には、常法に従って、カルボキシ保護基の脱離反応に付
すことにより上記化合物(Ia)を得ることができる。A reactive derivative thereof or a salt thereof at 1 or 7 groups, or a reactive derivative thereof or a salt thereof (X) at a carboxy group or a salt thereof [wherein R1, R4 and R5 have the same meanings as before] This application When R2 of the target compound (I) is a protected carboxy group, the above compound (Ia) can be obtained by subjecting it to an elimination reaction of the carboxy protecting group according to a conventional method.
本願目的化合物(I)は、上記7−アミノセファロスポ
リン化合物(X’l )の7位アシル化の原料としての
みならず、他の7−アミノセファロスポリン化合物の7
位アシル化の原料としても有用である。The object compound (I) of the present application is useful not only as a raw material for the 7-position acylation of the above-mentioned 7-aminocephalosporin compound (X'l), but also as a raw material for the 7-position acylation of the above-mentioned 7-aminocephalosporin compound (X'l), as well as for the 7-position acylation of other 7-aminocephalosporin compounds.
It is also useful as a raw material for positional acylation.
目的化合物(1)ならびに、その他の化合物(■a)、
(I)、(M a)、(I[b)、(IV)、(Vl)
、(■)、(■)、(IX)および(X)については、
シン異性体、アンチ異性体およびそれらの混合物が含ま
れるものとする0例えば化合物(I)、(II)、(V
l)、(■)、(■)および(IX)について説明すれ
ば、シン異性体は式:
(式中、RおよびR2は前と同じ意味)で示される部分
構造を有する一つの幾何異性体を意味し、アンチ異性体
は式:
(式中、RおよびR2は前と同じ意味)で示される部分
構造を有するもう一方の幾何異性体を意味する。Target compound (1) and other compounds (■a),
(I), (M a), (I[b), (IV), (Vl)
, (■), (■), (IX) and (X),
For example, compounds (I), (II), (V
l), (■), (■) and (IX), the syn isomer is one geometric isomer having a partial structure of the formula: (wherein R and R2 have the same meanings as before) and anti-isomer means the other geometric isomer having a partial structure of the formula: (wherein R and R2 have the same meanings as before).
他の化合物についても、シン異性体およびアンチ異性体
は上記で説明した幾何異性体と同様に説明することがで
きる。Regarding other compounds, the syn isomer and the anti isomer can be explained in the same manner as the geometric isomer explained above.
この明細書の以上および以下の記載における種々の定義
の好適な例を以下詳細に説明する。Preferred examples of the various definitions in the above and below descriptions of this specification will be explained in detail below.
「低級」とは、特に指示がなければ、炭素原子1〜6個
を意味するものとする。"Lower" shall mean 1 to 6 carbon atoms unless otherwise specified.
好適な「低級アルキル基4、ならびに「カルボキシ(低
級)アルキル基」およびr保護されたカルボキシ(低級
)アルキル基」の好適な「低級アルキル部分」としては
、メチル、エチル、プロピル、イソプロピル、ブチル、
イソブチル、第三級ブチル、ペンチル、ヘキシル等のよ
うな直鎖アルキルまたは分枝鎖アルキルが挙げられ、そ
れらの中で好ましいものとしては01〜C4アルキル基
が挙げられる。Preferred "lower alkyl moieties" of "lower alkyl group 4, and carboxy(lower) alkyl group" and r-protected carboxy(lower) alkyl group include methyl, ethyl, propyl, isopropyl, butyl,
Mention may be made of straight-chain or branched-chain alkyls such as isobutyl, tertiary-butyl, pentyl, hexyl, etc., among which preferred are 01-C4 alkyl groups.
好適な1保護されたカルボキシ基」および′保護された
カルボキシ(低級)アルキル基」の好適な1保護された
カルボキシ基」としてはエステル化されたカルボキシ基
等が挙げられ、そのエステル化されたカルボキシ基のエ
ステル部分の具体例としては、適当な置換基を有してい
てもよい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、イソプロピルエステル、ブチルエステル
、イソブチルエステル、第三級ブチルエステル、ペンチ
ルエステル、ヘキシルエステル、1−シクロプロピルエ
チルエステル等の低級アルキルエステル、その例として
、例えばアセトキシメチルエステル、プロピオニルオキ
シメチルエステル、ブチリルオキシメチルエステル、バ
レリルオキシメチルエステル、ピバロイルオキシメチル
エステル、1−アセトキシエチルエステル、1−プロピ
オニルオキシエチルエステル、2−プロピオニルオキシ
エチルエステル、ヘキサノイルオキシメチルエステル等
の低級アルカノイルオキシ(低級)アルキルエステル、
例えば2−メシルエチルエステル等の低級アルカンスル
ホニル(低級)アルキルエステルまたは例えば2−ヨー
ドエチルエステル、2.2.2−トリクロロエチルエス
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;例えハヒニルエステル、アリルエステル
等の低級アルケニルエステル;例えばエチニルエステル
、プロピニルエステル等の低級アルキニルエステル;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
トキシフェニル)メチルエステル、3.4−’;メトキ
シベンジルエステル、4−ヒドロキシ−3,5−’、;
第三級ブチルベンジルエステル等の適当な置換基を有し
ていてもよいアル(低級)アルキルエステル;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、4−第三級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、クメニルエステル等の
適当な置換基を有していてもよいアリールエステル等の
ようなものが挙げられる。Examples of the "preferred 1-protected carboxy group" and the "preferred 1-protected carboxy group" of the ``protected carboxy (lower) alkyl group'' include esterified carboxy groups, etc. Specific examples of the ester moiety of the group include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl, which may have an appropriate substituent. esters, lower alkyl esters such as 1-cyclopropylethyl ester, such as acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxy Lower alkanoyloxy (lower) alkyl esters such as ethyl ester, 1-propionyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester,
For example, lower alkanesulfonyl (lower) alkyl esters such as 2-mesylethyl ester or mono (or di or tri) halo (lower) alkyl esters such as 2-iodoethyl ester, 2.2.2-trichloroethyl ester; Lower alkenyl esters such as hahynyl ester and allyl ester; Lower alkynyl esters such as ethynyl ester and propynyl ester; For example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester,
Trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-'; methoxybenzyl ester, 4-hydroxy-3,5-';
Al (lower) alkyl esters which may have suitable substituents such as tertiary butyl benzyl ester; for example, phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tert butyl phenyl ester, xylyl ester, Examples include aryl esters which may have appropriate substituents such as mesityl ester and cumenyl ester.
好適な「ハロゲン」としては塩素、臭素、フッ素または
ヨウ素が挙げられる。Suitable "halogens" include chlorine, bromine, fluorine or iodine.
「保護されたアミノ基、の好適な「保護基」としては、
例えばホルミル、アセチル、プロピオニル、ヘキサノイ
ル、ピバロイル等の低級アルカノイル基、例えばクロロ
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(低級)アルカノイル基、例えばメトキ
シカルボニル、エトキシカルボニル、第三級ブトキシカ
ルボニル、第三級ペンチルオキシカルボニル、ヘキシル
オキシカルボニル等の低級アルコキシカルボニル基、例
えばベンゾイル、トルオイル、ナフトイル等のアロイル
基、例えばフェニルアセチル、フェニルプロピオニル等
のアル(低級)アルカノイル基、例えばフェノキシカル
ボニル、ナフチルオキシカルボニル等のアリールオキシ
カルボニル基、例えばフェノキシアセチル、フェノキシ
プロピ才二ル等のアリールオキシ(低級)アルカノイル
基等が挙げられる。Preferred "protecting groups" for "protected amino groups" include:
Lower alkanoyl groups such as formyl, acetyl, propionyl, hexanoyl, pivaloyl, mono(or di- or tri)halo(lower) alkanoyl groups such as chloroacetyl, trifluoroacetyl, etc., e.g. methoxycarbonyl, ethoxycarbonyl, tertiary-butoxy Lower alkoxycarbonyl groups such as carbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, aroyl groups such as benzoyl, toluoyl, naphthoyl, alkanoyl groups such as phenylacetyl, phenylpropionyl, e.g. phenoxycarbonyl, naphthyl Examples include aryloxycarbonyl groups such as oxycarbonyl, and aryloxy(lower)alkanoyl groups such as phenoxyacetyl and phenoxypropylene.
目的化合物(I>の好適な塩としては、例えばナトリウ
ム塩、カリウム塩等のアルカリ金属塩および例えばカル
シウム塩、マグネシウム塩等のアルカリ土金属塩のよう
な金属塩、アンモニウム塩、例えばトリメチルアミン塩
、トリエチルアミン塩、ピリジン塩、ピコリン塩、ジシ
クロヘキシルアミン塩、N、N’ −ジベンジルエチレ
ンジアミン塩等の有機塩基塩、例えばギ酸塩、酢酸塩、
トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、メタン
スルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホ
ン酸塩等の有機酸塩、例えば塩酸塩、臭化水素酸塩、硫
酸塩、燐酸塩等の無機酸塩、例えばアルギニン塩、アス
パラギン酸塩、グルタミン酸塩等のアミノ酸との塩等が
挙げられる。Suitable salts of the target compound (I) include metal salts such as alkali metal salts such as sodium salts and potassium salts and alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts such as trimethylamine salts and triethylamine salts; organic base salts such as pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, e.g. formates, acetates,
Organic acid salts such as trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate; inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc. Examples of acid salts include salts with amino acids such as arginine salts, aspartate salts, and glutamate salts.
目的化合物(1)またはその塩の製造法を下記に説明す
る。The method for producing the target compound (1) or a salt thereof will be explained below.
製造法:
化合物<I)またはその塩は、化合物(π)またはその
塩をチオシアン* (H5CN )の塩と反応させるこ
とにより製造することができる。Production method: Compound <I) or a salt thereof can be produced by reacting compound (π) or a salt thereof with a salt of thiocyanine* (H5CN).
化合物(I[)の好適な塩としては、化合物(I)につ
いて例示したものが挙げられる。Suitable salts of compound (I[) include those exemplified for compound (I).
チオシアン酸の好適な塩としては、例えばナトリウム塩
、カルシウム塩等のアルカリ金属塩等のような金属塩、
例えばトリメチルアミン、トリエチルアミン、ジメチル
アニリン等の有機第三級塩基との塩等が挙げられる。Suitable salts of thiocyanic acid include metal salts such as alkali metal salts such as sodium salts and calcium salts;
Examples include salts with organic tertiary bases such as trimethylamine, triethylamine, and dimethylaniline.
この反応は通常、反応に悪影響を及ぼきない溶媒、その
例として、例えばメタノール、エタノール等のアルコー
ル等の溶媒中で行なわれる。This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as an alcohol such as methanol or ethanol.
反応温度は特に限定されず、通常は冷却下ないし室温下
に反応が行われる。The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature.
次に、原料化合物(II)またはその塩の製造法を下記
に述べる。Next, a method for producing the starting compound (II) or its salt will be described below.
鉦IL!!jす上
化合物(VI)またはその塩は、化合物(IV)または
その塩を化合物(V)またはその塩と反応させることに
より製造することができる。Gong IL! ! j) Compound (VI) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof.
反応は、例えば、アルカリ金属水酸化物、アルカリ金属
炭酸塩、アルカリ金属炭酸水素塩のような無機塩基、ト
リアルキルアミンのような有機塩基等の塩基の存在下に
行うのが好ましい。The reaction is preferably carried out in the presence of a base such as an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal hydrogen carbonate, or an organic base such as a trialkylamine.
反応は通常、塩化メチレン、N、N−ジメチルホルムア
ミド、テトラヒドロフランのような溶媒中、またはそれ
らの混合物中で行われるが、反応に悪影響を及ぼきない
溶媒であればその他のいかなる溶媒中でも反応を行うこ
とができる。The reaction is usually carried out in a solvent such as methylene chloride, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof, but it can also be carried out in any other solvent that does not adversely affect the reaction. be able to.
反応温度は特に限定されないが、通常は室温ないし加温
下に反応が行われる。Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or with heating.
1監盗人二に
化合物(■)またはその塩は、化合物(Vl)またはそ
の塩をアンモニアと反応させることにより製造すること
ができる。1. Compound (■) or a salt thereof can be produced by reacting compound (Vl) or a salt thereof with ammonia.
反応は通常、水、例えばメタノール、エタノール等のア
ルコール、テトラヒドロフランのような溶媒中、または
それらの混合物中で行われるが、反応に悪影響を及ぼさ
ない溶媒であればその他のいかなる溶媒中でも反応を行
うことができる。The reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, or a solvent such as tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. Can be done.
反応温度は特に限定されないが、通常は冷却下ないし加
温下に反応が行われる。Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.
災IJ1L二墾工
化合物(■)または、その塩は、化合物(■)またはそ
の塩を脱水反応に付すことにより製造することができる
。The compound (■) or a salt thereof can be produced by subjecting the compound (■) or a salt thereof to a dehydration reaction.
この脱水反応に使用される脱水剤には、塩化ホスホリル
、塩化チオニル、五酸化リン、五塩化リン、五臭化リン
、無水酢酸、無水トリフルオロ酢酸などが含まれる。The dehydrating agent used in this dehydration reaction includes phosphoryl chloride, thionyl chloride, phosphorus pentoxide, phosphorus pentachloride, phosphorus pentabromide, acetic anhydride, trifluoroacetic anhydride, and the like.
この反、応は通常、例えばジオキサン、クロロホルム、
塩化メチレン、テトラヒドロフラン、ピリジン、N、N
−ジメチルホルムアミドなどの溶媒中で行なわれるが、
反応に悪影響を及ぼさない溶媒であればその他のどのよ
うな溶媒でも使用することができる。This reaction is usually carried out using dioxane, chloroform,
Methylene chloride, tetrahydrofuran, pyridine, N, N
- carried out in a solvent such as dimethylformamide,
Any other solvent can be used as long as it does not adversely affect the reaction.
反応温度は特に限定されず、反応は通常冷却下ないし加
温下の範囲で行なわれる。The reaction temperature is not particularly limited, and the reaction is usually carried out in a range of cooling to heating.
飯m二段上
化合物(DOまたはその塩は、化合物(■)またはその
塩とアンモニアおよび/またはアンモニウム塩と反応さ
せることにより製造することができる。The second-stage compound (DO or its salt) can be produced by reacting the compound (■) or its salt with ammonia and/or an ammonium salt.
適当なアンモニウム塩には酢酸アンモニウム、硫酸アン
モニウム、ハロゲン化アンモニウム(例えば、塩化アン
モニウム、臭化アンモニウム等)などが含まれる。Suitable ammonium salts include ammonium acetate, ammonium sulfate, ammonium halides (eg, ammonium chloride, ammonium bromide, etc.), and the like.
反応は通常、例えばメタノール、エタノール等のアルコ
ールのような溶媒中で行われるが、反応に悪影響を及ぼ
きない溶媒であればその他のいかなる溶媒中でも反応を
行うことができる。The reaction is usually carried out in a solvent such as an alcohol such as methanol or ethanol, but the reaction can be carried out in any other solvent that does not adversely affect the reaction.
反応温度は特に限定きれないが、通常は冷却下ないし加
温下に反応が行われる。Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.
B1見上
化合物(If)またはその塩は、化合物(IX)または
その塩をハロゲン化反応に付すことにより製造すること
ができる。B1-like compound (If) or a salt thereof can be produced by subjecting compound (IX) or a salt thereof to a halogenation reaction.
この反応に用いられる好適なハロゲン化剤としては、ハ
ロゲン(例えば塩素、臭素、フッ素またはヨウ素)、例
えばN−クロロサクシンイミド、N−プロモサクシンイ
ミド等のN−ハロゲン化すクシンイミド、例えば次亜塩
素酸、次亜臭素酸等の次亜ハロゲン酸、例えば塩化イン
シアヌル酸、臭化インシアヌル酸等のハロゲン化インシ
アヌル酸等がその例として挙げられる。Suitable halogenating agents used in this reaction include halogens (e.g. chlorine, bromine, fluorine or iodine), N-halogenated succinimides such as N-chlorosuccinimide, N-promosuccinimide, e.g. hypochlorous acid Examples include hypohalous acids such as , hypobromous acid, and halogenated incyanuric acids such as incyanuric chloride and incyanuric bromide.
反応は通常、例えばメタノール、エタノール等のアルコ
ール、塩化メチレン、テトラヒドロフラン、酢酸エチル
のような溶媒中、またはそれらの混合物中で行われるが
、反応に悪影響を及ぼさない溶媒であればその他のいか
なる溶媒中でも反応を行うことができる。The reaction is usually carried out in a solvent such as an alcohol such as methanol, ethanol, methylene chloride, tetrahydrofuran, ethyl acetate, or a mixture thereof, but may also be carried out in any other solvent that does not adversely affect the reaction. reactions can be carried out.
反応温度は特に限定きれないが、通常は冷却下ないし加
温下に反応が行われる。Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.
11盈1ユ
化合物(Ib)またはその塩は、化合物(Ha)または
その塩をカルボキシ保護基の脱離反応に付すことにより
製造することができる。Compound (Ib) or a salt thereof can be produced by subjecting compound (Ha) or a salt thereof to a carboxy-protecting group elimination reaction.
この反応は加水分解、還元等のような常法に従って行わ
れる。This reaction is carried out according to conventional methods such as hydrolysis, reduction, etc.
加水分解は塩基、または酸の存在下に行うのが好ましい
、好適な塩基としては、例えばナトリウム、カリウム等
のアルカリ金属、例えばマグネシウム、カルシウム等の
アルカリ土金属、それらの水酸化物または炭酸塩または
炭酸水素塩、例えばトリメチルアミン、トリエチルアミ
ン等のトリアルキルアミン、ピッリン、等のような無機
塩基および有機塩基が挙げられる。The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, their hydroxides or carbonates, or Included are inorganic and organic bases such as bicarbonates, trialkylamines such as trimethylamine, triethylamine, pilin, and the like.
好適な酸としては、例えばギ酸、酢酸、プロピオン酸、
トリクロロ酢酸、トリフルオロ酢酸等の有機酸および例
えば塩酸、臭化水素酸、硫酸、塩化水素、臭化水素等の
無機酸が挙げられる。Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.
脱離反応に適用きれうる還元法としては化学的還元およ
び接触還元が挙げられる。Reduction methods applicable to the elimination reaction include chemical reduction and catalytic reduction.
化学的還元に使用される好適な還元剤は、例えばスズ、
亜鉛、鉄等の金属または例えば塩化クロム、酢酸クロム
等の金属化合物と、例えばギ酸、酢酸、プロピオン酸、
トリフルオロ酢酸、p−トルエンスルホン酸、塩酸、臭
化水素酸等の有機酸または無機酸との組合わせである。Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.
接触還元に使用される好適な触媒は、例えば白金板、白
金海綿、白金黒、コロイド白金、酸化白金、白金線等の
白金触媒、例えばパラジウム海綿、パラジウム黒、酸化
パラジウム、バ!ラジウムー炭素、コロイドパラジウム
、パラジウム−硫酸バリウム、パラジウム−炭酸バリウ
ム等のパラジラム触媒、例えば還元ニッケル、酸化ニッ
ケル、ラネーニッケル等のニッケル触媒、例えば還元コ
バルト、ラネーコバルト等のコバルト触媒、例えば還元
鉄、ラネー鉄等の鉄触媒、例えば還元鋼、ラネー銅、ウ
ルマン銅等の銅触媒等のような常用のものである。Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, platinum catalysts such as palladium sponges, palladium black, palladium oxide, band! Palladium catalysts such as radium-carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, reduced iron, Raney iron, etc. and other commonly used iron catalysts, such as reduced steel, copper catalysts such as Raney copper, Ullmann copper, etc.
反応は通常、水、例えばメタノール、エタノール等のア
ル)−ノ呟塩化メチレン、ジオキサン、テトラヒドロフ
ランのような溶媒中またはそれらの混合物中で行われる
が、反応に悪影響を及ぼさない溶媒であればその他のい
かなる溶媒中でも反応を行うことができる。The reaction is usually carried out in a solvent such as water, methylene chloride such as methanol, ethanol, dioxane, tetrahydrofuran, or a mixture thereof, but other solvents may be used as long as they do not adversely affect the reaction. The reaction can be carried out in any solvent.
反応温度は特に限定されないが、通常は冷却下ないし加
温下に反応が行われる。Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.
次にセファロスポリン化合物(X)の製法を以下に示す
。Next, a method for producing cephalosporin compound (X) is shown below.
化合物(X)またはその塩は、化合物(XI)またはア
ミン基におけるその反応性誘導体またはその塩を、化合
物(Ia)またはカルボキシ基におけるその反応性誘導
体またはその塩と反応させることにより製造することが
できる。Compound (X) or a salt thereof can be produced by reacting compound (XI) or a reactive derivative thereof at an amine group or a salt thereof with compound (Ia) or a reactive derivative thereof at a carboxy group or a salt thereof. can.
化合物(XI)のアミノ基における好適な反応性誘導体
としては、化合物(XI)とアルデヒド、ケトン等のよ
うなカルボニル化合物との反応によって生成するシッフ
の塩基型イミノまたはそのエナミン型互変異性体;化合
物(XI)とビス(トリメチルシリル)アセトアミド、
例えばN−(トリメチルシリル)アセトアミド等のモノ
(トリメデルシリル)アセトアミド、ビス(トリメチル
シリル)尿素等のようなシリル化合物との反応によって
生成するシリル誘導体;化合物(Xl)と三塩化溝また
はホスゲンとの反応によって生成する誘導体等が挙げら
れる。Suitable reactive derivatives at the amino group of compound (XI) include Schiff's base-type imino or its enamine-type tautomer produced by the reaction of compound (XI) with a carbonyl compound such as an aldehyde, a ketone, etc.; Compound (XI) and bis(trimethylsilyl)acetamide,
A silyl derivative produced by reaction with a silyl compound such as mono(trimedersilyl)acetamide such as N-(trimethylsilyl)acetamide, bis(trimethylsilyl)urea, etc.; produced by reaction of compound (Xl) with a trichloride groove or phosgene. Examples include derivatives that
化合物(Ia)のカルボキシ基における好適な反応性誘
導体としては酸ハロゲン化物、酸無水物、活性化アミド
、活性化エステル等が挙げられる。Suitable reactive derivatives of the carboxy group of compound (Ia) include acid halides, acid anhydrides, activated amides, activated esters, and the like.
反応性誘導体の好適な例としては、酸塩化物;酸アジド
;例えばジアルキル燐酸、フェニル燐酸、ジフェニル燐
酸、ジベンジル燐酸、ハロゲン化燐酸等の置換された燐
酸、ジアルキル亜燐酸、亜硫酸、チオ硫酸、硫酸、例え
ばメタンスルホン酸等のスルホン酸、例えば酢酸、プロ
ピオン酸、酪酸、イソ酪酸、ピバリン酸、ペンタン酸、
イソペンタン酸、2−エチル酪酸、トリクロロ酢酸等の
脂肪族カルボン酸または例えば安息香酸等の芳香族カル
ボン酸のような酸との混合酸無水物;対称酸無水物;イ
ミダゾール、4−置換イミダゾール、ジメチルピラゾー
ル、トリアゾールまたはテトラゾールとの活性化アミド
;または例えばシアンメチルエステル、メトキシメチル
エステル、ジメチルイミノメチル[(cu3)2i−C
H−]エステル、ビニルエステル、プロパルギルエステ
ル、p−二トロフェニルエステル、2.4−ジニトロフ
ェニルエステル、トリクロロフェニルエステル、ペンタ
クロロフェニルエステル、メシルフェニルエステル、フ
ェニルアゾフェニルエステル、フェニルチオエステル、
p−ニトロフェニルチオエステル、p−タレシルチオエ
ステル、カルボキシメチルチオエステル、ピラニルエス
テル、ピリジルエステル、ピペリジルエステル、8−キ
ノリルチオエステル等の活性化エステルまたは例えばN
、N−ジメチルヒドロキシルアミン、1−ヒドロキシ−
2−(IH)−ピリドン、N−ヒドロキシスクシンイミ
ド、N−ヒドロキシフタルイミド、1−ヒドロキシ−I
H−ベンゾトリアゾール等のN−ヒドロキシ化合物との
エステル等が挙げられる。Suitable examples of reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid. , sulfonic acids such as methanesulfonic acid, such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid,
Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; symmetrical acid anhydrides; imidazole, 4-substituted imidazole, dimethyl activated amides with pyrazoles, triazoles or tetrazoles; or e.g. cyan methyl ester, methoxymethyl ester, dimethyliminomethyl [(cu3)2i-C
H-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester,
Activated esters such as p-nitrophenyl thioester, p-talesyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester or e.g.
, N-dimethylhydroxylamine, 1-hydroxy-
2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-I
Examples include esters with N-hydroxy compounds such as H-benzotriazole.
これらの反応性誘導体は使用すべき化合物(Ia)の種
類に応じてそれらの中から任意に選択することができる
。These reactive derivatives can be arbitrarily selected from them depending on the type of compound (Ia) to be used.
反応は通常、水、例えばメタノール、エタノール等のア
ルコール、アセトン、ジオキサン、アセトニトリル、ク
ロロホルム、塩化メチレン、塩化エチレン、テトラヒド
ロフラン、酢酸エチル、N、N−ジメチルホルムアミド
、ピリジンのような常用の溶媒中で行われるが、反応に
悪影響を及ぼさない溶媒であればその他のいかなる有機
溶媒中でも反応を行うことができる。これらの常用の溶
媒は水との混合物として使用してもよい。The reaction is usually carried out in a conventional solvent such as water, an alcohol such as methanol or ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, or pyridine. However, the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used in mixtures with water.
この反応において化合物(Ia)を遊離の形またはその
塩の形で使用する場合には、N、N’ −ジシクロへキ
シルカルボジイミド;N−シクロヘキシル−N′−モル
ホリノエチルカルボジイミド;N−シクロへキシル−N
’−(4−ジエチルアミノシクロヘキシル)カルボジイ
ミド、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−エチル−N’−
(3−ジメチルアミノプロピル)カルボジイミド;N。When compound (Ia) is used in the free form or its salt form in this reaction, N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl- N
'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'
-diisopropylcarbodiimide; N-ethyl-N'-
(3-dimethylaminopropyl)carbodiimide; N.
N′ −カルボニルビス−(2−メチルイミダゾール)
;ペンタメチレンケテン−N−シクロヘキシルイミン;
ジフェニルケテン−N−シクロヘキシルイミン;エトキ
シアセチレン;1−アルフキシー1−クロロエチレン;
亜燐酸トリアルキル;ポリ燐酸ニブル;ポリ燐酸イソプ
ロピル:オキシ塩化燐(塩化ホスホリル);三塩化燐;
塩化チオニル;塩化オキサリル;例えばクロロギ酸エチ
ル、クロロギ酸イソプロピル等のへロギ酸低級アルキル
;トリフェニルホスフィン;2−エチル−7−ヒドロキ
シベンズイソオキサゾリウム塩=2−二チルー5−(m
−スルホフェニル)イソ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−IH−ベンゾトリアゾール、N、N−
ジメチルホルムアミドと塩化チオニル、ホスゲン、クロ
ロギ酸トリクロロメチル、オキシ塩化燐等との反応によ
って調製されるいわゆるビルスマイヤー試薬等のような
常用の縮合剤の存在下に反応を行うのが好ましい。N'-carbonylbis-(2-methylimidazole)
;pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine;ethoxyacetylene;1-alfoxy-1-chloroethylene;
Trialkyl phosphite; Nibble polyphosphate; Isopropyl polyphosphate: Phosphorus oxychloride (phosphoryl chloride); Phosphorus trichloride;
thionyl chloride; oxalyl chloride; lower alkyl heroformates such as ethyl chloroformate, isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt = 2-dityl-5-(m
-sulfophenyl) isoxazolium hydroxide
Inner salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole, N,N-
Preferably, the reaction is carried out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, and the like.
反応はまたアルカリ金属炭酸水素塩、トリ(低級)アル
キルアミン、ピリジン、N−(低級)アルキルモルホリ
ン、N、N−ジ(低級)アルキルベンジルアミン等のよ
うな無機塩基または有機塩基の存在下に反応を行っても
よい。The reaction can also be carried out in the presence of inorganic or organic bases such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N,N-di(lower)alkylbenzylamines, etc. A reaction may also be carried out.
反応温度は特に限定されないが、通常は冷却下ないし加
温下に反応が行われる。Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating.
この様にして得られた化合物(X)のR1が保護された
カルボキシ(低級)アルキル基および/またはR5が保
護されたアミノ基の場合には、常法に従って保護基の脱
離反応に付してR1がカルボキシ(低級)アルキル基お
よび/またはR5がアミノ基である化合物に変えること
ができる。In the case where R1 of the thus obtained compound (X) is a protected carboxy(lower) alkyl group and/or R5 is a protected amino group, the compound (X) is subjected to an elimination reaction of the protecting group according to a conventional method. can be changed to a compound in which R1 is a carboxy (lower) alkyl group and/or R5 is an amino group.
以下、実施例および参考例に従ってこの発明をきらに詳
細に説明する。Hereinafter, this invention will be explained in detail according to Examples and Reference Examples.
夫轟3ユ
(l)2−ヒトミキシイミノマロン酸ジメチルエステル
(10g)および2−ブロモ−2−メチルプロピオン酸
第三級ブチルエステル(15,93g )のN。Todoroki 3U (l) 2-Hutomiximinomalonic acid dimethyl ester (10 g) and N of 2-bromo-2-methylpropionic acid tertiary butyl ester (15,93 g).
N−ジメチルホルムアミド(16111)に室温下トリ
エチルアミン(9,95IQ )を加え、50〜60°
Cで6時間攪拌後ジエデルエーテル(20G111 )
および水(5O1l)の混合物に注ぐ、有機層を分取し
、5%炭酸カリウム水溶液、水および塩化ナトリウム水
溶液で洗浄し、硫酸マグネシウムで乾燥後減圧下に溶媒
を留去して、2−(1−第三級ブトキシ力ルボニル−1
−メチルエトキシイミノ)マロン酸ジメチルエステル(
17,95g ’)を得た。Triethylamine (9,95IQ) was added to N-dimethylformamide (16111) at room temperature, and the mixture was heated at 50-60°C.
Diedelether (20G111) after stirring for 6 hours at C.
The organic layer was poured into a mixture of 2-( 1-Tertiary butoxycarbonyl-1
-methylethoxyimino)malonic acid dimethyl ester (
17.95 g') was obtained.
IR(フィルム) : 2980. 1740.
1605 cm、−’NMR(CDCl2.8 )
: 1.50 (9H,s)、 1.60 (6H,s
)。IR (film): 2980. 1740.
1605 cm, -'NMR (CDCl2.8)
: 1.50 (9H,s), 1.60 (6H,s
).
3.93 (3B、s)、 3.95 (3H,s)同
様にして、次の化合物を得た。3.93 (3B, s), 3.95 (3H, s) The following compounds were obtained in the same manner.
(2)2−第三級ブトキシカルボニルメトキシイミノマ
ロン酸ジメチルエステル
IR(スジ1−N) : 1775. 1730.
1615 cra−’NMR(CDCl2.8)
: 1.47 (9H,s)、 3.90 (6H,s
)。(2) 2-Tertiary butoxycarbonylmethoxyiminomalonic acid dimethyl ester IR (Stripe 1-N): 1775. 1730.
1615 cra-'NMR (CDCl2.8)
: 1.47 (9H,s), 3.90 (6H,s
).
4.68 <2H,s)
塞m呈
(1)2−(1−$三級ブトキシカルボニルー1−メチ
ルエトキシイミノ)マロン酸ジメチルエステル(16,
95g)のメタノール(85ffll+ )溶液に28
%アンモニア水(17,3411111)を室温下に加
え、1.5時間攪拌した後減圧下に溶媒を留去して2−
カルバモイル−2−(1−第三級ブトキシ力ルボニル−
1−メチルエトキシイミノ)酢酸メチルエステル(シン
異性体) (10,60g )を得た。4.68 <2H,s) 2-(1-$tert-butoxycarbonyl-1-methylethoxyimino)malonic acid dimethyl ester (16,
95g) in methanol (85ffll+) solution
% ammonia water (17,3411111) was added at room temperature, and after stirring for 1.5 hours, the solvent was distilled off under reduced pressure to obtain 2-
Carbamoyl-2-(1-tert-butoxycarbonyl-
1-Methylethoxyimino)acetic acid methyl ester (syn isomer) (10.60 g) was obtained.
元素分析” 12H2ON2°6
計算値: C49,99,H6,99,N 9.72実
験値: C49,81,、H6,91,N 9.68m
p:96−102℃
IR(スジ1−ル’) : 3430. 3330
. 1735. 1720゜1675 am’
NMR(DMSO−ds、l; ) ’ t、 42
(9H9s)、1.48 (6H1s)、 3.80
(38,s)、 7.67 (2H,ブロード
S)。Elemental analysis" 12H2ON2°6 Calculated value: C49,99, H6,99, N 9.72 Experimental value: C49,81,, H6,91, N 9.68m
p: 96-102°C IR (Stripe 1-L'): 3430. 3330
.. 1735. 1720°1675 am' NMR (DMSO-ds, l; ) 't, 42
(9H9s), 1.48 (6H1s), 3.80
(38,s), 7.67 (2H, Broad S).
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−カルバモイル−2−第三級ブトキシカルボニ
ルメトキシイミノ酢酸メチルエステル(シン異性体)
IR(スジl−ル) : 3430. 3400.
329G、 3200. 175G。(2) 2-Carbamoyl-2-tertiary-butoxycarbonylmethoxyiminoacetic acid methyl ester (synisomer) IR (synyl): 3430. 3400.
329G, 3200. 175G.
1730、1690.1615.1600 cm−’N
MR(DMSO−ds、8 ) :1.43 (9H1
s)、3−80 (3H1s)、 4.72 (2
H,s)、 7.73 (2B、ブロード S)。1730, 1690.1615.1600 cm-'N
MR (DMSO-ds, 8): 1.43 (9H1
s), 3-80 (3H1s), 4.72 (2
H,s), 7.73 (2B, Broad S).
未Uユ
(1)2−カルバモイル−2−(1−第三級プトキシ力
ルボニル−1−メチルエトキシイミノ)酢酸メチルエス
テル(シン異性体)(7g)およびピリジン(9,82
1nll )の塩化メチレン< 35m1l )溶液に
無水トリフルオロ酢酸(5,tarna )を氷冷下に
滴下し、同温で30分間攪拌し、塩化メチレン(301
1111)および水(501111)の混合物に注いだ
後6N塩酸でpH2,2に調製した。有機層を分取し、
水洗し6N塩酸でpH2に調整し、きらに有機層を分取
し、水洗し、硫酸マグネシウムで乾燥後減圧下°に溶媒
を留去して2−シアノ−2−(1−第三級ブトキシ力ル
ボニル−1−メチルエトキシイミノ)酢酸メチルエステ
ル(シン異性体)(6,51g)を得た。(1) 2-Carbamoyl-2-(1-tertiary-butoxycarbonyl-1-methylethoxyimino)acetic acid methyl ester (syn isomer) (7 g) and pyridine (9,82
Trifluoroacetic anhydride (5, tarna) was added dropwise to a solution of methylene chloride (<35 ml) under ice cooling, stirred at the same temperature for 30 minutes, and diluted with methylene chloride (30 ml).
The mixture was poured into a mixture of 1111) and water (501111) and adjusted to pH 2.2 with 6N hydrochloric acid. Separate the organic layer,
After washing with water and adjusting the pH to 2 with 6N hydrochloric acid, the organic layer was separated, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Carbonyl-1-methylethoxyimino)acetic acid methyl ester (synisomer) (6.51 g) was obtained.
元素分析:C1゜’18N205
計算値: C53,33,H6,71,N 10.36
実験値: C52,56,H6,64,N 10.19
IR(スジ1−ル) : 2980. 2230.
1740. 17M’ cm″″INMR(CDC1
a、f; ) ’ 1.45 (9H9s)、’ L、
55 (6H9s)。Elemental analysis: C1゜'18N205 Calculated value: C53,33,H6,71,N 10.36
Experimental value: C52,56, H6,64, N 10.19
IR (Streak 1-L): 2980. 2230.
1740. 17M'cm''''INMR (CDC1
a, f; ) ' 1.45 (9H9s), ' L,
55 (6H9s).
3.90 (3H,”s)。3.90 (3H,”s).
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−シアノ−2−第三級ブトキシカルボニルメト
キシイミノ酢酸メチルエステル(シン異性体)
IR(フィルム) : 2960. 2220.
1750. 1730゜1580 cm−1
NMR(CDCl2.δ) : 1.48 (9H,s
)、 3.93 (3H,s)。(2) 2-cyano-2-tertiary-butoxycarbonylmethoxyiminoacetic acid methyl ester (syn isomer) IR (film): 2960. 2220.
1750. 1730°1580 cm-1 NMR (CDCl2.δ): 1.48 (9H, s
), 3.93 (3H,s).
4.78 (2)1.s)。4.78 (2) 1. s).
東轟勇1
(1)2−シアノ−2−(1−第三級プトキシ力ルボニ
ル−1−メチルエトキシイミノ)酢酸メチルエステル(
シン異性体)(5g)のメタノール(5OffIIl)
@液に28%ナトリウムメトキシド水溶液(0,37
6m1 )を−5〜−10°Cで加え、水冷下に3時間
攪拌した。この混合物に酢酸アンモニウム(5,71g
)を水冷下に加え、室温で15時間攪拌し、炭酸カリウ
ム(2,56g)を加えた後減圧下にメタノールを留去
した。残渣に塩化メチレンおよび水に混液を加え、有機
層を分取し、塩化ナトリウム水溶液で洗浄し、酢酸(1
,Qfimi )を加えた後減圧下に溶媒を留去して2
−アミジノ−2−(1−第三級ブトキシ力ルボニル−1
−メチルエトキシイミノ)酢酸メチルエステル(シン異
性体)の酢酸塩(3,50g)を得た。Isamu Azuma 1 (1) 2-cyano-2-(1-tertiary-butoxycarbonyl-1-methylethoxyimino)acetic acid methyl ester (
syn isomer) (5g) of methanol (5OffIIl)
28% sodium methoxide aqueous solution (0,37
6 ml) was added at -5 to -10°C, and the mixture was stirred for 3 hours while cooling with water. Ammonium acetate (5.71g) was added to this mixture.
) was added under water cooling, stirred at room temperature for 15 hours, potassium carbonate (2.56 g) was added, and methanol was distilled off under reduced pressure. A mixture of methylene chloride and water was added to the residue, the organic layer was separated, washed with an aqueous sodium chloride solution, and diluted with acetic acid (1
, Qfimi), the solvent was distilled off under reduced pressure, and 2
-amidino-2-(1-tert-butoxycarbonyl-1
-Methylethoxyimino)acetic acid methyl ester (syn isomer) acetate salt (3.50 g) was obtained.
元素分析:C工4’25N30□
計算値: C48,41,H7,25,N 12.10
実験値: C47,93,H7,02,N 12.06
mp : 141−142℃
IR(スジ■−ル) ’ 1750. 1730.
1680 am−’NMR(CDCl2.8 )
71.42 <9H,s)、 1.53 (6H,s)
。Elemental analysis: C engineering 4'25N30□ Calculated value: C48,41,H7,25,N 12.10
Experimental value: C47.93, H7.02, N 12.06
mp: 141-142℃ IR (Streak)' 1750. 1730.
1680 am-'NMR (CDCl2.8)
71.42 <9H,s), 1.53 (6H,s)
.
1.93 (3H,s)、 3.95 (3H,s)、
8.53 (4H。1.93 (3H,s), 3.95 (3H,s),
8.53 (4H.
ブロード 3)。Broad 3).
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−アミジノ−2−第三級ブトキシカルボニルメ
トキシイミノ酢酸メチルエステル(シン異性体)の酢酸
塩
IR(スジ9−ル) : 1750. 1735.
1680. 1580゜1505 cm”!
NMR(DMSO−da 、S ) ’ 1.43
(9H、s) 、 1.83 (3H−s)、
3.78 (38,s)、 4.70 (2Ls)、
8.43(4H,ブロード s)。(2) Acetate IR of 2-amidino-2-tertiary-butoxycarbonylmethoxyiminoacetic acid methyl ester (syn isomer) (stir-9-l): 1750. 1735.
1680. 1580°1505 cm"! NMR (DMSO-da, S)' 1.43
(9H,s), 1.83 (3H-s),
3.78 (38,s), 4.70 (2Ls),
8.43 (4H, broad s).
宜Jl互
(1)2−アミジノ−2−(1−第三級ブトキシ力ルボ
ニル−1−メチルエトキシイミノ)酢酸メチルエステル
(シン異性体)の酢酸塩(5g)の酢酸エチル(35m
Q )およびメタ/ −ル(15mQ )溶液に、次亜
塩素酸の酢酸エチル溶液(27,511111) [次
亜塩素酸ナトリウム水溶液(50m11 )および酢酸
エチル(soma )の溶液中に水冷下6N塩酸(15
戚)を滴下して調t]を水冷下に滴下し、同温で1時間
攪拌した。この反応混合物に水(50+1111 )を
加え、有機層を分取し、水および塩化ナトリウム水溶液
で洗浄し、硫酸マグネシウムで乾燥後有機溶媒を減圧下
に留去して2−(N2−クロロ)アミジノ−2−(1−
第三級ブトキシ力ルポニル−1−メチルエトキシイミノ
)酢酸メチルエステル(シン異性体)(2,6g)を得
た。(1) Ethyl acetate (35 m
A solution of hypochlorous acid in ethyl acetate (27,511111) was added to the solution of sodium hypochlorite (50 mL) and methanol (15 mQ). (15
[Preparation t] was added dropwise while cooling with water, and the mixture was stirred at the same temperature for 1 hour. Water (50+1111) was added to the reaction mixture, the organic layer was separated, washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, and the organic solvent was distilled off under reduced pressure to obtain 2-(N2-chloro)amidino -2-(1-
Tertiary-butoxyluponyl-1-methylethoxyimino)acetic acid methyl ester (synisomer) (2.6 g) was obtained.
mp:・84.5−86℃
元素分析:C1□H2oCIN30゜
計算値: C44,79,H6,26,N 13.06
゜C111,02
実験値: C44,77、H6,18,N 13.05
゜C11103
IR(スジ3−ル) : 3460. 3360.
1735. 1640゜1605 am−1
NMR(CDCl2. l; ) : 1.44 (9
H,s)、 1.50 (6H,s)。mp:・84.5-86°C Elemental analysis: C1□H2oCIN30° Calculated value: C44,79, H6,26, N 13.06
゜C111,02 Experimental value: C44,77, H6,18, N 13.05
゜C11103 IR (Stripe 3-L): 3460. 3360.
1735. 1640°1605 am-1 NMR (CDCl2.l; ): 1.44 (9
H,s), 1.50 (6H,s).
3.89 (3H,s)、 5.58 (2H,
ブロード S)同様にして、次の化合物を得た。3.89 (3H, s), 5.58 (2H,
Broad S) The following compound was obtained in the same manner.
(2)2−(N2−クロロ)アミジノ−2−第三級ブト
キシカルボニルメトキシイミノ酢酸メチルエステル(シ
ン異性体)
mp : 68−70℃
元素分析:C1oH16CIN305
計算値: C40,89,H5,49,N 14.31
゜C112,07
実験値: C40,92,n s;’31. N 14
.48゜C112,30
IR(スジ3−ル) : 3450. 3330.
1745. 1735. 1640゜1610、15
75 cm’−1
HMR(アセトン−ds、l; ) ’ 1.4
7 (91,s)、 3.83 (3H1s)、
4.65 (2H,s)、 6.65 (2
H,ブロード s)。(2) 2-(N2-chloro)amidino-2-tertiary butoxycarbonylmethoxyiminoacetic acid methyl ester (syn isomer) mp: 68-70°C Elemental analysis: C1oH16CIN305 Calculated value: C40,89, H5,49, N 14.31
°C112,07 Experimental value: C40,92,ns;'31. N14
.. 48°C112,30 IR (3-line): 3450. 3330.
1745. 1735. 1640°1610, 15
75 cm'-1 HMR (acetone-ds, l; )' 1.4
7 (91,s), 3.83 (3H1s),
4.65 (2H,s), 6.65 (2
H, Broad s).
xJ1乱互
(1)2−(N2−クロロ)アミジノ−2−(1−第三
級プトキシ力ルポニル−1−メチルエトキシイミノ)酢
酸メチルエステル(シン異性体)(2g)のジオキサン
(4omu )および水(20ffll! ) (7)
混合溶液に0.311 N水酸化ナトリウム水溶液(2
0mE! )を水冷下に加え、同温で2時間攪拌した後
IN塩酸でpH6,5に11整した。有機溶媒を減圧下
に留去し、水層をジエチルエーテルで洗浄した後ジエチ
ルエーテルを加えた。混合物をIN塩酸でpH1,5に
調整し、有機層を分取し、塩化ナトリウム水溶液で洗浄
し、硫酸マグネシウムで乾燥した後溶媒を減圧下に留去
して、2−(N2−クロロ)アミジノ−2−(1−第三
級ブトキシ力ルポニル−1−メチルエトキシイミノ)酢
酸(シン異性体)(1,01g)を得た。xJ1 random (1) 2-(N2-chloro)amidino-2-(1-tertiary-butoxylponyl-1-methylethoxyimino)acetic acid methyl ester (syn isomer) (2g) in dioxane (4omu) and Water (20ffll!) (7)
Add 0.311 N sodium hydroxide aqueous solution (2
0mE! ) was added under water cooling, and after stirring at the same temperature for 2 hours, the pH was adjusted to 6.5 with IN hydrochloric acid. The organic solvent was distilled off under reduced pressure, the aqueous layer was washed with diethyl ether, and then diethyl ether was added. The mixture was adjusted to pH 1.5 with IN hydrochloric acid, the organic layer was separated, washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2-(N2-chloro)amidino. -2-(1-tert-butoxyluponyl-1-methylethoxyimino)acetic acid (synisomer) (1,01 g) was obtained.
mp : 156−157℃
元素分析: C11H18CIN305計算値: C4
2,93,H5,90,N 13.65゜C111,5
2
実験値: C43,07,H5,80,N 13.71
゜CI 11.68
IR(スジョール) : 3480. 3360.
3160. 1730. 1700゜1615 cm
’
NMR(CDCl2.δ) : 1.39 (9)1.
s)、 1.47 (3H,s)。mp: 156-157℃ Elemental analysis: C11H18CIN305 calculated value: C4
2,93,H5,90,N 13.65°C111,5
2 Experimental values: C43.07, H5.80, N 13.71
゜CI 11.68 IR (Sujoor): 3480. 3360.
3160. 1730. 1700°1615 cm
'NMR (CDCl2.δ): 1.39 (9)1.
s), 1.47 (3H, s).
1.55 (3H,s>、 5.93 (2H,
ブロード S)。1.55 (3H, s>, 5.93 (2H,
Broad S).
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−(N2−クロロ)アミジノ−2−第三級ブト
キシカルボニルメトキシイミノ酢酸(シン異性体)
mp : 128−130℃
元素分析:C0H14CIN305
計算値: C38,65,H5,15,N 15.02
゜C112,6g
実験値: C38,45,H4,88,N 15.09
゜C112,59
IR(ヌジジール) : 3410. 3310.
2560. 2450. 1740゜1730、16
35.1600.1582 cm−’NMR(7セトン
ーd6.δ ) i 1.47 (9H,s)、
4.67(2H,s)、 6.60 (2H,
ブロード s)、 10.57 (IH。(2) 2-(N2-chloro)amidino-2-tertiary butoxycarbonylmethoxyiminoacetic acid (syn isomer) mp: 128-130°C Elemental analysis: C0H14CIN305 Calculated value: C38,65, H5,15, N15 .02
°C112.6g Experimental value: C38.45, H4.88, N 15.09
゜C112,59 IR (nujijiru): 3410. 3310.
2560. 2450. 1740°1730, 16
35.1600.1582 cm-'NMR (7 setones - d6.δ) i 1.47 (9H, s),
4.67 (2H, s), 6.60 (2H,
Broad s), 10.57 (IH.
ブロード s)。Broad s).
メξ妻I」唯:乙
(1)2−(N2−クロロ)アミジノ−2−(1−第三
級プトキシ力ルボニル−1−メチルエトキシイミノ)酢
酸(シン異性体) (500mg )のメタノール(1
0fflQ )溶液にトリエチルアミン(0,453証
)およびチオシアン酸カリウム(157,9mg )の
メタノール(20+1111 ’)溶液を室温で加え、
72時間攪拌した後減圧下にメタノールを留去した。残
渣を水(7,5mQ)に溶解し、IN塩酸(3戚)を水
冷下に加え、同温で30分間攪拌した後結晶を濾取して
、2−(5−アミノ−1,2,4−チアジアゾール−3
−イル)−2−(1−第三級プトキシ力ルボニル−1−
メチルエトキシイミノ)酢酸(シン異性体) (501
,4mg )を得た。2-(N2-chloro)amidino-2-(1-tertiary-butoxycarbonyl-1-methylethoxyimino)acetic acid (synisomer) (500 mg) in methanol ( 1
A methanol (20 + 1111') solution of triethylamine (0,453 proof) and potassium thiocyanate (157,9 mg) was added to the 0fflQ ) solution at room temperature.
After stirring for 72 hours, methanol was distilled off under reduced pressure. The residue was dissolved in water (7.5 mQ), IN hydrochloric acid (3 relative) was added under water cooling, and after stirring at the same temperature for 30 minutes, the crystals were collected by filtration to give 2-(5-amino-1,2, 4-thiadiazole-3
-yl)-2-(1-tertiary poxycarbonyl-1-
Methylethoxyimino)acetic acid (syn isomer) (501
, 4 mg) was obtained.
mp : 203−204℃
元素分析:C1□H1gN405S
計算値: C43,64,)l 5.49. N 16
.99.59.71実験値: C43,30,H5,5
7,N 16.64. S 9.72IR(スジ9−ル
) : 3400. 3290. 3200. 1
740. 1705゜1615 am−’
NMR(DMSO−de、δ) : 1.35 (9H
,s)、 1.40 (6H。mp: 203-204°C Elemental analysis: C1□H1gN405S Calculated value: C43,64,)l 5.49. N16
.. 99.59.71 Experimental value: C43,30,H5,5
7, N 16.64. S 9.72IR (Streak 9-R): 3400. 3290. 3200. 1
740. 1705°1615 am-' NMR (DMSO-de, δ): 1.35 (9H
,s), 1.40 (6H.
s)、 8.18 (2H,ブロード s)。s), 8.18 (2H, Broad s).
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−(5−アミノ−1,2,4−チアジアゾール
−3−イル)−2−第三級ブトキシカルボニルメトキシ
イミノ酢酸(シン異性体)
IR(ス九−ル) : 3420. 3230.
3100. 1725. 1610゜1530 am−
1
NMR(DMSO−de、8 ) ’ 1−45 (9
H0s)、4.70 (2H1s)、 8.12
<2H,ブロード S)艶ま贋ユ
(1)2−(5−アミノ−1,2,4−チアジアゾール
−3−イル)−2−(1−第三級プトキシ力ルボニル−
1−メチルシトキシイミノ)酢酸(シン異性体) (1
7,8g )およびアニソール(18戚)のトリフルオ
ロ酢酸(3610Q )溶液を室温で4時間撹拌する1
反応混合物を減圧濃縮し、これに炭酸水素ナトリウム水
溶液を加えてpH6,0に調整する。(2) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-tertiary butoxycarbonylmethoxyiminoacetic acid (syn isomer) IR (sulfur): 3420. 3230.
3100. 1725. 1610°1530 am-
1 NMR (DMSO-de, 8)' 1-45 (9
H0s), 4.70 (2H1s), 8.12
<2H, Broad S) Glossy Counterfeit (1) 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(1-Tertiary Proxycarbonyl-
1-Methylcytoxyimino)acetic acid (syn isomer) (1
7.8 g ) and anisole (18 relative) in trifluoroacetic acid (3610Q) are stirred at room temperature for 4 hours.
The reaction mixture was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added thereto to adjust the pH to 6.0.
水溶液を酢酸エチルで洗浄し、6N塩酸でpH3,8に
調整して酢酸エチルで洗浄する。水層を分取し、これに
6N塩酸を加えてpH1,0に調整する。The aqueous solution is washed with ethyl acetate, adjusted to pH 3.8 with 6N hydrochloric acid, and washed with ethyl acetate. Separate the aqueous layer and adjust the pH to 1.0 by adding 6N hydrochloric acid.
混合物を10分間攪拌後、生成する沈殿を濾取して、2
−(5−アミノ−1,2,4−チアジアゾール−3−イ
ル)−2−(1−カルボキシ−1−メチルエトキシイミ
ノ)酢酸(シン異性体) (13,0g)を得た。After stirring the mixture for 10 minutes, the formed precipitate was collected by filtration and
-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid (syn isomer) (13.0 g) was obtained.
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−(5−アミノ−1,2,4−チアジアゾール
−3−イル)−2−カルボキシメトキシイミノ酢酸(シ
ン異性体)
IR(スジ1−ル) ? 3400. 3250.
3100. 2800−2200゜1730、163
0.1540 ca+−1HMR(DMSO−ds、E
) ’ 4.65 (2H,s)、 8.15(2H
4)
蔓ま遭1
(1)2−(5−アミノ−1,2,4−チアジアゾール
−3−イル)−2−(1−カルボキシ−1−メチルエト
キシイミノ)酢酸(シン異性体)(2,74g)のN、
N−ジメチルアセトアミド(45m11 )溶液に、゛
塩化メタンスルホニル(1,15g )および炭酸水素
カリウム(1,20g )を水浴中途却下に加える。混
合物を5℃で2.5時間攪拌し、水(200ml! )
、酢酸エチル(200mQ )およびIN塩酸(6mQ
)の冷混合物中に注ぐ。混合物を水浴中途却下に5分
間攪拌する。有機層を分取し、冷水(200mQ、2回
)および塩化ナトリウム冷飽和水溶液で洗浄し、硫酸マ
グネシウムで乾燥して溶媒を留去する。残渣にトルエン
を加える。この混合物に塩化メチレンを加え、混合物を
水浴中10分間冷却する。結晶を濾取して塩化メチレン
で洗浄し、風乾して、2−(5−アミノ−1,2,4−
チアジアゾール−3−イル)−2−(1−カルボキシ−
1−メチルエトキシイミノ)酢a1(シン異性体)メタ
ンスルホン酸無水物(t、xg)を得た。(2) 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetic acid (syn isomer) IR (stinyl)? 3400. 3250.
3100. 2800-2200°1730, 163
0.1540 ca+-1HMR (DMSO-ds, E
)' 4.65 (2H, s), 8.15 (2H
4) Encounter 1 (1) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid (syn isomer) (2 ,74g) of N,
Methanesulfonyl chloride (1.15 g) and potassium bicarbonate (1.20 g) were added to a solution of N-dimethylacetamide (45 ml) halfway through the water bath. The mixture was stirred at 5°C for 2.5 hours and then mixed with water (200 ml!)
, ethyl acetate (200 mQ) and IN hydrochloric acid (6 mQ
) into the cold mixture. The mixture is stirred for 5 minutes with the water bath halfway through. The organic layer is separated, washed with cold water (200 mQ, twice) and cold saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off. Add toluene to the residue. Methylene chloride is added to the mixture and the mixture is cooled in a water bath for 10 minutes. The crystals were collected by filtration, washed with methylene chloride, and air-dried to give 2-(5-amino-1,2,4-
Thiadiazol-3-yl)-2-(1-carboxy-
1-methylethoxyimino)acetic acid a1 (syn isomer) methanesulfonic anhydride (t, xg) was obtained.
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−(5−”アミノ−1,2,4−チアジアゾ−
ルー3−イル)−2−カルレボキシメトキシイミノ酢M
(シン異性体)メタンスルホン酸無水物IR(スジョー
ル) : 3410. 3280. 3100.
2750−2560゜1790、1730.1630.
1550゜1430 am−1
艶土忽ユ
(1)7β−アミノ−3−(3−アミノ−2−メチル−
1−ピラゾリオ)メチル−3−セフェム−4−カルボキ
シラード・二塩酸塩(o、4gg)、N−(トリメチル
シリル)アセトアミド(2,5g)およびテトラヒドロ
フランの混合物を室温で1.0時間攪拌する。(2) 2-(5-”amino-1,2,4-thiadiazole-
(3-yl)-2-callevoxymethoxyimino vinegar M
(Syn isomer) Methanesulfonic anhydride IR (Sujol): 3410. 3280. 3100.
2750-2560°1790, 1730.1630.
1550゜1430 am-1 7β-amino-3-(3-amino-2-methyl-
A mixture of 1-pyrazolio)methyl-3-cephem-4-carboxilade dihydrochloride (o, 4 gg), N-(trimethylsilyl)acetamide (2.5 g) and tetrahydrofuran is stirred at room temperature for 1.0 h.
これに、2−(5−アミノ−1,2,4−チアジアゾー
ル−3−イル)−2−(1−カルボキシ−1−メチルエ
トキシイミノ)酢酸(シン異性体)メタンスルホン酸無
水物(350mg)を室温で加え、同温で2時間攪拌す
る。混合物をジイソプロピルエーテル(5Qmll )
中に注ぎ、沈殿を濾取して水(50m11 )に溶解し
、炭酸水素ナトリウム水溶液でpH2,0に調整し、酢
酸エチルで洗浄して水層中の酢酸エチルを留去する。水
層を大孔非イオン吸着樹脂1ダイヤイオンHP−20J
(商標:三菱化成工業社製)を使用するカラムクロマ
トグラフィーに付し、30%メチルアルコール水溶液で
溶出する。目的化合物を含む画分のメチルアルコールを
留去し、残渣を凍結乾燥して、7β−[2−(5−アミ
ノ−1,2,4−チアジアゾール−3−イル)−2−(
1−カルボキシ−1−メチルエトキシイミノ)アセトア
ミトコ−3−(3−アミノ−2−メチル−1−ピラゾリ
オ)メチル−3−セフェム−4−カルボキシラード(シ
ン異性体)(330mg)を得た。To this was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic acid (synisomer) methanesulfonic anhydride (350 mg). was added at room temperature and stirred at the same temperature for 2 hours. The mixture was diisopropyl ether (5Qml)
The precipitate was collected by filtration, dissolved in water (50 ml), adjusted to pH 2.0 with an aqueous sodium bicarbonate solution, washed with ethyl acetate, and the ethyl acetate in the aqueous layer was distilled off. Water layer with large pore nonionic adsorption resin 1Diaion HP-20J
(trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with a 30% aqueous methyl alcohol solution. The methyl alcohol in the fraction containing the target compound was distilled off, and the residue was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(
1-Carboxy-1-methylethoxyimino)acetamitoco-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxilade (syn isomer) (330 mg) was obtained.
IR(スジ3−ル) : 3325. 1770.
1650. 1630゜1590 am−’
NMR(R20,l; ) :1.52 (6H,s)
、 a、 19および3.37 <2H,ABq、J=
18Hz)、 3.66 (3H,s)、 4.97お
よび5.25 (2H,ABq、J=15Hz)、 5
.20 (LH。IR (Streak 3-L): 3325. 1770.
1650. 1630°1590 am-' NMR (R20,l; ): 1.52 (6H,s)
, a, 19 and 3.37 <2H, ABq, J=
18Hz), 3.66 (3H, s), 4.97 and 5.25 (2H, ABq, J=15Hz), 5
.. 20 (LH.
d、J=5Hz>、 5.84 (IH,d、J=
5Hz)、 5.91 (IH。d, J=5Hz>, 5.84 (IH, d, J=
5Hz), 5.91 (IH.
d、J=3Hz)、 7.82 (IH,d、J=3H
z)−同様にして、次の化合物を得た。d, J=3Hz), 7.82 (IH, d, J=3H
z)-The following compound was obtained in the same manner.
(2)7β−[2−(5−アミノ−1,2,4−チアジ
アゾール−3−イル)−2−カルボキシメトキンイミノ
アセトアミド]−3−(3−アミノ−2−メチル−1−
ビラゾリオ)メチル−3−セフェム−4−カルボキシラ
ード(シン異性体)IR(Xジa−1−”) ’
3300. 1760. 1660. 1590 a
m−’NMR(R20,l; ) : 3.06および
3.33 (2H,ABq。(2) 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethquiniminoacetamide]-3-(3-amino-2-methyl-1-
virazolio) methyl-3-cephem-4-carboxilade (syn isomer) IR(Xdia-1-”)'
3300. 1760. 1660. 1590a
m-'NMR (R20,l; ): 3.06 and 3.33 (2H, ABq.
J=18Hz)、 3.63 (3H,s)、 4.6
0 (2H,s)、 4.93および5.21 (2H
,ABq、J=15Hz)、 5.16 (IH。J=18Hz), 3.63 (3H,s), 4.6
0 (2H,s), 4.93 and 5.21 (2H
, ABq, J=15Hz), 5.16 (IH.
d、J=5Hz>、 5.83 (IH,d、J=5H
z)、 5.88 (18゜d、J=3Hz>、 7.
78 (IH,d、に3Hz>。d, J=5Hz>, 5.83 (IH, d, J=5H
z), 5.88 (18°d, J=3Hz>, 7.
78 (IH, d, 3Hz>.
Lま旦1
7β−アミノ−3−(3−アミノ−2−メチル−1−ピ
ラゾリオ)メチル−3−セフェム−4−カルボキシラー
ド・二塩酸塩(5kg)を水(162)に溶解する。こ
の溶液を大孔非イオン吸着樹脂1ダイヤイオンHP−2
0Jを使用するカラムクロマトグラフィーに付す。L Madan 1 7β-Amino-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxilade dihydrochloride (5 kg) is dissolved in water (162). Add this solution to the large-pore non-ion adsorption resin 1 Diamond Ion HP-2
Subject to column chromatography using 0J.
所望の生成物を水で溶出する。溶出液(3(R1)にア
セトン(16oI2)を加え、混合物を室温で2時間攪
拌する。生成する沈殿を濾取して、7β−アミノー3−
(3−アミノ−2−メチル−1−ピラゾリオ)メチル−
3−セフェム−4−カルボキシラード・塩酸塩・三水化
物(1゜802kg )を結晶として得た。The desired product is eluted with water. Acetone (16oI2) is added to the eluate (3(R1)), and the mixture is stirred at room temperature for 2 hours. The formed precipitate is collected by filtration, and 7β-amino-3-
(3-amino-2-methyl-1-pyrazolio)methyl-
3-cephem-4-carboxilade hydrochloride trihydrate (1°802 kg) was obtained as crystals.
IR(スジョール) : 3540. 3350.
3150. 1775. 1635゜1585 cm
−’
NMR(DMSO−d6.δ) : 3.66 (3H
,s)、 4.83 (IH,d。IR (Sujoor): 3540. 3350.
3150. 1775. 1635°1585 cm
-' NMR (DMSO-d6.δ): 3.66 (3H
, s), 4.83 (IH, d.
、C3Hz)、 5.03 (IH,d、J=5Hz)
、 5.18および5.30 (2H,ABq、J=1
5Hz>、 5.85 (IH,d。, C3Hz), 5.03 (IH, d, J=5Hz)
, 5.18 and 5.30 (2H, ABq, J=1
5Hz>, 5.85 (IH, d.
J=3Hz>、 7.44 (2H,ブロード s
)、 8.08 (IH,d。J=3Hz>, 7.44 (2H, broad s
), 8.08 (IH, d.
J=3Hz)
参考例6
(1)2−(5−アミノ−1,2,4−チアジアゾール
−3−イル)−2−(1−第三級プトキシ力ルボニル−
1−メチルエトキシイミノ)酢酸(シン異性体) (5
00mg)のN、N−ジメチルアセトアミド(x、sm
u)溶液に塩化メタンスルホニ4 (0,234+ul
l )および炭酸カリウム(209,2mg)を水冷下
に加え、同温で1.5時間攪拌し、酢酸エチル(30m
1 )および水(1smBで希釈した後有機層を分取し
た。有機層を冷水(3回)および塩化ナトリウム水溶液
で洗浄し、硫酸マグネシウムで乾燥した後有機溶媒を減
圧下に留去して、2−(5−アミノ−1,2,4−デア
ジアゾール−3−イル)−2−(1−第三級ブトキシ力
ルボニル−1−メチルエトキシイミノ)酢酸(シン異性
体)メタンスルホン酸無水物(465,5mg )を得
た。J=3Hz) Reference Example 6 (1) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tertiary poxycarbonyl-
1-methylethoxyimino)acetic acid (syn isomer) (5
00mg) of N,N-dimethylacetamide (x,sm
u) Methanesulfony chloride 4 (0,234+ul
l ) and potassium carbonate (209.2 mg) were added under water cooling, stirred at the same temperature for 1.5 hours, and added with ethyl acetate (30 m
1) and water (1 smB), the organic layer was separated. The organic layer was washed with cold water (3 times) and an aqueous sodium chloride solution, dried over magnesium sulfate, and the organic solvent was distilled off under reduced pressure. 2-(5-amino-1,2,4-deadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid (synisomer) methanesulfonic anhydride ( 465.5 mg) was obtained.
mp :108−111℃(分解)
IR(スジ3−ル) : 3430. 3260.
3110. 1795. 1720゜1620 am
’
NMR(CDCl2.δ) Z 1.42 (9)1.
s)、 1.57 (6H,s)。mp: 108-111°C (decomposition) IR (streak 3-l): 3430. 3260.
3110. 1795. 1720°1620 am
'NMR (CDCl2.δ) Z 1.42 (9)1.
s), 1.57 (6H, s).
3.48 (3H,s)、 8.05 (2H,
ブロード S)。3.48 (3H, s), 8.05 (2H,
Broad S).
同様にして、次の化合物を得た。Similarly, the following compound was obtained.
(2)2−(5−アミノ−1,2,4−チアジアゾール
−3−イル)−2−第三級ブトキシカルボニルメトキシ
イミノ酢酸(シン異性体)メタンスルホン酸無水物
IR(スジタール) : 3450. 3260.
3130. 1790. 1730゜1620、15
40 cm−”
NMR(アセトシーds、S ) ’ 1.50
(9H1s)、 3.62 (31゜s)、
4.81 (2H,s)、 7.64 (2H,
ブロード s)。(2) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-tertiary-butoxycarbonylmethoxyiminoacetic acid (synisomer) methanesulfonic anhydride IR (sudital): 3450. 3260.
3130. 1790. 1730°1620, 15
40 cm-” NMR (Acetosee ds, S)' 1.50
(9H1s), 3.62 (31°s),
4.81 (2H, s), 7.64 (2H,
Broad s).
参考例7
(1)7β−アミノ−3−(3−アミノ−2−メチル−
1−ビラゾリオ)メチル−3−セフェム−4−カルボキ
シラード・塩酸塩・二本化物(0,83&)およびN−
(トリメチルシリル)アセトアミド(2,85g )
f)テトラヒドロフラン(3,3mQ )懸濁液にN、
N−ジメチルアセトアミド(6,611111)を室温
下に加え、35°Cで1時間攪拌した。この混合物に2
−(5−アミノ−1,2,4−チアジアゾール−3−イ
ル)−2−(1−第三級ブトキシ力ルボニル−1−メチ
ルエトキシイミノ)酢酸(シン異性体)メタンスルホン
酸無水物(888mg )を水冷下に加え、同温で攪拌
した後酢酸エチル(1001)およびジイソプロピルエ
ーテル(100nQ )の混合物に滴下する。結晶を濾
取し、五酸化リンで乾燥し、水(50mQ )に溶解し
た後puz、 5に調整する。この溶液を「ダイヤイオ
ンHP−20、を使用するカラムクロマトグラフィーに
付す。所望の生成物を50%メタノール水溶液で溶出し
、凍結乾燥して、7β−[2−(5−アミノ−1,2,
4−チアジアゾール−3−イル)−2−(1−カルボキ
シ−1−メチルエトキシイミノ)アセトアミトコ−3−
(3−アミノ−2−メチル−1−ピラゾリオ)メチル−
3−セフェム−4−カルボキシラード(シン異性体)
(744,2mg )を得た。Reference Example 7 (1) 7β-amino-3-(3-amino-2-methyl-
1-virazolio)methyl-3-cephem-4-carboxilade hydrochloride divalent compound (0,83&) and N-
(Trimethylsilyl)acetamide (2.85g)
f) Add N to the tetrahydrofuran (3,3 mQ) suspension,
N-dimethylacetamide (6,611111) was added at room temperature and stirred at 35°C for 1 hour. Add 2 to this mixture
-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetic acid (syn isomer) methanesulfonic anhydride (888 mg ) was added under water cooling, stirred at the same temperature, and then added dropwise to a mixture of ethyl acetate (1001) and diisopropyl ether (100 nQ). The crystals were collected by filtration, dried with phosphorus pentoxide, dissolved in water (50 mQ), and adjusted to a puz concentration of 5. This solution is subjected to column chromatography using a Diaion HP-20. The desired product is eluted with 50% aqueous methanol, lyophilized and 7β-[2-(5-amino-1,2 ,
4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamitoco-3-
(3-amino-2-methyl-1-pyrazolio)methyl-
3-cephem-4-carboxilade (syn isomer)
(744.2 mg) was obtained.
IR(スジョール) : 3325. 1770.
1650. 1630゜1590 am’
同様にして、次の化合物を得た。IR (Sujoor): 3325. 1770.
1650. 1630°1590 am' In the same manner, the following compound was obtained.
Claims (2)
保護されたカルボキシ(低級)アルキル基、R^2はカ
ルボキシ基または保護されたカルボキシ基、X^1はハ
ロゲンをそれぞれ意味する]で示される化合物またはそ
の塩をチオシアン酸の塩と反応させて、一般式: ▲数式、化学式、表等があります▼ [式中、R^1およびR^2は前と同じ意味]で示され
る化合物またはその塩を得ることを特徴とする酢酸誘導
体またはその塩の製造法。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R^2 is a carboxy group or a protected carboxy (lower) alkyl group. Carboxy group, X^1 means halogen respectively] or its salt is reacted with a salt of thiocyanate to form the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 and R^2 has the same meaning as above] or a salt thereof. A method for producing an acetic acid derivative or a salt thereof.
保護されたカルボキシ(低級)アルキル基、R^2はカ
ルボキシ基または保護されたカルボキシ基、X^1はハ
ロゲンをそれぞれ意味する]で示される化合物およびそ
の塩。(2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, and R^2 is a carboxy group or a protected a carboxy group, X^1 each represents a halogen] and salts thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62292815A JPH01135778A (en) | 1987-11-19 | 1987-11-19 | Production of acetic acid derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62292815A JPH01135778A (en) | 1987-11-19 | 1987-11-19 | Production of acetic acid derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH01135778A true JPH01135778A (en) | 1989-05-29 |
Family
ID=17786709
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62292815A Pending JPH01135778A (en) | 1987-11-19 | 1987-11-19 | Production of acetic acid derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH01135778A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016100897A1 (en) * | 2014-12-18 | 2016-06-23 | Merck Sharp & Dohme Corp. | Thiadiazolyl-oximinoacetic acid derivative compounds |
US10214543B2 (en) | 2014-12-30 | 2019-02-26 | Merck Sharp & Dohme Corp. | Synthesis of cephalosporin compounds |
-
1987
- 1987-11-19 JP JP62292815A patent/JPH01135778A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016100897A1 (en) * | 2014-12-18 | 2016-06-23 | Merck Sharp & Dohme Corp. | Thiadiazolyl-oximinoacetic acid derivative compounds |
US10059680B2 (en) | 2014-12-18 | 2018-08-28 | Merck Sharp & Dohme Corp. | Thiadiazolyl-oximinoacetic acid derivative compounds |
US10214543B2 (en) | 2014-12-30 | 2019-02-26 | Merck Sharp & Dohme Corp. | Synthesis of cephalosporin compounds |
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