JPH026757B2 - - Google Patents
Info
- Publication number
- JPH026757B2 JPH026757B2 JP59104759A JP10475984A JPH026757B2 JP H026757 B2 JPH026757 B2 JP H026757B2 JP 59104759 A JP59104759 A JP 59104759A JP 10475984 A JP10475984 A JP 10475984A JP H026757 B2 JPH026757 B2 JP H026757B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- general formula
- compound
- salt
- syn isomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 64
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 229930186147 Cephalosporin Natural products 0.000 claims description 18
- 229940124587 cephalosporin Drugs 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 229910015900 BF3 Inorganic materials 0.000 claims description 16
- 150000001780 cephalosporins Chemical class 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- -1 for example Chemical group 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- LXFQSRIDYRFTJW-UHFFFAOYSA-M 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S([O-])(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-M 0.000 description 2
- LIKWMDGAWXCECN-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid;dihydrate Chemical compound O.O.CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 LIKWMDGAWXCECN-UHFFFAOYSA-N 0.000 description 2
- UKYBHEPQCODSCP-UHFFFAOYSA-N 2-hydroxyimino-3-oxobutanamide Chemical compound CC(=O)C(=NO)C(N)=O UKYBHEPQCODSCP-UHFFFAOYSA-N 0.000 description 2
- TYEYBOSBBBHJIV-UHFFFAOYSA-N 2-oxobutanoic acid Chemical compound CCC(=O)C(O)=O TYEYBOSBBBHJIV-UHFFFAOYSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- GCPWJFKTWGFEHH-UHFFFAOYSA-N acetoacetamide Chemical compound CC(=O)CC(N)=O GCPWJFKTWGFEHH-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000005242 carbamoyl alkyl group Chemical group 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RFLSCADVOLSQPE-FYZOBXCZSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C1=CCS[C@@H]2CC(=O)N12 RFLSCADVOLSQPE-FYZOBXCZSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- XGYCWCIGCYGQFU-UHFFFAOYSA-N 1,2-thiazolidine 1,1-dioxide Chemical group O=S1(=O)CCCN1 XGYCWCIGCYGQFU-UHFFFAOYSA-N 0.000 description 1
- DVVGIUUJYPYENY-UHFFFAOYSA-N 1-methylpyridin-2-one Chemical compound CN1C=CC=CC1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 description 1
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-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
- BALWAOMWMFHXKC-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid Chemical class CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1.CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 BALWAOMWMFHXKC-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 description 1
- FLYPZWDELZKIOY-UHFFFAOYSA-O 2-carboxyethyl(triphenyl)phosphanium Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC(=O)O)C1=CC=CC=C1 FLYPZWDELZKIOY-UHFFFAOYSA-O 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004157 Nitrosyl chloride Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005354 acylalkyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940095564 anhydrous calcium sulfate Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- BMNDJWSIKZECMH-UHFFFAOYSA-N nitrosyl bromide Chemical compound BrN=O BMNDJWSIKZECMH-UHFFFAOYSA-N 0.000 description 1
- VPCDQGACGWYTMC-UHFFFAOYSA-N nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 description 1
- 235000019392 nitrosyl chloride Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 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 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000004964 sulfoalkyl group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- ZFCQDZKQFPEDJE-UHFFFAOYSA-N thiolane 1,1-dioxide trifluoroborane Chemical compound S1(=O)(=O)CCCC1.B(F)(F)F ZFCQDZKQFPEDJE-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Description
本発明は、セフアロスポリン類の製造法、すな
わち抗菌剤として有用な
一般式
〔式中、R2は低級アルキル基を、R3は水素原子
またはカルボキシル保護基を、R4は３位エキソ
メチレン基と炭素−窒素結合する置換されていて
もよい複素環式基を示す。〕
で表わされるセフアロスポリン（シン異性体）ま
たはその塩の製造法、さらに詳しくは、
一般式
〔式中、R1は水素原子または置換されていても
よいアルキル、アルアルキル、アリールまたは複
素環式基を示し、R2は前記と同じ意味を有す
る。〕
で表わされる化合物（シン異性体）と
一般式
〔式中、R3aはカルボキシル保護基を示し、R4は
前記と同じ意味を有する。〕
で表わされる化合物を、三弗化硼素またはその錯
化合物の存在下に反応させ、必要に応じ、カルボ
キシル保護基を脱離または塩に変換させて、一般
式〔〕で表わされるセフアロスポリン（シン異
性体）またはその塩を得る製造法に関するもので
ある。
本発明者らは、既に、一般式〔〕で表わされ
るセフアロスポリン（シン異性体）およびその塩
が抗菌剤として極めて有用な化合物であることを
見出し、先に特許出願した（特開昭57−99592号、
同59−93085号、同59−193893号、同60−4191号、
同60−6694号）。
その後、上記一般式〔〕の化合物またはその
塩の製造法について鋭意研究を重ねた結果、一般
式〔〕の化合物（シン異性体）と一般式〔〕
の化合物を三弗化硼素またはその錯化合物の存在
下に反応させ、必要に応じ、カルボキシル保護基
を脱離または塩に変換させることによつて、一般
式〔〕の有用なセフアロスポリン（シン異性
体）またはその塩が高収率にかつ容易に得られる
ことを見出し、ここに本発明を完成した。
すなわち、遊離のアミノ基を有する一般式
〔〕の酸アミドまたはモノ置換酸アミドを三弗
化硼素またはその錯化合物の存在下に一般式
〔〕の化合物と反応させることによつて、はじ
めて一般式〔〕のセフアロスポリン（シン異性
体）またはその塩が高収率にかつ容易に得られる
ことを見出したものである。
而して、本発明の目的は、優れた抗菌スペクト
ルを有する一般式〔〕のセフアロスポリン（シ
ン異性体）またはその塩の新規製造法を提供する
ことにある。
なお、本明細書において、特にことわらない限
り、アルキル基とは、直鎖または分枝鎖状C1〜14
アルキル、たとえば、メチル、エチル、ｎ−プロ
ピル、イソプロピル、ｎ−ブチル、イソブチル、
sec−ブチル、tert−ブチル、ペンチル、ヘキシ
ル、ヘプチル、オクチル、ドデシルなど；アリー
ルとは、たとえば、フエニル、トリル、ナフチ
ル、インダニルなど；アルアルキルとは、たとえ
ば、ベンジル、フエネチル、４−メチルベンジ
ル、ナフチルメチルなど；アシルとは、C1〜12ア
シル、たとえば、アセチル、プロピオニル、ｎ−
ブチリル、イソブチリル、バレリル、ピバロイ
ル、ペンタンカルボニル、シクロヘキサンカルボ
ニル、ベンゾイル、ナフトイル、フロイル、テノ
イルなど；ハロゲン原子とは、フツ素、塩素、臭
素、ヨウ素原子などをそれぞれ意味する。また低
級とは、炭素原子数１〜５を意味する。
さらに、本明細書で使用されている種々の用語
中、たとえば、アルキル、アリール、アルアルキ
ル、アシル基などの用語がある場合も、特にこと
わらない限り上述の意味を示すものである。
一般式〔〕におけるR1は、水素原子または
置換されていてもよいアルキル、アルアルキル、
アリールまたは複素環式基を意味するが、その複
素環式基としては、具体的には、たとえば、ピラ
ゾリル、イミダゾリル、トリアゾリル、テトラゾ
リル、ピリジル、ピリミジニル、ピリダジニリ
ル、ピラジニル、トリアジニルなどの含窒素５員
または６員複素環式基が挙げられる。これらR1
の置換基としては、たとえば、ハロゲン原子、ニ
トロ基、アルキル基、アリール基、アルコキシ
基、シアノ基、アミノ基、アルキルアミノ基、ジ
アルキルアミノ基、アシルアミノ基、アシル基、
アシルオキシ基、アシルアルキル基、カルボキシ
ル基、アルコキシカルボニル基、アルコキシカル
ボニルアルキル基、カルバモイル基、アミノアル
キル基、Ｎ−アルキルアミノアルキル基、Ｎ，Ｎ
−ジアルキルアミノアルキル基、ヒドロキシアル
キル基、ヒドロキシイミノアルキル基、アルコキ
シアルキル基、カルボキシアルキル基、スルホア
ルキル基、スルホ基、スルフアモイルアルキル
基、スルフアモイル基、カルバモイルアルキル
基、カルバモイルアルケニル基、Ｎ−ヒドロキシ
カルバモイルアルキル基などが挙げられ、前記し
たアルキル、アルアルキル、アリールまたは複素
環式基はこれら一種以上の置換基で置換されてい
てもよい。これらの置換基のうち、カルボキシル
基は、後述するR3aおよびR3のところで説明する
カルボキシル保護基で保護されていてもよい。
R3aはカルボキシル保護基を、またR3は水素原
子またはカルボキシル保護基を示すが、これらカ
ルボキシル基の保護基としては、従来ペニシリン
およびセフアロスポリン系化合物の分野で、通常
使用されているものが挙げられる。具体的には、
たとえば、アルキル、フタリジル、ジフエニルメ
チル、アセトキシメチル、ピバロイルオキシメチ
ル、プロピオニルオキシメチル、ブチリルオキシ
メチル、イソブチリルオキシメチル、バレリルオ
キシメチル、１−アセトキシエチル、１−アセト
キシ−ｎ−プロピル、１−ピバロイルオキシエチ
ル、１−ピバロイルオキシ−ｎ−プロピル、ベン
ゾイルオキシメチル、１−ベンゾイルオキシエチ
ル、α−ピバロイルオキシベンジル、α−アセト
キシベンジル基などが挙げられる。
つぎに、R4は３位エキソメチレン基と炭素−
窒素結合する置換されていてもよい複素環式基を
示すが、その複素環式基としては、たとえば、テ
トラゾリル、トリアゾリル、ピラジニル、ピリダ
ジニル、ピリミジニル基および
The present invention provides a method for producing cephalosporins, that is, a general formula useful as an antibacterial agent. [In the formula, R 2 represents a lower alkyl group, R 3 represents a hydrogen atom or a carboxyl protecting group, and R 4 represents an optionally substituted heterocyclic group that forms a carbon-nitrogen bond with the exomethylene group at the 3-position. ] The method for producing cephalosporin (syn isomer) or its salt represented by the general formula [In the formula, R 1 represents a hydrogen atom or an optionally substituted alkyl, aralkyl, aryl or heterocyclic group, and R 2 has the same meaning as above. ] Compound represented by (syn isomer) and general formula [In the formula, R 3a represents a carboxyl protecting group, and R 4 has the same meaning as above. ] The compound represented by the formula [] is reacted in the presence of boron trifluoride or its complex compound, and if necessary, the carboxyl protecting group is eliminated or converted into a salt, thereby producing a cephalosporin (synisomer) represented by the general formula [ ]. The present invention relates to a manufacturing method for obtaining a salt thereof or a salt thereof. The present inventors have already discovered that cephalosporin (syn isomer) represented by the general formula [ ] and its salts are extremely useful compounds as antibacterial agents, and have previously filed a patent application (Japanese Patent Application Laid-Open No. 57-99592 issue,
No. 59-93085, No. 59-193893, No. 60-4191,
60-6694). After that, as a result of intensive research into the production method of the compound of the above general formula [] or its salt, we found that the compound of the general formula [] (syn isomer) and the compound of the general formula []
A useful cephalosporin (syn isomer ) or a salt thereof can be easily obtained in high yield, and the present invention has now been completed. That is, by reacting an acid amide or monosubstituted acid amide of the general formula [] having a free amino group with a compound of the general formula [] in the presence of boron trifluoride or its complex compound, the general formula It has been found that cephalosporin (syn isomer) or a salt thereof can be easily obtained in high yield. Therefore, an object of the present invention is to provide a new method for producing cephalosporin (syn isomer) of the general formula [] or a salt thereof having an excellent antibacterial spectrum. In this specification, unless otherwise specified, an alkyl group refers to a linear or branched C 1-14
Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl, etc.; Aryl, for example, phenyl, tolyl, naphthyl, indanyl, etc.; Aralkyl, for example, benzyl, phenethyl, 4-methylbenzyl, Naphthylmethyl, etc.; acyl means C 1-12 acyl, such as acetyl, propionyl, n-
Butyryl, isobutyryl, valeryl, pivaloyl, pentanecarbonyl, cyclohexanecarbonyl, benzoyl, naphthoyl, furoyl, thenoyl, etc.; halogen atom means fluorine, chlorine, bromine, iodine atom, etc., respectively. Moreover, lower means having 1 to 5 carbon atoms. Further, among the various terms used in this specification, for example, terms such as alkyl, aryl, aralkyl, and acyl groups have the above-mentioned meanings unless otherwise specified. R 1 in the general formula [] is a hydrogen atom, an optionally substituted alkyl, aralkyl,
It means an aryl or a heterocyclic group, and the heterocyclic group specifically includes, for example, a nitrogen-containing 5-membered or Included are 6-membered heterocyclic groups. These R 1
Examples of substituents include halogen atom, nitro group, alkyl group, aryl group, alkoxy group, cyano group, amino group, alkylamino group, dialkylamino group, acylamino group, acyl group,
Acyloxy group, acylalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, carbamoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N
- dialkylaminoalkyl group, hydroxyalkyl group, hydroxyiminoalkyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group, sulfo group, sulfamoylalkyl group, sulfamoyl group, carbamoylalkyl group, carbamoylalkenyl group, N-hydroxy Examples include carbamoyl alkyl groups, and the alkyl, aralkyl, aryl, or heterocyclic groups described above may be substituted with one or more of these substituents. Among these substituents, the carboxyl group may be protected with a carboxyl protecting group as explained in R 3a and R 3 below. R 3a represents a carboxyl-protecting group, and R 3 represents a hydrogen atom or a carboxyl-protecting group. Protective groups for these carboxyl groups include those commonly used in the field of penicillin and cephalosporin compounds. . in particular,
For example, alkyl, phthalidyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, Examples include 1-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl, benzoyloxymethyl, 1-benzoyloxyethyl, α-pivaloyloxybenzyl, and α-acetoxybenzyl groups. Next, R 4 is the 3-position exomethylene group and the carbon-
Indicates a nitrogen-bonded optionally substituted heterocyclic group, examples of which include tetrazolyl, triazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and
【式】（式
中、Ｗは隣接する窒素原子およびスルホニル基と
一緒になつて、５員環または６員環を形成する二
価の基を示す。）で表わされる基、たとえば、１，
２，６−チアジアジン−１，１−ジオキシド、イ
ソチアゾリジン−１，１−ジオキシド基などの含
窒素５員または６員複素環式基が挙げられる。さ
らに具体的には、１−（１，２，３，４−テトラ
ゾリル）、２−（１，２，３，４−テトラゾリル）、
１−（１，２，３−トリアゾリル）、２−（１，２，
３−トリアゾリル）、１−（１，２，４−トリアゾ
リル）、４−（１，２，４−トリアゾリル）、２，
３−ジオキソ−１，２，３，４−テトラヒドロピ
ラジニル、３，６−ジオキソ−１，２，３，６−
テトラヒドロピリダジニル、６−オキソ−１，６
−ジヒドロピリダジニル、２−オキソ−１，２−
ジヒドロピラジニル、６−オキソ−１，６−ジヒ
ドロピリミジニル、２−オキソ−１，２−ジヒド
ロピリミジニル、１，２，６−チアジアジン−
１，１−ジオキシド−２−イル、イソチアゾリジ
ン−１，１−ジオキシド−２−イル基などが挙げ
られる。
その複素環式基における置換基としては、R1
のところで説明した置換基が挙げられる。これら
の置換基のうち、カルボキシル基は、R3aおよび
R3のところで説明したカルボキシル保護基で保
護されていてもよい。
一般式〔〕のセフアロスポリン（シン異性
体）の塩としては、従来ペニシリンおよびセフア
ロスポリン系化合物の分野で周知の塩基性基また
は酸性基における塩が挙げられる。そのような塩
基性基における塩としては、たとえば、塩酸、臭
化水素酸、ヨウ化水素酸、硝酸または硫酸などの
鉱酸との塩；シユウ酸、コハク酸、ギ酸、トリク
ロロ酢酸またはトリフルオロ酢酸などの有機カル
ボン酸との塩；メタンスルホン酸、エタンスルホ
ン酸、ベンゼンスルホン酸、トルエン−２−スル
ホン酸、トルエン−４−スルホン酸、メシチレン
スルホン酸（２，４，６−トリメチルベンゼンス
ルホン酸）などのスルホン酸との塩が挙げられ、
また酸性基における塩としては、たとえば、ナト
リウムまたはカリウムなどのアルカリ金属との
塩；カルシウムまたはマグネシウムなどのアルカ
リ土類金属との塩；アンモニウム塩；トリエチル
アミン、トリメチルアミン、アニリン、Ｎ，Ｎ−
ジメチルアニリン、ピリジン、ジシクロヘキシル
アミンなどの含窒素有機塩基との塩が挙げられ
る。
つぎに、本発明方法の実施態様について説明す
る。
本発明の一般式〔〕のセフアロスポリンまた
はその塩は、一般式〔〕の化合物と一般式
〔〕の化合物を、三弗化硼素またはその錯化合
物の存在下に反応させ、必要に応じ、カルボキシ
ル保護基を脱離または塩に変換させることによつ
て得ることができる。
一般式〔〕の化合物は、たとえば、７−アミ
ノセフアロスポラン酸を酸の存在下に、通常の三
位変換反応（特開昭57−99592号、同59−93085
号、同59−98089号、同59−193893号、同60−
4191号、同60−6694号など）を行い、その後４位
のカルボキシル基に保護基を導入すれば、容易に
得られる。
本発明で使用される三弗化硼素の錯化合物とし
ては、たとえば、三弗化硼素とギ酸エチルまたは
酢酸エチルなどとのカルボン酸エステル錯化合
物；ジエチルエーテルまたはジイソプロピルエー
テルなどとのジアルキルエーテル錯化合物；スル
ホランとのスルホラン錯化合物；アセトニトリル
またはプロピオニトリルなどとのニトリル錯化合
物などが挙げられ、好ましくは、三弗化硼素のス
ルホラン錯化合物、アセトニトリル錯化合物、ジ
エチルエーテル錯化合物および酢酸エチル錯化合
物が挙げられる。
また、本発明では有機溶媒を使用して反応を行
うのが好ましく、使用される有機溶媒としては、
たとえば、ニトロメタン、ニトロエタン、ニトロ
プロパンなどのニトロアルカン類；ジエチルエー
テル、ジイソプロピルエーテル、ジオキサン、テ
トラヒドロフラン、エチレングリコールジメチル
エーテル、アニソール、ジメチルセロソルブなど
のエーテル類；ギ酸エチル、炭酸ジエチル、酢酸
メチル、酢酸エチル、蓚酸ジエチル、クロロ酢酸
エチル、酢酸ブチルなどのエステル類；塩化メチ
レン、クロロホルム、１，２−ジクロロエタンな
どのハロゲン化炭化水素類；アセトニトリル、プ
ロピオニトリルなどのニトリル類；スルホランな
どのスルホラン類などが挙げられ、好ましくは、
ニトロアルカン類、エステル類、ニトリル類、ハ
ロゲン化炭化水素類およびスルホランが挙げられ
る。また、所望により、これらの溶媒を二種以上
混合して用いることもできる。さらに、これらの
有機溶媒と三弗化硼素で形成される錯化合物を溶
媒として使用してもよい。一般式〔〕の化合物
の使用量は、一般式〔〕の化合物に対して、通
常0.7〜５倍モル、好ましくは１〜３倍モルであ
る。また、三弗化硼素およびその錯化合物の使用
量は、一般式〔〕の化合物に対して、通常１〜
３倍モルである。また、本反応は一般に−10〜50
℃で、10分〜20時間で完了する。
この反応において、一般式〔〕および〔〕
の化合物および三弗化硼素（または三弗化硼素の
錯化合物）の添加順序は、特に限定されるもので
はないが、好ましくは、一般式〔〕の化合物と
三弗化硼素またはその錯化合物を反応させ、つい
で、一般式〔〕の化合物を反応させるのがよ
い。
さらに、一般式〔〕の化合物と三弗化硼素ま
たはその錯化合物と反応させて得られる化合物を
単離し、ついで、これと一般式〔〕の化合物を
反応させることが好ましい。この場合、一般式
〔〕の化合物と三弗化硼素またはその錯化合物
を反応させて得られる化合物の使用量は、一般式
〔〕の化合物に対して、通常１〜２倍モル（一
般式〔〕の化合物にて換算）である。
この反応の系内に水分が存在するとβ−ラクタ
ム環の開裂など好ましくない副反応を惹起するこ
とがあるので、反応系内を無水の状態に保つこと
が好ましい。この条件を満足させるために、反応
系内に適当な脱水剤、たとえば、塩化カルシウ
ム、無水硫酸ナトリウム、無水硫酸カルシウム、
無水硫酸マグネシウム、モレキユラーシーブなど
の脱水剤を添加してもよい。
このようにして得られた一般式〔〕のセフア
ロスポリンまたはその塩は、従来公知の方法で単
離精製することができるばかりでなく、必要に応
じ、常法によつてR3がカルボキシル保護基であ
る一般式〔〕の化合物をR3が水素原子である
一般式〔〕の化合物またはその塩に容易に変換
することができる。
つぎに、一般式〔〕の化合物の製造法につい
て説明する。この化合物は、たとえば、下に示す
製造法に従つて製造することができる。
製造法
〔式中、R1およびR2は前記と同じ意味を有し、
Ｘはハロゲン原子を、Ｚはハロゲン原子または−
OR1もしくは−SR1（式中、R1は前記と同じ意味
を有する。）で表わされる基を示し、はシンま
たはアンチ異性体またはそれらの混合物でもよい
ことを示す。〕
(1) 一般式〔〕の化合物の製造
一般式〔〕のニトロソ体は、一般式〔〕
の化合物にニトロソ化剤を反応させることによ
つて得ることができる。
この反応は、通常溶媒中で行われ、使用され
る溶媒としては、たとえば、水、酢酸、ベンゼ
ン、メタノール、エタノール、テトラヒドロフ
ランなどの反応に不活性な溶媒が挙げられる。
また、これらの溶媒を二種以上混合して用いる
こともできる。
つぎに、この反応で使用される好ましいニト
ロソ化剤としては、亜硝酸およびその誘導体、
たとえば、塩化ニトロシル、臭化ニトロシルな
どのハロゲン化ニトロシル；亜硝酸ナトリウ
ム、亜硝酸カリウムなどの亜硝酸アルカリ金属
塩；亜硝酸ブチルエステル、亜硝酸ペンチルエ
ステルなどの亜硝酸アルキルエステルなどが挙
げられる。ニトロソ化剤として亜硝酸の塩を使
用する場合には、塩酸、硫酸、ギ酸、酢酸など
の無機もしくは有機の酸の存在下に反応を行う
のが好ましい。また、ニトロソ化剤として亜硝
酸アルキルエステルを使用する場合には、アル
カリ金属アルコキシドのような強塩基の存在下
に行うとよい。
このニトロソ化反応は、０℃〜30℃で、10分
〜10時間で完了する。
(2) 一般式〔〕の化合物の製造
一般式〔〕の化合物は、一般式〔〕の化
合物にアルキル化剤を反応させることによつて
得ることができる。
このアルキル化反応は、常法に従つて行うこ
とができ、通常−20〜60℃で、５分〜10時間で
完了する。ここで使用される溶媒としては、反
応に悪影響を与えない限りいかなる溶媒でもよ
く、たとえば、テトラヒドロフラン、ジオキサ
ン、メタノール、エタノール、クロロホルム、
塩化メチレン、酢酸エチル、酢酸ブチル、Ｎ，
Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチル
アセトアミド、水などが挙げられる。また、こ
れらの溶媒を二種以上混合して用いることもで
きる。また、使用されるアルキル化剤として
は、たとえば、ヨウ化メチル、臭化メチル、ヨ
ウ化エチル、臭化エチルなどのハロゲン化低級
アルキル、硫酸ジメチル、硫酸ジエチル、ジア
ゾメタン、ジアゾエタンまたはｐ−トルエンス
ルホン酸メチルなどが挙げられる。アルキル化
剤としてジアゾメタン、ジアゾエタン以外の化
合物を使用する場合には、通常炭酸ナトリウ
ム、炭酸カリウムなどのアルカリ金属の炭酸
塩、水酸化ナトリウム、水酸化カリウムなどの
アルカリ金属の水酸化物、トリエチルアミン、
ピリジンなどの塩基の存在下に反応させるのが
よい。
また、一般式〔〕の化合物は、一般式
〔〕の化合物をアンモニアまたは一級アミン
で自体知のアミド化反応を付すことにより得る
こともできる。
(3) 一般式〔〕の化合物の製造
一般式〔〕のハロゲン体は、一般式〔〕
の化合物にハロゲン化剤を反応させることによ
つて得ることができる。
この反応は、通常溶媒中で行われ、使用され
る溶媒としては、塩化メチレン、クロロホルム
などのハロゲン化炭化水素；酢酸、プロピオン
酸などの有機酸；テトラヒドロフラン、ジオキ
サンなどのエーテルなどの反応に悪影響を与え
ない溶媒が挙げられる。また、これらの溶媒を
二種以上混合して用いることもできる。
このハロゲン化反応は、通常０〜50℃で、30
分〜24時間で完了する。
使用されるハロゲン化剤としては、臭素、塩
素などのハロゲン；塩化スルフリルなどのハロ
ゲン化スルフリル；次亜塩素酸、次亜臭素酸、
次亜塩素酸ナトリウムなどの次亜ハロゲン酸ま
たはその塩；Ｎ−ブロモスクシンイミド、Ｎ−
クロロスクシンイミド、Ｎ−ブロモフタルイミ
ドなどのＮ−ハロゲン化イミド化合物；ピリジ
ニウムハイドロブロマイド・パーブロマイド、
２−カルボキシエチルトリフエニルホスホニウ
ム・パーブロマイドなどのパーブロマイド化合
物などが挙げられる。
(4) 一般式〔〕の化合物の製造
一般式〔〕の化合物は、一般式〔〕の化
合物にチオ尿素で閉環反応させることによつて
得ることができる。この閉環反応は、通常溶媒
中で行われ、使用される溶媒としては、本反応
に悪影響を与えない限りいかなるものでもよ
く、たとえば、水、メタノール、エタノール、
アセトン、テトラヒドロフラン、ジオキサン、
Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメ
チルアセトアミド、Ｎ−メチルピリドンなどが
挙げられる。また、これらの溶媒を二種以上混
合して用いることもできる。
また、この反応において、脱酸剤を添加する
と円滑に反応が進行することもあり、使用され
る脱酸剤としては、たとえば、水酸化アルカリ
金属塩、炭酸水素アルカリ金属塩、トリエチル
アミン、ピリジン、Ｎ，Ｎ−ジメチルアニリン
などの無機または有機塩基などが挙げられる。
反応時間は、通常１〜48時間、好ましくは１
〜10時間である。
この閉環反応は、０〜100℃の範囲で行われ、
チオ尿素は、一般式〔〕の化合物に対して、
通常１〜数倍モル使用するのがよい。
なお、本反応は、中間体として、一般式[Formula] (wherein, W represents a divalent group that forms a 5- or 6-membered ring together with the adjacent nitrogen atom and sulfonyl group.) For example, 1,
Examples include nitrogen-containing 5- or 6-membered heterocyclic groups such as 2,6-thiadiazine-1,1-dioxide and isothiazolidine-1,1-dioxide groups. More specifically, 1-(1,2,3,4-tetrazolyl), 2-(1,2,3,4-tetrazolyl),
1-(1,2,3-triazolyl), 2-(1,2,
3-triazolyl), 1-(1,2,4-triazolyl), 4-(1,2,4-triazolyl), 2,
3-dioxo-1,2,3,4-tetrahydropyrazinyl, 3,6-dioxo-1,2,3,6-
Tetrahydropyridazinyl, 6-oxo-1,6
-dihydropyridazinyl, 2-oxo-1,2-
Dihydropyrazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2-oxo-1,2-dihydropyrimidinyl, 1,2,6-thiadiazine-
Examples include 1,1-dioxid-2-yl, isothiazolidine-1,1-dioxid-2-yl, and the like. As a substituent in the heterocyclic group, R 1
Examples include the substituents explained above. Among these substituents, the carboxyl group is R 3a and
It may be protected with the carboxyl protecting group explained in the section of R 3 . Examples of the salt of the cephalosporin (syn isomer) of the general formula [] include salts with basic or acidic groups that are well known in the field of penicillin and cephalosporin compounds. Salts of such basic groups include, for example, salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, nitric or sulfuric acids; oxalic, succinic, formic, trichloroacetic or trifluoroacetic acids. Salts with organic carboxylic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid) Salts with sulfonic acids such as
Salts with acidic groups include, for example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; triethylamine, trimethylamine, aniline, N,N-
Examples include salts with nitrogen-containing organic bases such as dimethylaniline, pyridine, and dicyclohexylamine. Next, embodiments of the method of the present invention will be described. The cephalosporin of the general formula [] or a salt thereof of the present invention can be obtained by reacting a compound of the general formula [] with a compound of the general formula [] in the presence of boron trifluoride or a complex compound thereof, and optionally carboxyl-protected. It can be obtained by eliminating the group or converting it into a salt. The compound of the general formula [] can be prepared, for example, by a conventional three-position conversion reaction of 7-aminocephalosporanic acid in the presence of an acid (JP-A No. 57-99592, No. 59-93085).
No. 59-98089, No. 59-193893, No. 60-
No. 4191, No. 60-6694, etc.) and then introducing a protecting group into the carboxyl group at the 4-position. The boron trifluoride complex used in the present invention includes, for example, a carboxylic acid ester complex of boron trifluoride and ethyl formate or ethyl acetate; a dialkyl ether complex with diethyl ether or diisopropyl ether; Examples include sulfolane complex compounds with sulfolane; nitrile complex compounds with acetonitrile or propionitrile, etc., and preferably boron trifluoride sulfolane complex compounds, acetonitrile complex compounds, diethyl ether complex compounds, and ethyl acetate complex compounds. It will be done. Furthermore, in the present invention, it is preferable to carry out the reaction using an organic solvent, and the organic solvent used is as follows:
For example, nitroalkanes such as nitromethane, nitroethane, and nitropropane; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole, and dimethyl cellosolve; ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, and oxalic acid. Examples include esters such as diethyl, ethyl chloroacetate, and butyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane; nitrites such as acetonitrile and propionitrile; and sulfolanes such as sulfolane. ,Preferably,
Mention may be made of nitroalkanes, esters, nitriles, halogenated hydrocarbons and sulfolanes. Furthermore, if desired, two or more of these solvents may be used in combination. Furthermore, a complex compound formed with these organic solvents and boron trifluoride may be used as a solvent. The amount of the compound of the general formula [] to be used is usually 0.7 to 5 times, preferably 1 to 3 times, the amount of the compound of the general formula []. In addition, the amount of boron trifluoride and its complex compound to be used is usually 1 to
It is 3 times the mole. In addition, this reaction is generally −10 to 50
Complete in 10 minutes to 20 hours at °C. In this reaction, the general formulas [] and []
Although the order of addition of the compound of general formula [] and boron trifluoride (or a complex compound of boron trifluoride) is not particularly limited, it is preferable to add the compound of general formula [ ] and boron trifluoride or a complex compound thereof. It is preferable to react, and then react the compound of the general formula []. Furthermore, it is preferable to isolate a compound obtained by reacting the compound of general formula [] with boron trifluoride or a complex compound thereof, and then react it with the compound of general formula []. In this case, the amount of the compound obtained by reacting the compound of the general formula [] with boron trifluoride or its complex compound is usually 1 to 2 times the mole of the compound of the general formula [] (general formula ). Since the presence of water in the reaction system may cause undesirable side reactions such as cleavage of the β-lactam ring, it is preferable to maintain the reaction system in an anhydrous state. In order to satisfy this condition, a suitable dehydrating agent is added to the reaction system, such as calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate,
A dehydrating agent such as anhydrous magnesium sulfate or molecular sieve may be added. The thus obtained cephalosporin of the general formula [] or its salt can not only be isolated and purified by conventionally known methods, but also, if necessary, by a conventional method in which R 3 is a carboxyl protecting group. A compound of a certain general formula [] can be easily converted into a compound of the general formula [] or a salt thereof in which R 3 is a hydrogen atom. Next, a method for producing the compound of general formula [] will be explained. This compound can be produced, for example, according to the production method shown below. Manufacturing method [In the formula, R 1 and R 2 have the same meanings as above,
X is a halogen atom, Z is a halogen atom or -
represents a group represented by OR 1 or -SR 1 (wherein R 1 has the same meaning as above), and indicates that it may be a syn or anti isomer or a mixture thereof. 〕 (1) Manufacture of the compound of the general formula [] The nitroso compound of the general formula []
can be obtained by reacting the compound with a nitrosating agent. This reaction is usually carried out in a solvent, and examples of the solvent used include solvents inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, and tetrahydrofuran.
Moreover, two or more kinds of these solvents can also be used as a mixture. Next, preferred nitrosating agents used in this reaction include nitrous acid and its derivatives,
Examples include nitrosyl halides such as nitrosyl chloride and nitrosyl bromide; alkali metal nitrites such as sodium nitrite and potassium nitrite; and alkyl nitrites such as butyl nitrite and pentyl nitrite. When using a salt of nitrous acid as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, or acetic acid. Furthermore, when a nitrous acid alkyl ester is used as a nitrosating agent, it is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. This nitrosation reaction is completed in 10 minutes to 10 hours at 0°C to 30°C. (2) Production of compound of general formula [] The compound of general formula [] can be obtained by reacting the compound of general formula [] with an alkylating agent. This alkylation reaction can be carried out according to a conventional method, and is usually completed in 5 minutes to 10 hours at -20 to 60°C. The solvent used here may be any solvent as long as it does not adversely affect the reaction, such as tetrahydrofuran, dioxane, methanol, ethanol, chloroform,
methylene chloride, ethyl acetate, butyl acetate, N,
Examples include N-dimethylformamide, N,N-dimethylacetamide, and water. Moreover, two or more kinds of these solvents can also be used as a mixture. The alkylating agents used include, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, and ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, or p-toluenesulfonic acid. Examples include methyl. When a compound other than diazomethane or diazoethane is used as an alkylating agent, it is usually an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, triethylamine,
The reaction is preferably carried out in the presence of a base such as pyridine. Further, the compound of the general formula [] can also be obtained by subjecting the compound of the general formula [] to a known amidation reaction with ammonia or a primary amine. (3) Production of compound of general formula [] The halogen compound of general formula []
It can be obtained by reacting the compound with a halogenating agent. This reaction is usually carried out in a solvent, and the solvents used include halogenated hydrocarbons such as methylene chloride and chloroform; organic acids such as acetic acid and propionic acid; and ethers such as tetrahydrofuran and dioxane, which adversely affect the reaction. Examples include solvents that do not give Moreover, two or more kinds of these solvents can also be used as a mixture. This halogenation reaction is usually carried out at 0 to 50°C for 30
Completes in minutes to 24 hours. The halogenating agents used include halogens such as bromine and chlorine; sulfuryl halides such as sulfuryl chloride; hypochlorous acid, hypobromous acid,
Hypohalous acid or its salts such as sodium hypochlorite; N-bromosuccinimide, N-
N-halogenated imide compounds such as chlorosuccinimide and N-bromophthalimide; pyridinium hydrobromide/perbromide,
Examples include perbromide compounds such as 2-carboxyethyltriphenylphosphonium perbromide. (4) Production of compound of general formula [] The compound of general formula [] can be obtained by ring-closing reaction of the compound of general formula [] with thiourea. This ring-closing reaction is usually carried out in a solvent, and any solvent may be used as long as it does not adversely affect the reaction, such as water, methanol, ethanol,
Acetone, tetrahydrofuran, dioxane,
Examples include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyridone. Moreover, two or more kinds of these solvents can also be used as a mixture. In addition, in this reaction, the reaction may proceed smoothly if a deoxidizing agent is added, and the deoxidizing agents used include, for example, alkali metal hydroxide, alkali metal hydrogen carbonate, triethylamine, pyridine, N , N-dimethylaniline, and other inorganic or organic bases. The reaction time is usually 1 to 48 hours, preferably 1 hour.
~10 hours. This ring-closing reaction is carried out in the range of 0 to 100°C,
Thiourea is a compound of the general formula [],
It is usually best to use one to several times the mole. In addition, this reaction uses the general formula as an intermediate.
【式】（式中、R1お
よびR2は前記と同じ意味を有する。）のチアゾ
リン化合物を経由することが確認された。この
反応において、上述のチアゾリン化合物を単離
し、ついで、脱水反応に付すことによつて、一
般式〔〕のチアゾール化合物を得ることもで
きる。
以上のようにして、一般式〔〕のチアゾール
化合物のシン異性体を選択的に、高収率かつ安価
に得ることができる。
つぎに、本発明を参考例および実施例を挙げて
説明するが、本発明は、これに限定されるもので
はない。
参考例 １
(1) アセト酢酸アミド10.1ｇを水35mlに溶解さ
せ、氷冷下、亜硝酸ナトリウム6.9ｇを加えて、
０〜５℃で撹拌下に4N−硫酸25mlを30分を要
して滴下する。滴下終了後、同温度で30分間反
応させた後、飽和炭酸水素ナトリウム水溶液で
PH6.0に調整する。
不溶物を除去した後、減圧下に水を留去し、
得られた残留物に酢酸エチル20mlを加えて析出
結晶を取すれば、融点96〜97℃を示す２−ヒ
ドロキシイミノ−３−オキソ酪酸アミド86ｇ
（収率66.2％）を得る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1670
NMR（d6−DMSO）δ値；
2.26（3H、ｓ、CH3CO−）、
7.46（1H、bs、It was confirmed that the reaction occurred via a thiazoline compound of the formula (wherein R 1 and R 2 have the same meanings as above). In this reaction, the thiazole compound of the general formula [] can also be obtained by isolating the above-mentioned thiazoline compound and then subjecting it to a dehydration reaction. As described above, the syn isomer of the thiazole compound of the general formula [] can be selectively obtained in high yield and at low cost. Next, the present invention will be explained with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference example 1 (1) Dissolve 10.1 g of acetoacetamide in 35 ml of water, add 6.9 g of sodium nitrite under ice cooling,
While stirring at 0-5°C, 25 ml of 4N sulfuric acid is added dropwise over 30 minutes. After dropping, react at the same temperature for 30 minutes, then add saturated sodium bicarbonate aqueous solution.
Adjust to PH6.0. After removing insoluble matter, water was distilled off under reduced pressure,
Add 20 ml of ethyl acetate to the resulting residue and remove the precipitated crystals to obtain 86 g of 2-hydroxyimino-3-oxobutyric acid amide with a melting point of 96-97°C.
(yield 66.2%). IR (KBr) cm -1 ; C=O 1670 NMR (d 6 -DMSO) δ value; 2.26 (3H, s, CH 3 CO-), 7.46 (1H, bs,
【式】）、 7.62（1H、bs、【formula】), 7.62 (1H, bs,
【式】）、
12.60（1H、ｓ、＝Ｎ−ＯＨ）
(2) ２−ヒドロキシイミノ−３−オキソ酪酸アミ
ド6.5ｇおよび無水炭酸ナトリウム5.6ｇを20℃
で水20mlに溶解させる。さらに、ジメチル硫酸
6.6ｇを20〜25℃で加えて、同温度で２時間撹
拌する。ついで、析出物を取し、得られた析
出物にメタノール100mlを加えて40〜50℃で30
分間撹拌する。ついで、不溶物を除去した後、
減圧下に溶媒を留去し、得られた残留物にエタ
ノール20mlを加えて結晶を取すれば、融点
156〜157℃の２−（シン）−メトキシイミノ−３
−オキソ酪酸アミド5.2ｇ（収率72.2％）を得
る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1700、1670
NMR（d6−DMSO）δ値；
2.26（3H、ｓ、CH3CO−）、
3.96（3H、ｓ、−OCH3）、
7.46（1H、bs、[Formula]), 12.60 (1H, s, = N- OH ) (2) 6.5 g of 2-hydroxyimino-3-oxobutyric acid amide and 5.6 g of anhydrous sodium carbonate were heated at 20°C.
Dissolve in 20ml of water. Furthermore, dimethyl sulfate
Add 6.6g at 20-25°C and stir at the same temperature for 2 hours. Next, collect the precipitate, add 100ml of methanol to the obtained precipitate, and heat at 40-50℃ for 30 minutes.
Stir for a minute. Then, after removing the insoluble matter,
The solvent is distilled off under reduced pressure, and 20 ml of ethanol is added to the resulting residue to collect crystals, and the melting point is
2-(syn)-methoxyimino-3 at 156-157℃
- Obtain 5.2 g (yield 72.2%) of oxobutyric acid amide. IR (KBr) cm -1 ; C=O 1700, 1670 NMR (d 6 -DMSO) δ value; 2.26 (3H, s, CH 3 CO-), 3.96 (3H, s, -OCH 3 ), 7.46 ( 1H, bs,
【式】）、 7.58（1H、bs、【formula】), 7.58 (1H, bs,
【式】）、
(3) ２−（シン）−メトキシイミノ−３−オキソ酪
酸アミド7.2ｇをテトラヒドロフラン36mlに懸
濁させ、40℃で臭素0.8ｇを撹拌下に加える。
臭素による着色が消失するのを確認した後、25
〜30℃で、さらに臭素7.2ｇを撹拌下に加える。
同温度で１時間反応させた後、減圧下に溶媒を
留去する。得られた残渣に酢酸エチル50mlおよ
び水20mlを加え、飽和炭酸水素ナトリウム水溶
液でPH6.0に調整した後、有機層を分取し、飽
和食塩水20mlで洗浄する。ついで、無水硫酸マ
グネシウムで乾燥させた後、減圧下に溶媒を留
去する。得られた残留物にジイソプロピルエー
テル−酢酸エチル（１：１）の混合溶媒20mlを
加えて結晶を取すれば、融点112〜113℃の４
−ブロモ−２−（シン）−メトキシイミノ−３−
オキソ酪酸アミド9.2ｇ（収率82.1％）を得る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1715、1660
NMR（d6−DMSO）δ値；
4.02（3H、ｓ、−OCH3）、
4.58（2H、ｓ、BrCH2CO−）、
7.72（2H、bs、−CONH2）
(4) ４−ブロモ−２−（シン）−メトキシイミノ−
３−オキソ酪酸アミド4.5ｇをエタノール13.5
mlに懸濁させ、チオ尿素1.5ｇを加えて20〜30
℃で１時間反応させる。析出晶を取し、エタ
ノールで洗浄した後、水25mlに懸濁させ、飽和
炭酸水素ナトリウム水溶液でPH6.0に調整する。
ついで、結晶を取し、水−メタノール（１：
１）の混合溶媒15mlで再結晶すれば、融点208
〜209℃の２−（２−アミノチアゾール−４−イ
ル）−２−（シン）−メトキシイミノ酢酸アミド
2.9ｇ（収率71.8％）を得る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1665
NMR（d6−DMSO）δ値；
3.84（3H、ｓ、−OCH3）、
6.75（1H、ｓ、[Formula]), (3) 7.2 g of 2-(syn)-methoxyimino-3-oxobutyric acid amide is suspended in 36 ml of tetrahydrofuran, and 0.8 g of bromine is added under stirring at 40°C.
After confirming that the coloring caused by bromine has disappeared, 25
At ~30°C, add a further 7.2 g of bromine with stirring.
After reacting at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Add 50 ml of ethyl acetate and 20 ml of water to the resulting residue, adjust the pH to 6.0 with a saturated aqueous sodium bicarbonate solution, and then separate the organic layer and wash with 20 ml of saturated brine. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. 20 ml of a mixed solvent of diisopropyl ether and ethyl acetate (1:1) is added to the resulting residue to collect crystals, resulting in 4.
-bromo-2-(syn)-methoxyimino-3-
9.2 g (yield 82.1%) of oxobutyric acid amide is obtained. IR (KBr) cm -1 ; C=O 1715, 1660 NMR (d 6 -DMSO) δ value; 4.02 (3H, s, -OCH 3 ), 4.58 (2H, s, BrCH 2 CO -), 7.72 ( 2H, bs, -CONH 2 ) (4) 4-bromo-2-(syn)-methoxyimino-
4.5g of 3-oxobutyric acid amide and 13.5g of ethanol
ml, add 1.5 g of thiourea, and add 20 to 30 g of thiourea.
Incubate at ℃ for 1 hour. Collect the precipitated crystals, wash them with ethanol, suspend them in 25 ml of water, and adjust the pH to 6.0 with a saturated aqueous sodium bicarbonate solution.
Next, the crystals were collected and mixed with water-methanol (1:
If recrystallized with 15 ml of the mixed solvent of 1), the melting point will be 208.
2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid amide at ~209°C
Obtain 2.9 g (yield 71.8%). IR (KBr) cm -1 ; C=O 1665 NMR (d 6 -DMSO) δ value; 3.84 (3H, s, -OCH 3 ), 6.75 (1H, s,
【式】）、 7.26（2H、bs、−NH2）、 7.61（1H、bs、[Formula]), 7.26 (2H, bs, −NH 2 ), 7.61 (1H, bs,
【式】）、 7.91（1H、bs、【formula】), 7.91 (1H, bs,
【式】） 同様にして、表−１の化合物を得た。【formula】) In the same manner, the compounds shown in Table 1 were obtained.
【表】【table】
【表】
実施例 １
(1) ２−（２−アミノチアゾール−４−イル）−２
−（シン）−メトキシイミノ酢酸アミド10.0ｇ
を、三弗化硼素10.2ｇ含むスルホラン20mlおよ
び無水塩化メチレン20mlの混合溶媒中へ加え
る。室温で１時間反応させた後、結晶を取す
る。ついで、結晶を酢酸エチル100mlに懸濁さ
せ、１時間撹拌した後取する。酢酸エチル20
mlで２回洗浄し、乾燥すれば、結晶を14.1ｇ得
る。
IR（KBr）cm-1；1680、1650、1620、1200〜1000
(2) ピバロイルオキシメチル＝７−アミノ−３−
〔（５−メチル−１，２，３，４−テトラゾール
−２−イル）メチル〕−△3−セフエム−４−カ
ルボキシレート4.10ｇを酢酸エチル41mlに溶解
させ、(1)で得られた結晶3.36ｇを加えて室温で
３時間反応させる。ついで、反応液に水41mlを
加え、炭酸水素ナトリウムでPH4.5に調整する。
有機層を分取し、水20mlで洗浄した後、無水硫
酸マグネシウムで乾燥させる。ついで、メシチ
レンスルホン酸・２水和物2.4ｇを加えて室温
で１時間反応させる。得られた結晶を取し、
酢酸エチル５mlで洗浄すれば、融点218〜220℃
（分解）を示すピバロイルオキシメチル＝７−
〔２−（２−アミノチアゾール−４−イル）−２
−（シン）−メトキシイミノアセトアミド〕−３
−〔（５−メチル−１，２，３，４−テトラゾー
ル−２−イル）メチル〕−△3−セフエム−４−
カルボキシレートのメチレンスルホン酸塩7.18
ｇ（収率90.5％）を得る。
実施例 ２
(1) ２−（２−アミノチアゾール−４−イル）−２
−（シン）−メトキシイミノ酢酸アミド6.0ｇを
無水塩化メチレン13mlに懸濁させ、15〜20℃で
三弗化硼素2.72ｇを含むスルホラン−無水塩化
メチレン（１：１）の混合溶液10.3mlを加えて
同温度で10分間反応させる。ついで、ピバロイ
ルオキシメチル＝７−アミノ−３−（５−メチ
ル−１，２，３，４−テトラゾール−２−イ
ル）メチル−△3−セフエム−４−カルボキシ
レート4.10ｇを含む無水塩化メチレン溶液13ml
を加えて30〜35℃で２時間30分反応させる。つ
いで、反応液を氷水15ml中へ導入し、飽和炭酸
水素ナトリウム水溶液でPH5.5に調整する。つ
いで、不溶物を除去した後、有機層を分取し、
飽和食塩水15mlで洗浄した後、無水硫酸マグネ
シウムで乾燥させる。減圧下に溶媒を留去し、
得られた残留物に酢酸エチル60mlを加えて溶解
させた後、メシチレンスルホン酸・２水和物
2.36ｇを加えて30分間撹拌し、析出晶を取す
れば、融点218〜220℃（分解）を示すピバロイ
ルオキシメチル＝７−〔２−（２−アミノチアゾ
ール−４−イル）−２−（シン）−メトキシイミ
ノアセトアミド〕−３−（５−メチル−１，２，
３，４−テトラゾール−２−イル）メチル−△
３−セフエム−４−カルボキシレートのメシチ
レンスルホン酸塩6.37ｇ（収率80.2％）を得
る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1782、1745、1680
(2) 表−２に示す反応条件で、上記(1)と同様に反
応を行えば、ピバロイルオキシメチル＝７−
〔２−（２−アミノチアゾール−４−イル）−２
−（シン）−メトキシイミノアセトアミド〕−３
−（５−メチル−１，２，３，４−テトラゾー
ル−２−イル）メチル−△3−セフエム−４−
カルボキシレートのメシチレンスルホン酸塩を
得る。なお、得られたものの物性（融点、IR）
は、上記(1)で得られた化合物の物性と一致し
た。[Table] Example 1 (1) 2-(2-aminothiazol-4-yl)-2
-(Syn)-methoxyiminoacetic acid amide 10.0g
was added to a mixed solvent of 20 ml of sulfolane and 20 ml of anhydrous methylene chloride containing 10.2 g of boron trifluoride. After reacting for 1 hour at room temperature, the crystals are collected. Then, the crystals were suspended in 100 ml of ethyl acetate, stirred for 1 hour, and then collected. ethyl acetate 20
ml twice and dried to obtain 14.1 g of crystals. IR (KBr) cm -1 ; 1680, 1650, 1620, 1200-1000 (2) Pivaloyloxymethyl = 7-amino-3-
Dissolve 4.10 g of [(5-methyl-1,2,3,4-tetrazol-2-yl)methyl]-△ 3 -cephem-4-carboxylate in 41 ml of ethyl acetate to obtain the crystals obtained in (1). Add 3.36g and react at room temperature for 3 hours. Next, add 41 ml of water to the reaction solution, and adjust the pH to 4.5 with sodium hydrogen carbonate.
The organic layer is separated, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate. Then, 2.4 g of mesitylene sulfonic acid dihydrate was added and reacted for 1 hour at room temperature. Take the obtained crystals,
If washed with 5 ml of ethyl acetate, the melting point is 218-220℃.
(decomposition) pivaloyloxymethyl=7-
[2-(2-aminothiazol-4-yl)-2
-(syn)-methoxyiminoacetamide]-3
-[(5-methyl-1,2,3,4-tetrazol-2-yl)methyl]-△ 3 -Cefem-4-
Carboxylate methylene sulfonate 7.18
g (yield 90.5%). Example 2 (1) 2-(2-aminothiazol-4-yl)-2
6.0 g of -(syn)-methoxyiminoacetic acid amide was suspended in 13 ml of anhydrous methylene chloride, and 10.3 ml of a mixed solution of sulfolane-anhydrous methylene chloride (1:1) containing 2.72 g of boron trifluoride was added at 15 to 20°C. In addition, react at the same temperature for 10 minutes. Then, anhydrous chloride containing 4.10 g of pivaloyloxymethyl 7-amino-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-Δ 3 -cephem -4-carboxylate was added. 13ml methylene solution
and react at 30-35°C for 2 hours and 30 minutes. Then, the reaction solution was introduced into 15 ml of ice water, and the pH was adjusted to 5.5 with a saturated aqueous sodium hydrogen carbonate solution. Then, after removing insoluble matter, the organic layer is separated,
After washing with 15 ml of saturated saline, dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
After adding 60 ml of ethyl acetate to the obtained residue and dissolving it, mesitylene sulfonic acid dihydrate was added.
Add 2.36g and stir for 30 minutes, then remove the precipitated crystals to obtain pivaloyloxymethyl 7-[2-(2-aminothiazol-4-yl)-2, which has a melting point of 218-220℃ (decomposed). -(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,
3,4-tetrazol-2-yl)methyl-△
6.37 g (yield: 80.2%) of mesitylene sulfonate of 3- cephem-4-carboxylate is obtained. IR (KBr) cm -1 ; C=O 1782, 1745, 1680 (2) If the reaction is carried out in the same manner as in (1) above under the reaction conditions shown in Table 2, pivaloyloxymethyl = 7-
[2-(2-aminothiazol-4-yl)-2
-(syn)-methoxyiminoacetamide]-3
-(5-Methyl-1,2,3,4-tetrazol-2-yl)methyl-△ 3 -Cefem-4-
Mesitylene sulfonate of carboxylate is obtained. In addition, the physical properties (melting point, IR) of the obtained product
were consistent with the physical properties of the compound obtained in (1) above.
【表】
(3) ２−（２−アミノチアゾール−４−イル）−２
−（シン）−メトキシイミノ酢酸アミドの代わり
に表−３に示す原料化合物を用いて、上記(1)と
同様に反応を行えば、ピバロイルオキシメチル
＝７−〔２−（２−アミノチアゾール−４−イ
ル）−２−（シン）−メトキシイミノアセトアミ
ド〕−３−（５−メチル−１，２，３，４−テト
ラゾール−２−イル）メチル−△3−セフエム
−４−カルボキシレートのメシチレンスルホン
酸塩を得る。なお、得られたものの物性（融
点、IR）は上記(1)で得られた化合物の物性と
一致した。[Table] (3) 2-(2-aminothiazol-4-yl)-2
If the reaction is carried out in the same manner as in (1) above using the raw material compounds shown in Table 3 instead of -(syn)-methoxyiminoacetic acid amide, pivaloyloxymethyl=7-[2-(2-amino Thiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-△ 3 -cephem-4-carboxylate to obtain mesitylene sulfonate. The physical properties (melting point, IR) of the obtained product matched those of the compound obtained in (1) above.
【表】【table】
【表】
実施例 ３
(1) ２−（２−アミノチアゾール−４−イル）−２
−（シン）−メトキシイミノ酢酸アミド6.0ｇを
無水塩化メチレン13mlに懸濁させ、15〜20℃で
三弗化硼素2.72ｇを含むスルホラン−無水塩化
メチレン（１：１）の混合溶液10.3mlを加えて
同温度で10分間反応させる。ついで、ジフエニ
ルメチル＝７−アミノ−３−（５−メチル−１，
２，３，４−テトラゾール−２−イル）メチル
−△3−セフエム−４−カルボキシレート4.62
ｇを含む無水塩化メチレン溶液40mlを加えて30
〜35℃で３時間反応させる。反応液を水50ml中
に導入した後、炭酸水素ナトリウムでPH5.5に
調整する。不溶物を除去した後有機層を分取
し、飽和食塩水20mlで洗浄した後、無水硫酸マ
グネシウムで乾燥させる。減圧下に溶媒を留去
し、得られた残留物をカラムクロマトグラフイ
ー（和光シリカゲルＣ−200、溶出溶媒：クロ
ロホルム−メタノール）で精製すれば、融点
102〜105℃（分解）を示すジフエニルメチル＝
７−〔２−（２−アミノチアゾール−４−イル）
−２−（シン）−メトキシイミノアセトアミド〕
−３−（５−メチル−１，２，３，４−テトラ
ゾール−２−イル）メチル−△3−セフエム−
４−カルボキシレート4.2ｇ（収率65.1％）を
得る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1778、1720、1660
同様に反応させて、表−４の化合物を得た。[Table] Example 3 (1) 2-(2-aminothiazol-4-yl)-2
6.0 g of -(syn)-methoxyiminoacetic acid amide was suspended in 13 ml of anhydrous methylene chloride, and 10.3 ml of a mixed solution of sulfolane-anhydrous methylene chloride (1:1) containing 2.72 g of boron trifluoride was added at 15 to 20°C. In addition, react at the same temperature for 10 minutes. Then, diphenylmethyl=7-amino-3-(5-methyl-1,
2,3,4-tetrazol-2-yl)methyl-△ 3 -cephem-4-carboxylate 4.62
Add 40 ml of anhydrous methylene chloride solution containing 30 g
Incubate for 3 hours at ~35°C. After introducing the reaction solution into 50 ml of water, the pH was adjusted to 5.5 with sodium hydrogen carbonate. After removing insoluble materials, the organic layer is separated, washed with 20 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (Wako silica gel C-200, elution solvent: chloroform-methanol).
Diphenylmethyl showing 102-105℃ (decomposition) =
7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide]
-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-△ 3 -cephem-
4.2 g (65.1% yield) of 4-carboxylate are obtained. IR (KBr) cm -1 ; C=O 1778, 1720, 1660 The compounds shown in Table 4 were obtained by reacting in the same manner.
【表】
(2) (1)で得られたジフエニルメチル＝７−〔２−
（２−アミノチアゾール−４−イル）−２−（シ
ン）−メトキシイミノアセトアミド〕−３−（５
−メチル−１，２，３，４−テトラゾール−２
−イル）メチル−△3−セフエム−４−カルボ
キシレート6.45ｇをトリフルオロ酢酸35mlおよ
アニソール10mlの混合溶液に溶解させ、室温で
１時間反応させる。ついで、減圧下に溶媒を留
去し、残留物にジエチルエーテルを加えて、得
られた結晶を取し、ジエチルエーテルで十分
洗浄した後乾燥すれば、融点123〜125℃（分
解）を示す７−〔２−（２−アミノチアゾール−
４−イル）−２−（シン）−メトキシイミノアセ
トアミド〕−３−（５−メチル−１，２，３，４
−テトラゾール−２−イル）メチル−△3−セ
フエム−４−カルボン酸のトリフルオロ酢酸塩
5.46ｇ（収率92.1％）を得る。
IR（KBr）cm-1；〓Ｃ＝Ｏ 1790、1720〜1635
実施例 ４
実施例１、２または３と同様に反応させて、表
−５に示す化合物を65〜85％の収率で得た。[Table] (2) Diphenylmethyl obtained in (1) = 7-[2-
(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5
-Methyl-1,2,3,4-tetrazole-2
6.45 g of -yl)methyl-Δ 3 -cephem-4-carboxylate is dissolved in a mixed solution of 35 ml of trifluoroacetic acid and 10 ml of anisole, and reacted for 1 hour at room temperature. Then, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected, thoroughly washed with diethyl ether, and then dried to give a crystal with a melting point of 123-125°C (decomposed). -[2-(2-aminothiazole-
4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,3,4
-tetrazol-2-yl)methyl-△ 3 -cephem-4-carboxylic acid trifluoroacetate
Obtain 5.46 g (92.1% yield). IR (KBr) cm -1 ; C=O 1790, 1720-1635 Example 4 The compound shown in Table 5 was obtained in a yield of 65-85% by reacting in the same manner as in Example 1, 2 or 3. Ta.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
Claims (1)
よいアルキル、アルアルキル、アリールまたは複
素環式基を、R2は低級アルキル基を示す。〕 で表わされる化合物（シン異性体）と 一般式 〔式中、R3aはカルボキシル保護基を、R4は３位
エキソメチレン基と炭素−窒素結合する置換され
ていてもよい複素環式基を示す。〕 で表わされる化合物を、三弗化硼素またはその錯
化合物の存在下に反応させ、必要に応じ、カルボ
キシル保護基を脱離または塩に変換させることを
特徴とする 一般式 〔式中、R2およびR4は前記と同じ意味を有し、
R3は水素原子またはカルボキシル保護基を示
す。〕 で表わされるセフアロスポリン（シン異性体）ま
たはその塩の製造法。 ２ R1が水素原子である特許請求の範囲第１項
記載のセフアロスポリン（シン異性体）またはそ
の塩の製造法。 ３ R1が置換されていてもよいアルキル基であ
る特許請求の範囲第１項記載のセフアロスポリン
（シン異性体）またはその塩の製造法。 ４ R1が置換されていてもよいアリール基であ
る特許請求の範囲第１項記載のセフアロスポリン
（シン異性体）またはその塩の製造法。 ５ 反応を有機溶媒中で行う特許請求の範囲第１
〜４項いずれかの項記載のセフアロスポリン（シ
ン異性体）またはその塩の製造法。 ６ 有機溶媒が、ニトロアルカン類、エステル
類、ハロゲン化炭化水素類、ニトリル類またはス
ルホランである特許請求の範囲第５項記載のセフ
アロスポリン（シン異性体）またはその塩の製造
法。[Claims] 1. General formula [In the formula, R 1 represents a hydrogen atom or an optionally substituted alkyl, aralkyl, aryl, or heterocyclic group, and R 2 represents a lower alkyl group. ] Compound represented by (syn isomer) and general formula [In the formula, R 3a represents a carboxyl protecting group, and R 4 represents an optionally substituted heterocyclic group that forms a carbon-nitrogen bond with the 3-position exomethylene group. ] The compound represented by the general formula is reacted in the presence of boron trifluoride or its complex compound, and if necessary, the carboxyl protecting group is eliminated or converted into a salt. [In the formula, R 2 and R 4 have the same meanings as above,
R 3 represents a hydrogen atom or a carboxyl protecting group. ] A method for producing cephalosporin (syn isomer) or its salt represented by 2. The method for producing cephalosporin (syn isomer) or a salt thereof according to claim 1, wherein R 1 is a hydrogen atom. 3. The method for producing cephalosporin (syn isomer) or a salt thereof according to claim 1, wherein R 1 is an optionally substituted alkyl group. 4. The method for producing cephalosporin (syn isomer) or a salt thereof according to claim 1, wherein R 1 is an optionally substituted aryl group. 5 Claim 1 in which the reaction is carried out in an organic solvent
A method for producing cephalosporin (syn isomer) or a salt thereof according to any one of items 1 to 4. 6. The method for producing cephalosporin (syn isomer) or a salt thereof according to claim 5, wherein the organic solvent is nitroalkanes, esters, halogenated hydrocarbons, nitriles, or sulfolane.
Priority Applications (48)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59104759A JPS60248691A (en) | 1984-05-25 | 1984-05-25 | Novel preparation of cephalosporin compound and its intermediate |
| GB08424417A GB2161476B (en) | 1984-05-25 | 1984-09-27 | 2-aminothiazolyl-2-methoxyimino acetamides and their use in preparing cephalosporins |
| PH31281A PH20486A (en) | 1984-05-25 | 1984-09-28 | A process for producing a cephalosporin |
| CA000464295A CA1225391A (en) | 1984-05-25 | 1984-09-28 | Process for producing a cephalosporin, an intermediate for the cephalosporin and a process for producing the intermediate |
| IN701/CAL/84A IN163562B (en) | 1984-05-25 | 1984-09-29 | |
| ZA847713A ZA847713B (en) | 1984-05-25 | 1984-10-01 | Process for producing a cephalosporin,an intermediate for the cephalosporin,and a process for producing the intermediate |
| AU33751/84A AU555399B2 (en) | 1984-05-25 | 1984-10-01 | 2-amino thiazole derivatives |
| NZ209725A NZ209725A (en) | 1984-05-25 | 1984-10-01 | Production of cephalosporin derivatives |
| NZ219361A NZ219361A (en) | 1984-05-25 | 1984-10-01 | Thiazole derivatives |
| DE19843436603 DE3436603A1 (en) | 1984-05-25 | 1984-10-05 | NEW METHOD FOR PRODUCING A CEPHALOSPORINE, AN INTERMEDIATE PRODUCT FOR THE CEPHALOSPORINE AND A METHOD FOR PRODUCING THE INTERMEDIATE PRODUCT |
| EG621/84A EG16588A (en) | 1984-05-25 | 1984-10-07 | A novel process for producing cephalosporins |
| DD84290158A DD253819A5 (en) | 1984-05-25 | 1984-10-08 | PROCESS FOR PREPARING A NEW INTERMEDIATE PRODUCT FOR CEPHALOSPORINES |
| IT48974/84A IT1199207B (en) | 1984-05-25 | 1984-10-08 | PROCEDURE FOR PRODUCING A CEPHALOSPORINE AND AN INTERMEDIATE FOR IT |
| FR8415373A FR2564840B1 (en) | 1984-05-25 | 1984-10-08 | PROCESS FOR THE PRODUCTION OF A CEPHALOSPORIN, AN INTERMEDIATE FOR THE SYNTHESIS OF THIS CEPHALOSPORIN AND A PROCESS FOR THE PRODUCTION OF THIS INTERMEDIATE |
| DD84268154A DD234272A5 (en) | 1984-05-25 | 1984-10-08 | NEW METHOD FOR PRODUCING A CEPHALOSPORIN |
| CH4822/84A CH664965A5 (en) | 1984-05-25 | 1984-10-08 | METHOD FOR PRODUCING CEPHALOSPORINES. |
| CS847593A CS247185B2 (en) | 1984-05-25 | 1984-10-08 | Method of cephalosporine production |
| BE0/213793A BE900770A (en) | 1984-05-25 | 1984-10-08 | PROCESS FOR THE PRODUCTION OF A CEPHALOSPORIN, AN INTERMEDIATE FOR THE SYNTHESIS OF THIS CEPHALOSPORIN AND A PROCESS FOR THE PRODUCTION OF THIS INTERMEDIATE. |
| FI843959A FI80886C (en) | 1984-05-25 | 1984-10-09 | NYTT FOERFARANDE FOER FRAMSTAELLNING AV 7- / 2- (2-AMINOTIAZOL-4-YL) -2- (SYN) -SUBSTITUERAD OXIMINOACETAMIDO / CEFALOSPORIN. |
| AT0320884A AT386412B (en) | 1984-05-25 | 1984-10-09 | METHOD FOR PRODUCING A CEPHALOSPORINE |
| DK482184A DK482184A (en) | 1984-05-25 | 1984-10-09 | PROCEDURE FOR MANUFACTURING CEPHALOSPORINES AND INTERMEDIATES FOR USE |
| NL8403069A NL8403069A (en) | 1984-05-25 | 1984-10-09 | NEW PROCESS FOR PREPARING A CEPHALOSPORIN, AN INTERMEDIATE PRODUCT FOR THE CEPHALOSPORIN, AND METHOD FOR PREPARING THE INTERMEDIATE PRODUCT. |
| PL1984249955A PL144987B1 (en) | 1984-05-25 | 1984-10-09 | Method of obtaining cephalosporines |
| ES536633A ES536633A0 (en) | 1984-05-25 | 1984-10-09 | A PROCEDURE FOR THE PRODUCTION OF A CEPHALOSPORIN |
| RO121801A RO92777B (en) | 1984-05-25 | 1984-10-09 | Process for the preparation of thiazole derivatives |
| RO84115929A RO89363A (en) | 1984-05-25 | 1984-10-09 | PROCESS FOR THE PREPARATION OF CEFALOSPORINE |
| SE8405043A SE463973B (en) | 1984-05-25 | 1984-10-09 | PROCEDURES FOR PRODUCING A CEPHALOSPORIN, INTERMEDIATE PRODUCT FOR CEFALOSPORIN AND PROCEDURES FOR PRODUCING THE INTERMEDIATE PRODUCT |
| PL1984255588A PL145022B1 (en) | 1984-05-25 | 1984-10-09 | Method of obtaining novel derivatives of iminacetamide |
| PT79331A PT79331B (en) | 1984-05-25 | 1984-10-09 | Process for producing cephalosporins and of intermediate compounds used for preparing the same |
| AR298215A AR240827A1 (en) | 1984-05-25 | 1984-10-09 | PROCEDURE FOR THE PREPARATION OF A CEPHALOSPORIN AND COMPOUND EXCLUSIVELY AS AN INTERMEDIARY FOR THE PROCEDURE. |
| HU843797A HU192469B (en) | 1984-05-25 | 1984-10-09 | Process for production of derivatives of cefem-carbonic acid and their intermediers |
| NO844036A NO164772C (en) | 1984-05-25 | 1984-10-09 | PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINE DERIVATIVES. |
| HU863366A HU201034B (en) | 1984-05-25 | 1984-10-09 | Process for production of intermediere compositions of tiasole of cefalosporine |
| KR1019840006266A KR870001251B1 (en) | 1984-05-25 | 1984-10-10 | Process for preparing cephalosporin derivatives |
| IL73234A IL73234A (en) | 1984-05-25 | 1984-10-14 | Process for producing a cephalosporin,an intermediate for the cephalosporin,and a process for producing the intermediate |
| CS853551A CS247197B2 (en) | 1984-05-25 | 1985-05-17 | Method of new intermediate product production for cephalosporines |
| LU85909A LU85909A1 (en) | 1984-05-25 | 1985-05-22 | NOVEL PROCESS FOR THE PRODUCTION OF CEPHALOSPORIN, AN INTERMEDIATE PRODUCT FOR CEPHALOSPORINE AND PROCESS FOR THE PRODUCTION OF THE INTERMEDIATE PRODUCT |
| US06/753,942 US4656287A (en) | 1984-05-25 | 1985-07-11 | Aminothiazole intermediate for a cephalosporin |
| ES546296A ES8604181A1 (en) | 1984-05-25 | 1985-08-20 | Aminothiazole intermediate for a cephalosporin |
| NO853578A NO165293C (en) | 1984-05-25 | 1985-09-12 | NEW CEPHALOSPORIN INTERMEDIATES. |
| PH33048A PH21264A (en) | 1984-05-25 | 1985-11-12 | 2-(syn)-methoxyiminoacetamide derivatives and process for preparing thereof |
| US06/879,540 US4736026A (en) | 1984-05-25 | 1986-06-24 | Novel process for producing a cephalosporin |
| AT0024887A AT397086B (en) | 1984-05-25 | 1987-02-06 | Process for the preparation of novel 2-(2-aminothiazol-4- yl)-2-(syn)-alkoxyiminoacetamides |
| CA000532283A CA1231343A (en) | 1984-05-25 | 1987-03-17 | 2-(2-aminothiazol-4-yl)-2 (syn)-alkoxyiminoacetamide intermediates |
| KR1019870004590A KR870001250B1 (en) | 1984-05-25 | 1987-05-11 | Process for preparing intermediates for cephalosporin |
| IN515/CAL/87A IN163740B (en) | 1984-05-25 | 1987-07-03 | |
| FI882603A FI82830C (en) | 1984-05-25 | 1988-06-02 | NY FOERENING SOM AER ANVAENDBAR SOM MELLANPRODUKT VID FRAMSTAELLNING AV CEFALOSPORINER OCH FOERFARANDE FOER DESS FRAMSTAELLNING. |
| SE8804101A SE502208C2 (en) | 1984-05-25 | 1988-11-14 | Intermediate for cephalosporin and process for its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59104759A JPS60248691A (en) | 1984-05-25 | 1984-05-25 | Novel preparation of cephalosporin compound and its intermediate |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60089938A Division JPS60252473A (en) | 1985-04-27 | 1985-04-27 | 2-aminothiazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60248691A JPS60248691A (en) | 1985-12-09 |
| JPH026757B2 true JPH026757B2 (en) | 1990-02-13 |
Family
ID=14389414
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59104759A Granted JPS60248691A (en) | 1984-05-25 | 1984-05-25 | Novel preparation of cephalosporin compound and its intermediate |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS60248691A (en) |
| AU (1) | AU555399B2 (en) |
| DD (2) | DD234272A5 (en) |
| ES (1) | ES536633A0 (en) |
| HU (1) | HU201034B (en) |
| IN (1) | IN163562B (en) |
| PL (1) | PL145022B1 (en) |
| ZA (1) | ZA847713B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6172788A (en) * | 1984-09-17 | 1986-04-14 | Toyama Chem Co Ltd | Novel synthetic method of cephalosporin |
| GB8614710D0 (en) * | 1986-06-17 | 1986-07-23 | Ici Plc | Process |
-
1984
- 1984-05-25 JP JP59104759A patent/JPS60248691A/en active Granted
- 1984-09-29 IN IN701/CAL/84A patent/IN163562B/en unknown
- 1984-10-01 AU AU33751/84A patent/AU555399B2/en not_active Ceased
- 1984-10-01 ZA ZA847713A patent/ZA847713B/en unknown
- 1984-10-08 DD DD84268154A patent/DD234272A5/en not_active IP Right Cessation
- 1984-10-08 DD DD84290158A patent/DD253819A5/en not_active IP Right Cessation
- 1984-10-09 ES ES536633A patent/ES536633A0/en active Granted
- 1984-10-09 PL PL1984255588A patent/PL145022B1/en unknown
- 1984-10-09 HU HU863366A patent/HU201034B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PL255588A1 (en) | 1986-10-21 |
| JPS60248691A (en) | 1985-12-09 |
| DD234272A5 (en) | 1986-03-26 |
| AU555399B2 (en) | 1986-09-25 |
| IN163562B (en) | 1988-10-08 |
| ZA847713B (en) | 1986-05-28 |
| AU3375184A (en) | 1985-11-28 |
| ES8603895A1 (en) | 1986-01-01 |
| DD253819A5 (en) | 1988-02-03 |
| HU201034B (en) | 1990-09-28 |
| ES536633A0 (en) | 1986-01-01 |
| PL145022B1 (en) | 1988-07-30 |
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