JPH0629247B2 - 5-fluoronicotinic acid derivative and its salt - Google Patents
5-fluoronicotinic acid derivative and its saltInfo
- Publication number
- JPH0629247B2 JPH0629247B2 JP60009191A JP919185A JPH0629247B2 JP H0629247 B2 JPH0629247 B2 JP H0629247B2 JP 60009191 A JP60009191 A JP 60009191A JP 919185 A JP919185 A JP 919185A JP H0629247 B2 JPH0629247 B2 JP H0629247B2
- Authority
- JP
- Japan
- Prior art keywords
- salt
- general formula
- compound represented
- solvent
- acid
- 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
- 150000003839 salts Chemical class 0.000 title claims description 83
- BXZSBDDOYIWMGC-UHFFFAOYSA-N 5-fluoropyridine-3-carboxylic acid Chemical class OC(=O)C1=CN=CC(F)=C1 BXZSBDDOYIWMGC-UHFFFAOYSA-N 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
- 239000002904 solvent Substances 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 40
- 238000002844 melting Methods 0.000 description 39
- 230000008018 melting Effects 0.000 description 39
- -1 pivaloyloxymethyl group Chemical group 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000013078 crystal Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000002411 adverse Effects 0.000 description 8
- OCDVMYOLEVTDBO-UHFFFAOYSA-N methyl 2-(2,4-difluoroanilino)-5-fluoro-6-oxo-1h-pyridine-3-carboxylate Chemical compound COC(=O)C1=CC(F)=C(O)N=C1NC1=CC=C(F)C=C1F OCDVMYOLEVTDBO-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- ZGEXIEGODYEUSK-UHFFFAOYSA-N methyl 2-(2,4-difluoroanilino)-5-fluoro-6-methoxypyridine-3-carboxylate Chemical compound COC(=O)C1=CC(F)=C(OC)N=C1NC1=CC=C(F)C=C1F ZGEXIEGODYEUSK-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- PMBXCGGQNSVESQ-UHFFFAOYSA-N 1-Hexanethiol Chemical compound CCCCCCS PMBXCGGQNSVESQ-UHFFFAOYSA-N 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- BDFAOUQQXJIZDG-UHFFFAOYSA-N 2-methylpropane-1-thiol Chemical compound CC(C)CS BDFAOUQQXJIZDG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- UANRJKODPIQWKQ-UHFFFAOYSA-N ethyl 3-[6-(3-acetamidopyrrolidin-1-yl)-2-(2,4-difluoroanilino)-5-fluoropyridin-3-yl]-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC(F)=C(N2CC(CC2)NC(C)=O)N=C1NC1=CC=C(F)C=C1F UANRJKODPIQWKQ-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- NJPNCMOUEXEGBL-UHFFFAOYSA-N pyrrolidin-1-ium-3-ylazanium;dichloride Chemical compound Cl.Cl.NC1CCNC1 NJPNCMOUEXEGBL-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- VPAHTUQECJIGCK-UHFFFAOYSA-N (2-methylphenyl)sulfonyl 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=CC=C1C VPAHTUQECJIGCK-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
- ZRKMQKLGEQPLNS-UHFFFAOYSA-N 1-Pentanethiol Chemical compound CCCCCS ZRKMQKLGEQPLNS-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- NQUIRWXTTAMWIU-UHFFFAOYSA-N 1h-1,8-naphthyridin-4-one Chemical class C1=CC=C2C(O)=CC=NC2=N1 NQUIRWXTTAMWIU-UHFFFAOYSA-N 0.000 description 1
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 description 1
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 description 1
- AOOLLLAVLIDGQW-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-5-fluoro-6-(2,4,6-trimethylphenyl)sulfonyloxypyridine-3-carboxylic acid Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)OC1=NC(NC=2C(=CC(F)=CC=2)F)=C(C(O)=O)C=C1F AOOLLLAVLIDGQW-UHFFFAOYSA-N 0.000 description 1
- UQZOROGLEIVSRX-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-5-fluoro-6-methoxypyridine-3-carboxylic acid Chemical compound C1=C(F)C(OC)=NC(NC=2C(=CC(F)=CC=2)F)=C1C(O)=O UQZOROGLEIVSRX-UHFFFAOYSA-N 0.000 description 1
- HQXZJEJWQGGLLZ-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-5-fluoro-6-oxo-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(F)=C(O)N=C1NC1=CC=C(F)C=C1F HQXZJEJWQGGLLZ-UHFFFAOYSA-N 0.000 description 1
- QIIJYNSGOILNGW-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-5-fluoro-6-phenylpyridine-3-carbothioic s-acid Chemical compound OC(=S)C1=CC(F)=C(C=2C=CC=CC=2)N=C1NC1=CC=C(F)C=C1F QIIJYNSGOILNGW-UHFFFAOYSA-N 0.000 description 1
- BKWGQAINHJLMKG-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-5-fluoro-6-piperazin-1-ylpyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(F)=C(N2CCNCC2)N=C1NC1=CC=C(F)C=C1F BKWGQAINHJLMKG-UHFFFAOYSA-N 0.000 description 1
- JYQCRMPPBYIQAB-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-5-fluoropyridine-3-carboxylic acid Chemical compound FC1=C(C=CC(=C1)F)NC1=C(C(=O)O)C=C(C=N1)F JYQCRMPPBYIQAB-UHFFFAOYSA-N 0.000 description 1
- CZMCFDPBFJAZJD-UHFFFAOYSA-N 2-(2,4-difluoroanilino)-6-ethylsulfanyl-5-fluoropyridine-3-carboxylic acid Chemical compound C1=C(F)C(SCC)=NC(NC=2C(=CC(F)=CC=2)F)=C1C(O)=O CZMCFDPBFJAZJD-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-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
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QXUSBOKZKRAPTI-UHFFFAOYSA-N 3h-1,8-naphthyridin-4-one Chemical class C1=CC=C2C(=O)CC=NC2=N1 QXUSBOKZKRAPTI-UHFFFAOYSA-N 0.000 description 1
- HVORETHSDAJBJF-UHFFFAOYSA-N 5-fluoro-2-(4-fluoroanilino)-6-oxo-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(F)=C(O)N=C1NC1=CC=C(F)C=C1 HVORETHSDAJBJF-UHFFFAOYSA-N 0.000 description 1
- GRNQHQAWAJUDOV-UHFFFAOYSA-N 6-(3-aminopyrrolidin-1-yl)-2-(2,4-difluoroanilino)-5-fluoropyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C1=NC(NC=2C(=CC(F)=CC=2)F)=C(C(O)=O)C=C1F GRNQHQAWAJUDOV-UHFFFAOYSA-N 0.000 description 1
- BWFHVVNATYUVPZ-UHFFFAOYSA-N 6-(4-acetylpiperazin-1-yl)-2-(2,4-difluoroanilino)-5-fluoropyridine-3-carboxylic acid Chemical compound C1CN(C(=O)C)CCN1C1=NC(NC=2C(=CC(F)=CC=2)F)=C(C(O)=O)C=C1F BWFHVVNATYUVPZ-UHFFFAOYSA-N 0.000 description 1
- KWRPTSJANTUJQW-UHFFFAOYSA-N 6-chloro-2-(2,4-difluoroanilino)-5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(F)=C(Cl)N=C1NC1=CC=C(F)C=C1F KWRPTSJANTUJQW-UHFFFAOYSA-N 0.000 description 1
- 241001120493 Arene Species 0.000 description 1
- USHMMHVBVARJEG-UHFFFAOYSA-N CC(C=C1C)=CC(C)=C1S(OC(N=CC=C1)=C1C(OC)=O)(=O)=O Chemical compound CC(C=C1C)=CC(C)=C1S(OC(N=CC=C1)=C1C(OC)=O)(=O)=O USHMMHVBVARJEG-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- VPIAKHNXCOTPAY-UHFFFAOYSA-N Heptane-1-thiol Chemical compound CCCCCCCS VPIAKHNXCOTPAY-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
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical compound CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides 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
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- MLWPJXZKQOPTKZ-UHFFFAOYSA-N benzenesulfonyl benzenesulfonate Chemical compound C=1C=CC=CC=1S(=O)(=O)OS(=O)(=O)C1=CC=CC=C1 MLWPJXZKQOPTKZ-UHFFFAOYSA-N 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
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- INVLKTXYEVBVCC-UHFFFAOYSA-N ethyl 2-(2,4-difluoroanilino)-5-fluoro-6-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(F)=C(O)N=C1NC1=CC=C(F)C=C1F INVLKTXYEVBVCC-UHFFFAOYSA-N 0.000 description 1
- QRSCFNPVDJKGGB-UHFFFAOYSA-N ethyl 2-fluoro-3-oxopropanoate Chemical compound CCOC(=O)C(F)C=O QRSCFNPVDJKGGB-UHFFFAOYSA-N 0.000 description 1
- PIHWQJBFCRABCQ-UHFFFAOYSA-N ethyl 2-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound C1=CN=C2NC(=O)C(C(=O)OCC)=CC2=C1 PIHWQJBFCRABCQ-UHFFFAOYSA-N 0.000 description 1
- HSDKTLKBDJXJQU-UHFFFAOYSA-N ethyl 3-amino-3-iminopropanoate Chemical compound CCOC(=O)CC(N)=N HSDKTLKBDJXJQU-UHFFFAOYSA-N 0.000 description 1
- ZOVLHBKOIZXEOK-UHFFFAOYSA-N ethyl 3-imino-3-phenoxypropanoate;hydrochloride Chemical compound Cl.CCOC(=O)CC(=N)OC1=CC=CC=C1 ZOVLHBKOIZXEOK-UHFFFAOYSA-N 0.000 description 1
- KVDWVVFKJXRGLQ-UHFFFAOYSA-N ethyl 7-(3-acetamidopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(N3CC(CC3)NC(C)=O)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1=CC=C(F)C=C1F KVDWVVFKJXRGLQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- 238000002955 isolation Methods 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
- 159000000003 magnesium salts Chemical class 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- ATQGPUDIORZOAV-UHFFFAOYSA-N methyl 2-(2,4-difluoroanilino)-5-fluoro-6-methylsulfonyloxypyridine-3-carboxylate Chemical compound COC(=O)C1=CC(F)=C(OS(C)(=O)=O)N=C1NC1=CC=C(F)C=C1F ATQGPUDIORZOAV-UHFFFAOYSA-N 0.000 description 1
- LGOWYAHPWSCHQV-UHFFFAOYSA-N methyl 2-(2,4-difluoroanilino)-6-ethylsulfanyl-5-fluoropyridine-3-carboxylate Chemical compound C1=C(F)C(SCC)=NC(NC=2C(=CC(F)=CC=2)F)=C1C(=O)OC LGOWYAHPWSCHQV-UHFFFAOYSA-N 0.000 description 1
- JXAAHZKGLJESQW-UHFFFAOYSA-N methyl 3-amino-3-(2,4-difluorophenyl)iminopropanoate Chemical compound COC(=O)CC(N)=NC1=CC=C(F)C=C1F JXAAHZKGLJESQW-UHFFFAOYSA-N 0.000 description 1
- HJFFQOGLGYFMBT-UHFFFAOYSA-N methyl 3-amino-3-(2,4-difluorophenyl)iminopropanoate;hydrochloride Chemical compound Cl.COC(=O)CC(=N)NC1=CC=C(F)C=C1F HJFFQOGLGYFMBT-UHFFFAOYSA-N 0.000 description 1
- UGJPPPRNRFJDSC-UHFFFAOYSA-N methyl 3-amino-3-(4-fluorophenyl)iminopropanoate;hydrochloride Chemical compound Cl.COC(=O)CC(=N)NC1=CC=C(F)C=C1 UGJPPPRNRFJDSC-UHFFFAOYSA-N 0.000 description 1
- OINGLXMHAQEKMA-UHFFFAOYSA-N methyl 5-fluoro-2-(4-fluoroanilino)-6-oxo-1h-pyridine-3-carboxylate Chemical compound COC(=O)C1=CC(F)=C(O)N=C1NC1=CC=C(F)C=C1 OINGLXMHAQEKMA-UHFFFAOYSA-N 0.000 description 1
- PGCFLXMMCWKPDU-UHFFFAOYSA-N methyl 5-fluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=CC(F)=C1 PGCFLXMMCWKPDU-UHFFFAOYSA-N 0.000 description 1
- HWPRUABWMGIDGD-UHFFFAOYSA-N methyl 6-(3-aminopyrrolidin-1-yl)-2-(2,4-difluoroanilino)-5-fluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CC(F)=C(N2CC(N)CC2)N=C1NC1=CC=C(F)C=C1F HWPRUABWMGIDGD-UHFFFAOYSA-N 0.000 description 1
- DRTNYKBVSXCTKB-UHFFFAOYSA-N methyl 6-(4-acetylpiperazin-1-yl)-2-(2,4-difluoroanilino)-5-fluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CC(F)=C(N2CCN(CC2)C(C)=O)N=C1NC1=CC=C(F)C=C1F DRTNYKBVSXCTKB-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- DASJFYAPNPUBGG-UHFFFAOYSA-N naphthalene-1-sulfonyl chloride Chemical compound C1=CC=C2C(S(=O)(=O)Cl)=CC=CC2=C1 DASJFYAPNPUBGG-UHFFFAOYSA-N 0.000 description 1
- SEXOVMIIVBKGGM-UHFFFAOYSA-N naphthalene-1-thiol Chemical compound C1=CC=C2C(S)=CC=CC2=C1 SEXOVMIIVBKGGM-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- ZIPWMHWQZAESNH-UHFFFAOYSA-N o-methyl 2-(2,4-difluoroanilino)-5-fluoro-6-phenylpyridine-3-carbothioate Chemical compound COC(=S)C1=CC(F)=C(C=2C=CC=CC=2)N=C1NC1=CC=C(F)C=C1F ZIPWMHWQZAESNH-UHFFFAOYSA-N 0.000 description 1
- KZCOBXFFBQJQHH-UHFFFAOYSA-N octane-1-thiol Chemical compound CCCCCCCCS KZCOBXFFBQJQHH-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 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
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([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
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明はグラム陽性菌およびグラム陰性菌に強力な抗菌
作用を示す、一般式 で表わされる１−アリール−1,4−ジヒドロ−４−オキ
ソナフチリジン誘導体およびその塩の重要な中間体であ
る一般式 で表わされる５−フルオロニコチン酸誘導体およびその
塩に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention has a general formula showing a strong antibacterial action against Gram-positive and Gram-negative bacteria. A 1-aryl-1,4-dihydro-4-oxonaphthyridine derivative represented by The present invention relates to a 5-fluoronicotinic acid derivative and a salt thereof.
一般式(I)で表わされる１−アリール−1,4−ジヒドロ−
４−オキソナフチリジン誘導体およびその塩は、第２４
回インターサイエンス・コンフアランス・オン・アンチ
ミクロバイアル・エージエンツ・アンド・ケモセラビー
（Ｉ．Ｃ．Ａ．Ａ．Ｃ．）要旨集第102〜104頁および特
願昭59-84963号（特開昭60-228479号公報参照）におい
て、グラム陽性菌およびグラム陰性菌に強い抗菌力を示
し、経口または非経口投与により高い血中濃度が得ら
れ、かつ安全性が高いなど優れた性質を有することが示
されている。しかしこれらの化合物を製造する方法とし
て、一般式（II）で表わされる５−フルオロニコチン酸
誘導体またはその塩を経由する方法は全く知られていな
い。1-aryl-1,4-dihydro-represented by the general formula (I)
4-oxonaphthyridine derivatives and salts thereof can be prepared according to the 24th
Annual Interscience Conference on Anti-micro Vial Ages and Chemocerabie (I.C.A.A.C.) Abstracts 102-104 and Japanese Patent Application No. 59-84963 No. 228479), it shows strong antibacterial activity against Gram-positive and Gram-negative bacteria, high blood concentration is obtained by oral or parenteral administration, and it has excellent properties such as high safety. ing. However, as a method for producing these compounds, a method via a 5-fluoronicotinic acid derivative represented by the general formula (II) or a salt thereof is not known at all.
本発明の目的は一般式(I)で表わされる１−アリール−
1,4−ジヒドロ−４−オキソナフチリジン誘導体および
その塩を製造するための新規な中間体を提供することに
ある。The object of the present invention is 1-aryl-represented by the general formula (I)
It is to provide a novel intermediate for producing a 1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof.
かかる状況下において、本発明者らは鋭意研究した結
果、一般式（II）で表わされる５−フルオロニコチン酸
誘導体およびその塩が、中間体として有用であることを
見出し、本発明を完成するに至つた。Under such circumstances, the present inventors have conducted extensive studies, and as a result, found that the 5-fluoronicotinic acid derivative represented by the general formula (II) and a salt thereof were useful as intermediates, and completed the present invention. It arrived.
以下、本発明を詳細に説明する。Hereinafter, the present invention will be described in detail.
本明細書中でR1で示されるカルボキシル保護形成基とし
ては通常当該分野で使用されるもの、たとえば、アルキ
ル基、ベンジル基、ピバロイルオキシメチル基、トリメ
チルシリル基など、特開昭59-80665号公報などに記載さ
れた通常のカルボキシル基の保護基が挙げられる。As the carboxyl-protecting group represented by R 1 in the present specification, those usually used in the art, for example, an alkyl group, a benzyl group, a pivaloyloxymethyl group, a trimethylsilyl group and the like, JP-A-59-80665 can be used. Ordinary protecting groups for carboxyl groups described in, for example, JP-A Nos.
R2におけるハロゲン原子としては、フッ素原子、塩素原
子、臭素原子、ヨウ素原子；アルコキシ基としては、た
とえば、メトキシ、エトキシ、ｎ−プロポキシ、イソブ
トキシ、ペンチルオキシ、ヘキシルオキシ、ヘプチルオ
キシ、オクチルオキシ、ドデシルオキシなどのアルコキ
シ基；アルキルチオ基としては、たとえば、メチルチ
オ、エチルチオ、ｎ−プロピルチオ、イソブチルチオ、
ペンチルチオ、ヘキシルチオ、ヘプチルチオ、オクチル
チオ、ドデシルチオなどのアルキルチオ基；アリールチ
オ基としては、たとえば、フエニルチオ、ナフチルチオ
など；アルカンスルホニルオキシ基としては、たとえ
ば、メタンスルホニルオキシ、エタンスルホニルオキ
シ、イソプロパンスルホニルオキシ、tert.−ブタンス
ルホニルオキシなど；アレーンスルホニルオキシ基とし
ては、たとえば、ベンゼンスルホニルオキシ、ナフタレ
ンスルホニルオキシなど；アミノ基が保護されていても
よい３−アミノピロリジニル基およびイミノ基が保護さ
れていてもよいピペラジニル基におけるアミノ基および
イミノ基の保護基としては、通常当該分野で使用される
もの、たとえば、ホルミル、アセチルなどのアシル基な
どが挙げられる。The halogen atom in R 2 is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the alkoxy group is, for example, methoxy, ethoxy, n-propoxy, isobutoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, dodecyl. Alkoxy groups such as oxy; alkylthio groups include, for example, methylthio, ethylthio, n-propylthio, isobutylthio,
Alkylthio groups such as pentylthio, hexylthio, heptylthio, octylthio, dodecylthio; examples of arylthio groups include phenylthio, naphthylthio, etc .; examples of alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, tert. -Butanesulfonyloxy, etc .; arenesulfonyloxy groups, for example, benzenesulfonyloxy, naphthalenesulfonyloxy, etc .; amino group may be protected, 3-aminopyrrolidinyl group and imino group may be protected. Examples of the protecting group for the amino group and imino group in the piperazinyl group include those commonly used in the art, for example, acyl groups such as formyl and acetyl.
上記したうち、アルコキシ、アルキルチオ、アリールチ
オ、アルカンスルホニルオキシおよびアレーンスルホニ
ルオキシ基は置換基を有していてもよく、これらの置換
基としては、たとえば、フツ素原子、塩素原子、臭素素
子、ヨウ素原子などのハロゲン原子；ニトロ基；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−ブチルなどのア
ルキル基；メトキシ、エトキシ、ｎ−プロポキシ、イソ
プロポキシ、ｎ−ブトキシ、イソブトキシ、sec.−ブト
キシ、tert−ブトキシなどのアルコキシなどが挙げられ
る。Among the above, alkoxy, alkylthio, arylthio, alkanesulfonyloxy and arenesulfonyloxy groups may have a substituent, and these substituents include, for example, fluorine atom, chlorine atom, bromine element, iodine atom. Halogen atom such as; Nitro group; Alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert-butyl; methoxy, ethoxy, n-propoxy, isopropoxy, n- Examples thereof include butoxy, isobutoxy, sec.-butoxy, alkoxy such as tert-butoxy, and the like.
また、一般式(I)および（II）で表わされる化合物の塩
としては、通常知られているアミノ基、イミノ基などの
塩基性基またはカルボキシル基、ヒドロキシル基などの
酸性基における塩が挙げられる。Examples of the salts of the compounds represented by the general formulas (I) and (II) include salts of commonly known basic groups such as amino groups and imino groups, or carboxyl groups, and acidic groups such as hydroxyl groups. .
塩基性基における塩としては、たとえば、塩酸、硫酸な
どの鉱酸との塩；シユウ酸、クエン酸、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、ｐ
−トルエンスルホン酸、ナフタレンスルホン酸などのス
ルホン酸との塩を、酸性基における塩としては、たとえ
ば、ナトリウム、カリウムなどのアルカリ金属との塩；
カルシウム、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；プロカイン、ジベンジルアミン、
Ｎ，Ｎ−ジベンジルエチレンジアミン、トリエチルアミ
ン、ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ−メチル
ピペリジン、ジエチルアミン、ジシクロヘキシルアミン
などの含窒素有機塩基との塩を挙げることができる。Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with organic carboxylic acids such as oxalic acid, citric acid and trifluoroacetic acid; methanesulfonic acid, p
A salt with a sulfonic acid such as toluenesulfonic acid or naphthalenesulfonic acid, and a salt with an alkali metal such as sodium or potassium as an acid group salt;
Salts with alkaline earth metals such as calcium and magnesium; ammonium salts; procaine, dibenzylamine,
Examples thereof include salts with nitrogen-containing organic bases such as N, N-dibenzylethylenediamine, triethylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, diethylamine and dicyclohexylamine.
次に、本発明化合物の製造法について詳説する。Next, the method for producing the compound of the present invention will be described in detail.
一般式（II）で表わされる化合物またはその塩は、たと
えば、つぎの製造ルートに従つて製造することができ
る。The compound represented by the general formula (II) or a salt thereof can be produced, for example, according to the following production route.
また、上記式（IIa）〜（IIe）、(V)および（VI）にお
ける化合物の塩としては、一般式(I)および（II）で表
わされる化合物で説明したと同様の塩が挙げられる。 In addition, as salts of the compounds in the above formulas (IIa) to (IIe), (V) and (VI), the same salts as those described for the compounds represented by the general formulas (I) and (II) can be mentioned.
(1)一般式（IIa）で表わされる化合物またはその塩の製
法 一般式（IIa）で表わされる化合物またはその塩は、縮
合剤の存在下または不存在下、一般式(V)で表わされる
化合物またはその塩に、一般式（VI）で表わされる化合
物またはその塩を反応させることによつて得ることがで
きる。(1) Method for producing a compound represented by the general formula (IIa) or a salt thereof A compound represented by the general formula (IIa) or a salt thereof is a compound represented by the general formula (V) in the presence or absence of a condensing agent. Alternatively, it can be obtained by reacting the salt thereof with a compound represented by the general formula (VI) or a salt thereof.
本反応を溶媒中で行う場合、使用される溶媒としては反
応に悪影響を与えないものであれば特に限定されない
が、具体的には、水；メタノール、エタノール、イソプ
ロパノール、ブタソール、エチレングリコール、メチル
セロソルブなどのアルコール類；ベンゼン、トルエンな
どの芳香族炭化水素類；塩化メチレン、クロロホルム、
ジクロロエタンなどのハロゲン化炭化水素類；テトラヒ
ドロフラン、ジオキサン、アニソール、ジエチレングリ
コールジメチルエーテル、ジメチルセロソルブなどのエ
ーテル類；アセトニトリルなどのニトリル類；アセト
ン、メチルエチルケトンなどのケトン類；酢酸エチル、
酢酸メチルなどのエステル類；Ｎ，Ｎ−ジメチルホルム
アミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド
類；ジメチルスルホキシドなどのスルホキシド類などが
挙げられる。これらの溶媒を２種若しくはそれ以上混合
して使用してもよい。When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; methanol, ethanol, isopropanol, butasol, ethylene glycol, methyl cellosolve. Alcohols such as; aromatic hydrocarbons such as benzene and toluene; methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane; ethers such as tetrahydrofuran, dioxane, anisole, diethylene glycol dimethyl ether, dimethyl cellosolve; nitriles such as acetonitrile; ketones such as acetone and methyl ethyl ketone; ethyl acetate,
Examples thereof include esters such as methyl acetate; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide. You may use these solvents in mixture of 2 or more types.
縮合剤としては、たとえば、水酸化ナトリウム、水酸化
カリウム、tert.−ブトキシカリウム、水酸化ナトリウ
ム、ナトリウムメチラート、ナトリウムエチラート、カ
リウムメチラート、カリウムエチラートなどが挙げられ
る。Examples of the condensing agent include sodium hydroxide, potassium hydroxide, tert.-butoxy potassium, sodium hydroxide, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate and the like.
本反応において、一般式（VI）で表わされる化合物また
はその塩の使用量は、特に限定されないが、通常、一般
式(V)で表わされる化合物またはその塩に対して当モル
以上、好ましくは1.0〜3.0倍モルである。また、本反応
は通常０〜150℃、好ましくは25〜100℃で５分〜３０時
間実施すればよい。In this reaction, the amount of the compound represented by the general formula (VI) or a salt thereof is not particularly limited, and is usually equimolar or more, preferably 1.0 mol or more with respect to the compound represented by the general formula (V) or a salt thereof. ~ 3.0 times mole. Further, this reaction may be carried out usually at 0 to 150 ° C., preferably 25 to 100 ° C. for 5 minutes to 30 hours.
(2)一般式（IIb）で表わされる化合物またはその塩の製
法（アルキル化） 一般式（IIb）で表わされる化合物またはその塩は、一
般式（IIa）で表わされる化合物またはその塩をアルキ
ル化反応に付すことにより得ることができる。使用され
るアルキル化剤としては特に限定されないが、好ましい
ものとして、ジアゾアルカン、ジアルキル硫酸およびハ
ロゲン化アルキルなどが挙げられる。(2) Method for producing compound represented by general formula (IIb) or a salt thereof (alkylation) The compound represented by general formula (IIb) or a salt thereof is obtained by alkylating a compound represented by general formula (IIa) or a salt thereof. It can be obtained by subjecting it to a reaction. The alkylating agent used is not particularly limited, but preferred examples include diazoalkanes, dialkylsulfates and alkyl halides.
(イ)ジアゾアルカンによるアルキル化反応 一般式（IIb）で表わされる化合物またはその塩は、一
般式（IIa）で表わされる化合物またはその塩にジアゾ
アルカンを反応させることによつて得ることができる。
本反応を溶媒中で行う場合使用される溶媒としては、反
応に悪影響を与えないものであれば特に限定されない
が、具体的には、メタノール、エタノール、イソプロパ
ノールなどのアルコール類；ジエチルエーテル、テトラ
ヒドロフラン、ジオキサンなどのエーテル類；アセト
ン、メチルエチルケトンなどのケトン類；酢酸エチル、
酢酸メチルなどのエステル類；ベンゼン、トルエンなど
の芳香族炭化水素類などが挙げられる。これらの溶媒を
２種若しくはそれ以上混合して使用してもよい。ジアゾ
アルカンとしては、たとえば、ジアゾメタン、ジアゾエ
タンなどが挙げられ、その使用量は、一般式（IIa）で
表わされる化合物またはその塩に対して当モル以上、好
ましくは1.0〜1.5倍モルである。また本反応は通常０〜
５０℃、好ましくは０〜２５℃で、５分〜３０時間実施
すればよい。(A) Alkylation Reaction with Diazoalkane The compound represented by the general formula (IIb) or a salt thereof can be obtained by reacting the compound represented by the general formula (IIa) or a salt thereof with a diazoalkane.
When the reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, alcohols such as methanol, ethanol and isopropanol; diethyl ether, tetrahydrofuran, Ethers such as dioxane; ketones such as acetone and methyl ethyl ketone; ethyl acetate,
Examples thereof include esters such as methyl acetate; aromatic hydrocarbons such as benzene and toluene. You may use these solvents in mixture of 2 or more types. Examples of the diazoalkane include diazomethane, diazoethane and the like, and the amount thereof used is equimolar or more, preferably 1.0 to 1.5 times the molar amount of the compound represented by the general formula (IIa) or a salt thereof. The reaction is usually 0 to
It may be carried out at 50 ° C., preferably 0 to 25 ° C., for 5 minutes to 30 hours.
(ロ)ジアルキル硫酸によるアルキル化反応 一般式（IIb）で表わされる化合物またはその塩は一般
式（IIa）で表わされる化合物またはその塩に、脱酸剤
の存在下または不存在下、ジアルキル硫酸を反応させる
ことによつて得ることができる。本反応を溶媒中で行う
場合、使用される溶媒としては反応に悪影響を与えない
ものであれば特に限定されないが、具体的には、水；ア
セトン、メチルエチルケトンなどのケトン類；酢酸メチ
ル、酢酸エチルなどのエステル類；テトラヒドロフラ
ン、ジオキサンなどのエーテル類；Ｎ，Ｎ−ジメチルホ
ルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミ
ド類；ジメチルスルホキシドなどのスルホキシド類など
が挙げられる。これらの溶媒を２種若しくはそれ以上混
合して使用してもよい。脱酸剤としては、たとえば、水
酸化アルカリ、炭酸アルカリなどの無機塩基が挙げられ
る。ジアルキル硫酸としては、たとえば、ジメチル硫
酸、ジエチル硫酸などが挙げられる。(B) Alkylation reaction with dialkylsulfuric acid A compound represented by the general formula (IIb) or a salt thereof can be prepared by adding a dialkylsulfuric acid to a compound represented by the general formula (IIa) or a salt thereof in the presence or absence of a deoxidizing agent. It can be obtained by reacting. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; ketones such as acetone and methyl ethyl ketone; methyl acetate, ethyl acetate And the like; ethers such as tetrahydrofuran and dioxane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. You may use these solvents in mixture of 2 or more types. Examples of the deoxidizing agent include inorganic bases such as alkali hydroxide and alkali carbonate. Examples of the dialkyl sulfuric acid include dimethyl sulfuric acid and diethyl sulfuric acid.
本反応においてジアルキル硫酸および所望に応じて使用
される脱酸剤の使用量は、一般式（IIa）で表わされる
化合物またはその塩に対してそれぞれ当モル以上、好ま
しくは１〜２倍モルである。本反応は通常０〜150℃、
好ましくは０〜５０℃で、５分〜３０時間実施すればよ
い。In this reaction, the amount of the dialkyl sulfuric acid and the deoxidizing agent optionally used is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the formula (IIa) or a salt thereof. . This reaction is usually 0 ~ 150 ℃,
Preferably, it may be carried out at 0 to 50 ° C. for 5 minutes to 30 hours.
(ハ)ハロゲン化アルキルによるアルキル化反応 一般式（IIb）で表わされる化合物またはその塩は、脱
酸剤の存在下または不存在下、一般式（IIa）で表わさ
れる化合物またはその塩にハロゲン化アルキルを反応さ
せることによつて得ることができる。本反応を溶媒中で
行う場合、使用される溶媒としては反応に悪影響を与え
ないものであれば特に限定されないが、具体的には、塩
化メチレン、クロロホルムなどのハロゲン化炭化水素
類；ジエチルエーテル、テトラヒドロフラン、ジオキサ
ンなどのエーテル類；Ｎ，Ｎ−ジメチルホルムアミド、
Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類；ジメチ
ルスルホキシドなどのスルホキシド類などが挙げられ
る。これらの溶媒は２種若しくはそれ以上混合して使用
してもよい。脱酸剤としては、たとえば、炭酸アルカリ
などの無機塩基、またはトリメチルアミン、トリエチル
アミン、トリブチルアミン、ピリジン、Ｎ−メチルピペ
リジン、Ｎ−メチルモルホリン、ルチジン、コリジンな
どの有機塩基が挙げられる。ハロゲン化アルキルとして
は、たとえば、ヨウ化メチル、臭化メチル、臭化エチル
などが挙げられる。(C) Alkylation Reaction with Alkyl Halide The compound represented by the general formula (IIb) or a salt thereof is halogenated to the compound represented by the general formula (IIa) or a salt thereof in the presence or absence of a deoxidizing agent. It can be obtained by reacting an alkyl. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, halogenated hydrocarbons such as methylene chloride and chloroform; diethyl ether, Ethers such as tetrahydrofuran and dioxane; N, N-dimethylformamide,
Examples thereof include amides such as N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide. You may use these solvents in mixture of 2 or more types. Examples of the deoxidizing agent include inorganic bases such as alkali carbonate, and organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine and collidine. Examples of the alkyl halide include methyl iodide, methyl bromide, ethyl bromide and the like.
本反応において、ハロゲン化アルキルおよび所望に応じ
て使用される脱酸剤の使用量は、一般式（IIa）で表わ
される化合物またはその塩に対して当モル以上、好まし
くは１〜２倍モルである。本反応は、通常０〜150℃、
好ましくは０〜５０℃で、５分〜30時間実施すればよ
い。In this reaction, the amount of the alkyl halide and, if desired, the deoxidizing agent used is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the general formula (IIa) or a salt thereof. is there. This reaction is usually 0 ~ 150 ℃,
Preferably, it may be carried out at 0 to 50 ° C. for 5 minutes to 30 hours.
(3)一般式（IIc）で表わされる化合物またはその塩の製
法 一般式（IIc）で表わされる化合物またはその塩は、一
般式（IIa）で表わされる化合物またはその塩をハロゲ
ン化またはスルホニル化することによつて得ることがで
きる。(3) Method for producing a compound represented by the general formula (IIc) or a salt thereof A compound represented by the general formula (IIc) or a salt thereof is obtained by halogenating or sulfonylating a compound represented by the general formula (IIa) or a salt thereof. It can be obtained.
(イ)ハロゲン化反応 一般式（IIc）で表わされる化合物またはその塩のう
ち、R2cがハロゲン原子である化合物は、一般式（IIa）
で表わされる化合物またはその塩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。本反応を溶媒中
で行う場合、使用される溶媒としては反応に悪影響を与
えないものであれば特に限定されないが、具体的には、
ベンゼン、トルエン、キシレンなどの芳香族炭化水素
類；塩化メチレン、クロロホルム、ジクロロエタンなど
のハロゲン化炭化水素類；Ｎ，Ｎ−ジメチルホルムアミ
ド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類など
が挙げられる。これらの溶媒は２種若しくはそれ以上混
合して使用してもよい。ハロゲン化剤としては、たとえ
ば、オキシ塩化リン、オキシ臭化リン、五塩化リン、五
臭化リン、三塩化リン、塩化チオニル、ホスゲンなどが
挙げられ、これらの試剤を２種若しくはそれ以上混合し
て使用してもよく、これらのハロゲン化剤は溶媒として
用いてもよい。ハロゲン化剤の使用量は、一般式（II
a）で表わされる化合物またはその塩に対して当モル以
上である。本反応は、通常０〜１５０℃好ましくは５０
〜110℃で、３０分〜３０時間実施すればよい。(A) Halogenation reaction Among the compounds represented by the general formula (IIc) or salts thereof, compounds in which R 2c is a halogen atom are represented by the general formula (IIa)
It can be obtained by reacting a compound represented by or a salt thereof with a halogenating agent. When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, but specifically,
Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide. You may use these solvents in mixture of 2 or more types. Examples of the halogenating agent include phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, thionyl chloride, phosgene and the like, and two or more kinds of these agents are mixed. These halogenating agents may be used as a solvent. The amount of the halogenating agent used is determined by the formula (II
The amount is equimolar or more based on the compound represented by a) or a salt thereof. This reaction is generally 0 to 150 ° C., preferably 50.
It may be carried out at ˜110 ° C. for 30 minutes to 30 hours.
(ロ)スルホニル化反応 一般式（IIc）で表わされる化合物またはその塩のう
ち、R2cが置換基を有していてもよいアルカンスルホニ
ルオキシまたはアレーンスルホニルオキシ基である化合
物は、一般式（IIa）で表わされる化合物またはその塩
に、脱酸剤の存在下または不存在下、スルホニル化剤を
反応させることによつて得ることができる。(B) Sulfonylation reaction Among the compounds represented by the general formula (IIc) or salts thereof, the compound in which R 2c is an optionally substituted alkanesulfonyloxy or arenesulfonyloxy group is represented by the general formula (IIa ), Or a salt thereof, with a sulfonylating agent in the presence or absence of a deoxidizing agent.
本反応を溶媒中で行う場合、使用される溶媒としては反
応に悪影響を与えないものであれば特に限定されない
が、具体的には、水；ベンゼン、トルエン、キシレンな
どの芳香族炭化水素類；ジオキサン、テトラヒドロフラ
ン、アニソール、ジエチレングリコールジメチルエーテ
ルなどのエーテル類；塩化メチレン、クロロホルム、ジ
クロロエタンなどのハロゲン化炭化水素類；アセトン、
メチルエチルケトンなどのケトン類；Ｎ，Ｎ−ジメチル
ホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのア
ミド類；ジメチルスルホキシドなどのアスホキシド類；
ヘキサメチルホスホルアミド；ピリジンなどが挙げられ
る。これらの溶媒は２種若しくはそれ以上混合して使用
してもよい。脱酸剤としては、たとえば、トリエチルア
ミン、ジイソプロピルエチルアミン、1,8−ジアザビシ
クロ−〔5,4,0〕−ウンデセ−７−エン（ＤＢＵ）、ピ
リジン、tert.−ブトキシカリウム、炭酸カリウム、炭
酸ナトリウム、水素化ナトリウムなどの有機または無機
塩基が挙げられる。スルホニル化剤としては、たとえ
ば、メタンスルホニルクロリド、エタンスルホニルクロ
リド、イソプロパンスルホニルクロリド、tert.−ブタ
ンスルホニルクロリドなどのアルカンスルホニルハロゲ
ニド類、ベンゼンスルホニルクロリド、トルエンスルホ
ニルクロリド、２−ニトロベンゼンスルホニルクロリ
ド、メシチレンスルホニルクロリド、2,4,6−トリイソ
プロピルベンゼンスルホニルクロリド、ナフタレンスル
ホニルクロリドなどのアレーンスルホニルハロゲニド
類、ベンゼンスルホン酸無水物、トルエンスルホン酸無
水物、メタンスルホン酸無水物などのアルカン−または
アレーンースルホン酸無水物などが挙げられる。When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, water; aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole and diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; acetone,
Ketones such as methyl ethyl ketone; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; asphoxides such as dimethyl sulfoxide;
Hexamethylphosphoramide; pyridine and the like. You may use these solvents in mixture of 2 or more types. Examples of the deoxidizing agent include triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5,4,0] -undec-7-ene (DBU), pyridine, tert.-butoxypotassium, potassium carbonate, sodium carbonate, Organic or inorganic bases such as sodium hydride are mentioned. Examples of the sulfonylating agent include alkanesulfonyl halides such as methanesulfonyl chloride, ethanesulfonyl chloride, isopropanesulfonyl chloride, tert.-butanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride and mesitylene. Arenesulfonyl halides such as sulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride and naphthalenesulfonyl chloride, alkanes such as benzenesulfonic anhydride, toluenesulfonic anhydride and methanesulfonic anhydride, or arenes. Examples thereof include sulfonic acid anhydride.
スルホニル化剤および所望に応じて用いられる脱酸剤の
使用量は、一般式（IIa）で表わされる化合物またはそ
の塩に対して、当モル以上、好ましくは１〜２倍モルで
ある。本反応は通常−10〜150℃、好ましくは０〜80℃
で、５分〜３０時間実施すればよい。The amount of the sulfonylating agent and the deoxidizing agent used as required is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the general formula (IIa) or a salt thereof. This reaction is generally -10 to 150 ° C, preferably 0 to 80 ° C.
Then, it may be carried out for 5 minutes to 30 hours.
(4)一般式（IId）で表わされる化合物またはその塩の製
法 一般式（IId）で表わされる化合物またはその塩は、一
般式（IIc）で表わされる化合物またはその塩に、脱酸
剤の存在下、一般式（VII）で表わされるチオール類を
反応させることによつて得ることができる。(4) Method for producing a compound represented by the general formula (IId) or a salt thereof A compound represented by the general formula (IId) or a salt thereof is prepared by adding a deoxidizing agent to the compound represented by the general formula (IIc) or a salt thereof. It can be obtained by reacting a thiol represented by the general formula (VII) below.
本反応を溶媒中で行う場合、使用される溶媒としては反
応に悪影響を与えないものであれば特に限定されない
が、具体的には、ベンゼン、トルエン、キシレンなどの
芳香族炭化水素類；ジオキサン、テトラヒドロフラン、
アニソール、ジエチレングリコールジエチルエーテルな
どのエーテル類；塩化メチレン、クロロホルム、ジクロ
ロエタンなどのハロゲン化炭化水素類；Ｎ，Ｎ−ジメチ
ルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどの
アミド類；ジメチルスルホキシドなどのスルホキシド類
などが挙げられる。これらの溶媒は２種若しくはそれ以
上混合して使用してもよい。脱酸剤としては、(3)−(ロ)
で挙げたと同様の無機または有機塩基が挙げられる。When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, Tetrahydrofuran,
Ethers such as anisole and diethylene glycol diethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide Can be mentioned. You may use these solvents in mixture of 2 or more types. As the deoxidizer, (3)-(B)
The same inorganic or organic bases as those mentioned above can be used.
一般式（VII）で表わされるチオール類としては、たと
えば、メタンチオール、エタンチオール、ｎ−プロパン
チオール、イソブタンチオール、ペンタンチオール、ヘ
キサンチオール、ヘプタンチオール、オクタンチオー
ル、ドデカンチオール、チオフエノール、ナフタレンチ
オールなどが挙げられる。Examples of the thiols represented by the general formula (VII) include methanethiol, ethanethiol, n-propanethiol, isobutanethiol, pentanethiol, hexanethiol, heptanethiol, octanethiol, dodecanethiol, thiophenol and naphthalenethiol. Is mentioned.
一般式（VII）で表わされるチオール類および脱酸剤の
使用量は、一般式（IIc）で表わされる化合物またはそ
の塩に対して当モル以上、好ましくは１〜２倍モルであ
る。本反応は、０〜150℃、好ましくは０〜７０℃で、
５分〜３０時間実施すればよい。The amount of the thiol represented by the general formula (VII) and the deoxidizing agent used is equimolar or more, preferably 1 to 2 times the molar amount of the compound represented by the general formula (IIc) or a salt thereof. This reaction is carried out at 0 to 150 ° C, preferably 0 to 70 ° C,
It may be carried out for 5 minutes to 30 hours.
(5)一般式（IIe）で表わされる化合物またはその塩の製
法 一般式（IIe）で表わされる化合物またはその塩は、一
般式（IIc）で表わされる化合物またはその塩に、脱酸
剤の存在下または不存在下に一般式（VIII）で表わされ
るアミノ類を反応させることによつて得ることができ
る。(5) Method for producing a compound represented by the general formula (IIe) or a salt thereof A compound represented by the general formula (IIe) or a salt thereof is obtained by adding a deoxidizing agent to the compound represented by the general formula (IIc) or a salt thereof. It can be obtained by reacting the amino compound represented by the general formula (VIII) with or without.
本反応を溶媒中で行う場合、使用される溶媒としては反
応に悪影響を与えないものであれば特に限定されない
が、具体的には、(4)で挙げたと同様のものが使用され
る。When this reaction is carried out in a solvent, the solvent used is not particularly limited as long as it does not adversely affect the reaction, and specifically, the same solvents as those mentioned in (4) are used.
また、所望に応じて用いられる脱酸剤としては、たとえ
ば、(3)−(ロ)で挙げたと同様のものが使用される。Further, as the deoxidizing agent used as desired, for example, the same ones as mentioned in (3)-(b) are used.
一般式（VIII）で表わされるアミン類の使用量は脱酸剤
を用いない場合一般式（IIc）で表わされる化合物また
はその塩に対して当モル以上、好ましくは２〜５倍モル
である。特に、脱酸剤を適宜使用することによつて一般
式（VIII）で表わされるアミン類の使用量を減らすこと
ができる。本反応は、通常０〜150℃、好ましくは１５
〜１００℃で、５分〜３０時間実施すればよい。The amount of the amines represented by the general formula (VIII) to be used is equimolar or more, preferably 2 to 5 times the molar amount of the compound represented by the general formula (IIc) or a salt thereof when a deoxidizing agent is not used. In particular, the amount of the amines represented by the general formula (VIII) can be reduced by properly using a deoxidizing agent. This reaction is generally 0 to 150 ° C., preferably 15
It may be carried out at -100 ° C for 5 minutes to 30 hours.
以上説明した一般式（IIa），（IIb），（IIc），（II
d）および（IIe）の化合物が保護基を有する場合は、所
望に応じ、公知方法により保護基を脱離させ、それぞれ
対応する遊離の化合物へ導くことができる。また、一般
式（IIa），（IIb），（IIc），（IId）および（IIe）
の化合物が遊離の化合物である場合は、所望に応じて、
自体公知の塩形成反応または保護形成反応に付してそれ
ぞれ対応する化合物の塩または保護基を有する化合物へ
導くことができる。The general formulas (IIa), (IIb), (IIc), (II
When the compounds d) and (IIe) have a protecting group, the protecting group can be eliminated by a known method, if desired, to give a corresponding free compound. In addition, the general formulas (IIa), (IIb), (IIc), (IId) and (IIe)
If the compound is a free compound, if desired,
A salt-forming reaction or a protection-forming reaction known per se can be carried out to give a salt of the corresponding compound or a compound having a protecting group.
つぎに、上記製造法の原料化合物である一般式（V）お
よび（VI）の化合物の製造法について説明する。Next, a method for producing the compounds of the general formulas (V) and (VI), which are the raw material compounds of the above production method, will be explained.
一般式（V）の化合物は、英国特許第1409987号に記載の
方法に準じて一般式（IX） 〔式中、R1は前記したと同じ意味を有する。〕 の化合物またはその塩に一般式（X） 〔式中、Ｘは前記したと同様の意味を有する。〕 の化合物を反応させることによつて得られる。なお、一
般式（IX）の化合物塩としては、たとえば、塩酸、臭化
水素酸などとの塩が挙げられる。また、一般式（VI）の
化合物は、ブレタン・ド・ラ・ソシエテ・シミク・ドウ
・フランス（Bull.Soc.Chim.Fr.）1165〜1169（1975）
に記載の方法に従つて製造することができる。The compound of the general formula (V) can be obtained by the general formula (IX) according to the method described in British Patent No. 1409987. [In the formula, R 1 has the same meaning as described above. ] The compound or salt thereof of the general formula (X) [In the formula, X has the same meaning as described above. ] It is obtained by reacting the compound of. Examples of the compound salt of general formula (IX) include salts with hydrochloric acid, hydrobromic acid and the like. Further, the compound represented by the general formula (VI) is represented by Bretin de la Societe Simique de France (Bull.Soc.Chim.Fr.) 1165 to 1169 (1975).
It can be manufactured according to the method described in.
以上説明したそれぞれの反応によつて得られる化合物は
常法によつて単離または分離することができ、また単離
または分離することなくつぎの反応に使用することもで
きる。The compound obtained by each of the reactions described above can be isolated or separated by a conventional method, or can be used in the next reaction without isolation or separation.
このようにして得られた一般式（II）で表わされる化合
物またはその塩は、たとえば、次に示すルートによつて
一般式（I）で表わされる化合物またはその塩へ誘導す
ることができる。The compound represented by the general formula (II) thus obtained or a salt thereof can be derived into the compound represented by the general formula (I) or a salt thereof by, for example, the route shown below.
上述した工程において、一般式（II）で表わされる化合
物またはその塩が、一般式（IIa）で表わされる化合物
またはその塩である場合は、これをたとえば、一般式
（IIc）で表わされる化合物またはその塩に変換し、つ
いで一般式（IIe）で表わされる化合物またはその塩に
変換した後、一般式（III）で表わされる化合物または
その塩を経由して一般式（I）で表わされる化合物また
はその塩へ誘導することができる。また、一般式（II）
で表わされる化合物またはその塩が、一般式（IIa）で
表わされる化合物またはその塩である場合は、これをR2
が対応する一般式（III）もしくは（IV）で表わされる
化合物またはそれらの塩に誘導し、ついでR2が置換基を
有していてもよいアルカンスルホニルオキシ基またはア
レーンスルホニルオキシ基である一般式（III）もしく
は（IV）で表わされる化合物またはそれらの塩に変換し
た後、一般式（VIII）で表わされる化合物を作用させ、
一般式（I）で表わされる化合物またはその塩に誘導す
ることができる。また、一般式（II）で表わされる化合
物またはその塩が、一般式（IIb）で表わされる化合物
またはその塩である場合は、これをR2が対応する一般式
（IV）で表わされる化合物またはその塩に誘導し、つい
でR2がハロゲン原子である一般式（IV）で表わされる化
合物またはその塩に変換した後、一般式（VIII）で表わ
される化合物を作用させ、一般式（I）で表わされる化
合物またはその塩に誘導することができる。さらに一般
式（II）の化合物またはその塩が、一般式（IId）で表
わされる化合物またはその塩の場合は、これをR2が対応
する一般式（III）もしくは（IV）で表わされる化合物
またはそれらの塩へ誘導し、ついでR2が対応するスルホ
キシまたはスルホンである化合物またはそれらの塩に変
換した後、一般式（VIII）で表わされる化合物を作用さ
せ、一般式（I）で表わされる化合物またはその塩へ誘
導することができる。 In the above-mentioned steps, when the compound represented by the general formula (II) or a salt thereof is the compound represented by the general formula (IIa) or a salt thereof, the compound represented by the general formula (IIc) or After being converted into the salt thereof and then into the compound represented by the general formula (IIe) or the salt thereof, the compound represented by the general formula (I) via the compound represented by the general formula (III) or the salt thereof, or It can be induced to its salt. In addition, the general formula (II)
When the compound represented by or a salt thereof is a compound represented by the general formula (IIa) or a salt thereof, it is represented by R 2
Is derived to the corresponding compound represented by the general formula (III) or (IV) or a salt thereof, and then R 2 is an optionally substituted alkanesulfonyloxy group or arenesulfonyloxy group. After converting to a compound represented by (III) or (IV) or a salt thereof, a compound represented by the general formula (VIII) is allowed to act,
The compound can be derived from the compound represented by the general formula (I) or a salt thereof. When the compound represented by the general formula (II) or a salt thereof is a compound represented by the general formula (IIb) or a salt thereof, the compound represented by the general formula (IV) represented by R 2 is After being converted to a salt thereof and then converted to a compound represented by the general formula (IV) in which R 2 is a halogen atom or a salt thereof, a compound represented by the general formula (VIII) is allowed to act on the compound represented by the general formula (I) It can be derivatized to the compounds represented or salts thereof. Further, when the compound of the general formula (II) or a salt thereof is a compound represented by the general formula (IId) or a salt thereof, the compound represented by the general formula (III) or (IV) to which R 2 corresponds, or A compound represented by the general formula (I) is obtained by deriving the compound into a salt thereof and then converting the compound into a compound in which R 2 is a corresponding sulfoxy or sulfone or a salt thereof, and then reacting with a compound represented by the general formula (VIII). Alternatively, it can be induced to its salt.
一般式（III）および（IV）で表わされる化合物の塩と
しては、一般式（I）および（II）で表わされる化合物
で説明したと同様の塩が挙げられる。Examples of the salts of the compounds represented by the general formulas (III) and (IV) include the same salts as those explained for the compounds represented by the general formulas (I) and (II).
つぎに本発明を実施例および参考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。Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited thereto.
実施例１ Ｎ−（2,4−ジフルオロフエニル）アミジノ酢酸メチル
エステルの塩酸塩23.0ｇを水92ｍおよび塩化メチレン
９２ｍの混合液に溶解させ、２Ｎ−水酸化ナトリウム
水溶液でpH13に調整する。ついで、有機層を分取し、水
５０ｍおよび飽和食塩水５０ｍで順次洗浄し、無水
硫酸マグネシウムで乾燥させる。この溶液にα−ホルミ
ル−α−フルオロ酢酸エチルエステルのナトリウム塩2
7.1ｇを室温で加え、加熱還流下で４時間反応させた
後、減圧下に溶媒を留去する。得られた残留物に水92ｍ
および酢酸エチル４６ｍを加え、析出結晶を取す
る。ついで、得られた結晶を水184ｍに懸濁させ、６
Ｎ−塩酸でpH1.0に調整した後、析出結晶を水４６ｍ
およびイソプロパノール４６ｍで順次洗浄すれば、融
点222〜223℃を示す２−（2,4−ジフルオロフエニルア
ミノ）−５−フルオロ−６−ヒドロキシニコチン酸メチ
ルエステル15.0ｇ（収率57.9％）を得る。Example 1 N- (2,4-difluorophenyl) amidinoacetic acid methyl ester hydrochloride (23.0 g) is dissolved in a mixed solution of water (92 m) and methylene chloride (92 m), and the pH is adjusted to 13 with a 2N aqueous sodium hydroxide solution. Then, the organic layer is separated, washed successively with 50 m of water and 50 m of saturated saline and dried over anhydrous magnesium sulfate. To this solution was added sodium salt of α-formyl-α-fluoroacetic acid ethyl ester 2
After adding 7.1 g at room temperature and reacting for 4 hours under heating under reflux, the solvent is distilled off under reduced pressure. 92m of water in the obtained residue
And 46 m of ethyl acetate are added, and the precipitated crystals are collected. Then, the obtained crystals were suspended in 184 m of water,
After adjusting the pH to 1.0 with N-hydrochloric acid, the precipitated crystals were washed with water (46 m).
Then, by sequentially washing with 46 m of isopropanol, 15.0 g (yield 57.9%) of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester having a melting point of 222 to 223 ° C is obtained. .
融点；222〜223℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1700 ＮＭＲ（ＴＦＡ−d1）δ値； 4.06（３Ｈ，ｓ），6.71〜7.65（３Ｈ，ｍ） 8.12（１Ｈ，ｄ，Ｊ＝11Hz） 同様にして、つぎの化合物を得る。Melting point; 222 to 223 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm −1 ; ν c = o 1700 NMR (TFA-d 1 ) δ value; 4.06 (3H, s), 6.71 to 7.65 (3H, m) 8.12 (1H, d, J = 11Hz) Similarly, the following compound is obtained.
２−（2,4−ジフルオロフエニルアミノ）−５−フル
オロ−６−ヒドロキシニコチン酸エチルエステル 融点；177〜178℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1700 ＮＭＲ（ＴＦＡ−d1）δ値； 1.52（３Ｈ，ｔ，Ｊ＝７Hz），4.50（２Ｈ，ｑ，Ｊ＝７
Hz），6.80〜7.65（３Ｈ，ｍ），8.15（１Ｈ，ｄ，Ｊ＝
11Hz） ５−フルオロ−２−（４−フルオロフエニルアミノ）
−６−ヒドロキシニコチン酸メチルエステル 融点；227〜228℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1690 ＮＭＲ（ＴＦＡ−d1）δ値； 4.05（３Ｈ，ｓ），6.89〜7.53（４Ｈ，ｍ），8.11（１
Ｈ，ｄ，Ｊ＝11Hz） 実施例２ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−ヒドロキシニコチン酸メチルエステル0.20ｇを
テトラヒドロフラン６ｍに溶解させ、約0.04ｇのジア
ゾメタンを含むジエチルエーテル溶液を氷冷下に添加し
た後、室温で３０分間反応させる。ついで、反応液に発
泡がなくなるまで酢酸を加えた後、減圧下に溶媒を留去
する。得られた結晶をイソプロパノール６ｍで洗浄す
れば、融点160〜161℃を示す２−（2,4−ジフルオロフ
エニルアミノ）−５−フルオロ−６−メトキシニコチン
酸メチルエステル0.15ｇ（収率71.6％）を得る。2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid ethyl ester melting point; 177 to 178 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm −1 ; ν c = o 1700 NMR (TFA-d 1 ) δ value; 1.52 (3H, t, J = 7Hz), 4.50 (2H, q, J = 7)
Hz), 6.80 to 7.65 (3H, m), 8.15 (1H, d, J =
11Hz) 5-Fluoro-2- (4-fluorophenylamino)
6-hydroxy-nicotinic acid methyl ester mp: two hundred twenty-seven to two hundred twenty-eight ° C. (recrystallization solvent: ethyl acetate) IR (KBr) cm -1; ν c = o 1690 NMR (TFA-d 1) δ value; 4.05 (3H, s ), 6.89 to 7.53 (4H, m), 8.11 (1
H, d, J = 11 Hz) Example 2 0.20 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was dissolved in 6 m of tetrahydrofuran to give about 0.04 g of diazomethane. After adding the diethyl ether solution containing it under ice-cooling, it is made to react at room temperature for 30 minutes. Then, acetic acid is added to the reaction solution until foaming stops, and the solvent is distilled off under reduced pressure. If the obtained crystals were washed with 6 m of isopropanol, 0.15 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid methyl ester showing a melting point of 160-161 ° C (yield 71.6% ) Get.
融点；160.5〜161.5℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1690 ＮＭＲ（ＣＤＣｌ3）δ値； 3.89（３Ｈ，ｓ），3.98（３Ｈ，ｓ），6.57〜7.08（２
Ｈ，ｍ），7.81（１Ｈ，ｄ，Ｊ＝11Hz），8.10〜8.97
（１Ｈ，ｍ），10.24（１Ｈ，ｂｓ） 実施例３ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−ヒドロキシニコチン酸メチルエステル0.20ｇを
Ｎ，Ｎ−ジメチルホルムアミド５ｍに溶解させ、炭酸
カリウム0.11ｇおよびジメチル酸0.093ｇを室温で添加
し、同温度で２時間反応させる。ついで反応液に水２０
ｍおよび酢酸エチル２０ｍを加え、有機層を分取
し、水10ｍおよび飽和食塩水１０ｍで順次洗浄した
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、得られた結晶をイソプロパノール５ｍで洗
浄すれば、２−（2,4−ジフルオロフエニルアミノ）−
５−フルオロ−６−メトキシニコチン酸メチルエステル
0.18ｇ（収率86.0％）を得る。Melting point; 160.5 to 161.5 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm −1 ; ν c = o 1690 NMR (CDCl 3 ) δ value; 3.89 (3H, s), 3.98 (3H, s), 6.57 ~ 7.08 (2
H, m), 7.81 (1H, d, J = 11Hz), 8.10-8.97
(1H, m), 10.24 (1H, bs) Example 3 0.20 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was added to 5 m of N, N-dimethylformamide. After dissolution, 0.11 g of potassium carbonate and 0.093 g of dimethyl acid are added at room temperature, and the mixture is reacted at the same temperature for 2 hours. Then add 20 to the reaction mixture.
m and ethyl acetate 20 m are added, the organic layer is separated, washed successively with water 10 m and saturated saline solution 10 m, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with 5 m of isopropanol to give 2- (2,4-difluorophenylamino)-
5-Fluoro-6-methoxynicotinic acid methyl ester
0.18 g (yield 86.0%) is obtained.
このものの物性は実施例２で得られたものと一致した。The physical properties of this product were in agreement with those obtained in Example 2.
実施例４ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−ヒドロキシニコチン酸メチルエステル0.20ｇを
Ｎ，Ｎ−ジメチルホルムアミド５ｍに溶解させ、炭酸
カリウム0.11ｇおよびヨウ化メチル0.11ｇを室温で添加
し同温度で１時間反応させる。反応液に水２０ｍおよ
び酢酸エチル２０ｍを加え、有機層を分取し水１０ｍ
および飽和食塩水１０ｍで順次洗浄した後、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、
得られた結晶をイソプロパノール５ｍで洗浄すれば、
２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−メトキシニコチン酸メチルエステル0.19ｇ（収
率90.7）を得る。Example 4 0.20 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was dissolved in 5 m of N, N-dimethylformamide, and 0.11 g of potassium carbonate and 0.11 of methyl iodide were dissolved. g is added at room temperature and reacted at the same temperature for 1 hour. 20 m of water and 20 m of ethyl acetate were added to the reaction solution, the organic layer was separated, and 10 m of water
Then, it is washed successively with 10 m of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
If the obtained crystals are washed with 5 ml of isopropanol,
2- (2,4-Difluorophenylamino) -5-fluoro-6-methoxynicotinic acid methyl ester 0.19 g (yield 90.7) is obtained.
このものの物性は実施例２で得られたものと一致した。The physical properties of this product were in agreement with those obtained in Example 2.
実施例５ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−ヒドロキシニコチン酸メチルエステル9.5ｇ、
五塩化リン26.5ｇおよびオキシ塩化リン46.0ｇの混合物
を７０〜８０℃で４時間反応させる。ついで、反応液を
水２８５ｍに徐々に加え、析出する結晶を取した
後、水５７ｍで洗浄する。得られた結晶をカラムクロ
マトグラフイー〔和光シリカゲルＣ−200，溶出溶媒：
トルエン〕せ精製すれば、融点137〜139℃を示す６−ク
ロロ−２−（2,4−ジフルオロフエニルアミノ）−５−
フルオロニコチン酸メチルエステル3.5ｇ（収率34.7
％）を得る。Example 5 9.5 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester,
A mixture of 26.5 g of phosphorus pentachloride and 46.0 g of phosphorus oxychloride is reacted at 70-80 ° C for 4 hours. Then, the reaction solution is gradually added to 285 m of water, the precipitated crystals are collected, and then washed with 57 m of water. The obtained crystals were subjected to column chromatography [Wako Silica Gel C-200, eluting solvent:
Toluene] and purified to give 6-chloro-2- (2,4-difluorophenylamino) -5-, which has a melting point of 137-139 ° C.
Fluoronicotinic acid methyl ester 3.5 g (yield 34.7
%).
融点；139.5〜140.5℃（再結溶媒；ジイソプロピルエー
テル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1695 ＮＭＲ（ＣＤＣｌ3）δ値； 3.93（３Ｈ，ｓ），6.61〜7.06（２Ｈ，ｍ），7.94（１
Ｈ，ｄ，Ｊ＝９Hz），8.15〜8.57（１Ｈ，ｍ），10.13
（１Ｈ，ｂｓ） 実施例６ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−ヒドロキシニコチン酸メチルエステル0.50ｇを
塩化メチレン１０ｍに懸濁させ、2,4,6−トリメチル
ベンゼンスルホニルクロリド0.44ｇおよびトリエチルア
ミン0.22ｇを加え、室温で３時間反応させる。この溶液
に水15ｍを加え、有機層を分取し、水１５ｍ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、得られた結晶をジエチルエーテル１５ｍ
で洗浄すれば、融点153〜155℃を示す２−（2,4−ジ
フルオロフエニルアミノ）−５−フルオロ−６−（2,4,
6−トリメチルベンゼンスルホニルオキシ）ニコチン酸
メチルエステル0.66ｇ（収率81.9％）を得る。Melting point: 139.5-140.5 ° C. (resolving solvent; diisopropyl ether) IR (KBr) cm −1 ; ν c = o 1695 NMR (CDCl 3 ) δ value; 3.93 (3H, s), 6.61 to 7.06 (2H, m) , 7.94 (1
H, d, J = 9Hz), 8.15 to 8.57 (1H, m), 10.13
(1H, bs) Example 6 0.50 g of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid methyl ester was suspended in 10 m of methylene chloride to give 2,4,6-trimethyl. 0.44 g of benzenesulfonyl chloride and 0.22 g of triethylamine are added, and the mixture is reacted at room temperature for 3 hours. Water (15 m) is added to this solution, the organic layer is separated, washed with water (15 m), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were removed with 15 m of diethyl ether.
And washed with 2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,
0.66 g (yield 81.9%) of methyl ester of 6-trimethylbenzenesulfonyloxy) nicotinic acid is obtained.
融点；155〜156℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1700 ＮＭＲ（ＣＤＣｌ3）δ値； 2.33（３Ｈ，ｓ），2.59（６Ｈ，ｓ），3.92（３Ｈ，
ｓ），6.32〜6.84（２Ｈ，ｍ），6.92（２Ｈ，ｓ），7.
35〜7.94（１Ｈ，ｍ），8.05（１Ｈ，ｄ，Ｊ＝９Hz），
10.17（１Ｈ，ｂｓ） 同様にして、つぎの化合物を得る。Melting point: 155 to 156 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm −1 ; ν c = o 1700 NMR (CDCl 3 ) δ value; 2.33 (3H, s), 2.59 (6H, s), 3.92 (3H,
s), 6.32 to 6.84 (2H, m), 6.92 (2H, s), 7.
35 to 7.94 (1H, m), 8.05 (1H, d, J = 9Hz),
10.17 (1H, bs) Similarly, the following compound is obtained.
２−（2,4−ジフルオロフエニルアミノ）−５−フル
オロ−６−メタンスルホニルオキシニコチン酸メチルエ
ステル 融点；120〜121℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1690 ＮＭＲ（ＣＤＣｌ3）δ値； 3.30（３Ｈ，ｓ），3.94（３Ｈ，ｓ），6.60〜7.15（２
Ｈ，ｍ）， 10.00（１Ｈ，ｂｓ） 実施例７ ６−クロロ−２−（2,4−ジフルオロフエニルアミノ）
−５−フルオロニコチン酸メチルエステル0.70ｇをＮ，
Ｎ−ジメチルホルムアミド７ｍに懸濁させ、室温でト
リエチルアミン0.34ｇおよびエタンチオール0.21ｇを添
加し、５０℃で４時間反応させる。ついで、反応液に酢
酸エチル４０ｍおよび水３０ｍを加え、２Ｎ−塩酸
でpH２に調整する。有機層を分取し、水２０ｍおよび
飽和食塩水２０ｍで順次洗浄した後、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
結晶をヘキサン１０ｍで洗浄すれば、融点113〜114℃
を示す６−エチルチオ−２−（2,4−ジフルオロフエニ
ルアミノ）−５−フルオロニコチン酸メチルエステル0.
62ｇ（収率81.9％）を得る。2- (2,4-Difluorophenylamino) -5-fluoro-6-methanesulfonyloxynicotinic acid methyl ester melting point; 120 to 121 ° C (resolving solvent; ethyl acetate) IR (KBr) cm -1 ; ν c = O 1690 NMR (CDCl 3 ) δ value; 3.30 (3H, s), 3.94 (3H, s), 6.60 to 7.15 (2
H, m), 10.00 (1H, bs) Example 7 6-chloro-2- (2,4-difluorophenylamino)
0.70 g of -5-fluoronicotinic acid methyl ester was added to N,
The suspension is suspended in 7 m of N-dimethylformamide, 0.34 g of triethylamine and 0.21 g of ethanethiol are added at room temperature, and the mixture is reacted at 50 ° C. for 4 hours. Then, 40 m of ethyl acetate and 30 m of water are added to the reaction solution and the pH is adjusted to 2 with 2N-hydrochloric acid. The organic layer is separated, washed successively with 20 m of water and 20 m of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were washed with 10 m of hexane to give a melting point of 113 to 114 ° C.
6-ethylthio-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid methyl ester showing
62 g (81.9% yield) are obtained.
融点；113.5〜114℃（再結溶媒；ジイソプロピルエーテ
ル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1680 ＮＭＲ（ＣＤＣｌ3）δ値； 1.29（３Ｈ，ｔ，Ｊ＝７Hz），3.07（２Ｈ，ｑ，Ｊ＝７
Hz），3.90（３Ｈ，ｓ），6.50〜7.20（２Ｈ，ｍ），7.
66（１Ｈ，ｄ，Ｊ＝１０Hz），7.80〜8.50（１Ｈ，
ｍ），10.00（１Ｈ，ｓ） 同様にして、つぎの化合物を得る。Melting point: 113.5 to 114 ° C. (resolving solvent; diisopropyl ether) IR (KBr) cm −1 ; ν c = o 1680 NMR (CDCl 3 ) δ value; 1.29 (3H, t, J = 7 Hz), 3.07 (2H, q, J = 7
Hz), 3.90 (3H, s), 6.50 to 7.20 (2H, m), 7.
66 (1H, d, J = 10Hz), 7.80 to 8.50 (1H,
m), 10.00 (1H, s) Similarly, the following compound is obtained.
２−（2,4−ジフルオロフエニルアミノ）−５−フル
オロ−６−フエニルチオニコチン酸メチルエステル 融点；128〜128.5℃（再結溶媒；ジイソプロピルエーテ
ル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1685 ＮＭＲ（ＣＤＣｌ3）δ値； 3.90（３Ｈ，ｓ）， 10.25（１Ｈ，ｄｓ） 実施例８ ６−クロロ−２−（2,4−ジフルオロフエニルアミノ）
−５−フルオロニコチン酸メチルエステル1.00ｇをＮ，
Ｎ−ジメチルホルムアミド１０ｍに懸濁させ、３−ア
ミノピロリジンの二塩酸塩0.75ｇおよびトリエチルアミ
ン1.44ｇを加え、７０℃で３０分間反応させる。ついで
クロロホルム５０ｍおよび水５０ｍを加え、有機層
を分取し、水２５ｍおよび飽和食塩水２５ｍで順次
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、得られた結晶をジエチルエーテル５
ｍで洗浄すれば、融点139〜140℃を示す６−（３−ア
ミノ−１−ピロリジニル）−２−（2,4−ジフルオロフ
エニルアミノ）−５−フルオロニコチン酸メチルエステ
ル1.10ｇ（収率95.1％）を得る。2- (2,4-Difluorophenylamino) -5-fluoro-6-phenylthionicotinic acid methyl ester Melting point: 128-128.5 ° C (resolving solvent; diisopropyl ether) IR (KBr) cm -1 ; ν c = O 1685 NMR (CDCl 3 ) δ value; 3.90 (3H, s), 10.25 (1H, ds) Example 8 6-chloro-2- (2,4-difluorophenylamino)
-5 g of 5-fluoronicotinic acid methyl ester was added to N,
It is suspended in 10 m of N-dimethylformamide, 0.75 g of 3-aminopyrrolidine dihydrochloride and 1.44 g of triethylamine are added, and the mixture is reacted at 70 ° C. for 30 minutes. Then, chloroform 50m and water 50m are added, the organic layer is separated, washed successively with water 25m and saturated saline solution 25m, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were mixed with diethyl ether 5
If washed with m, 1-g of 6- (3-amino-1-pyrrolidinyl) -2- (2,4-difluorophenylamino) -5-fluoronicotinic acid methyl ester showing a melting point of 139-140 ° C (yield 95.1%).
ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1670 ＮＭＲ（ＣＤＣｌ3）δ値； 1.58〜2.27（２Ｈ，ｍ）， 6.57〜7.12（２Ｈ，ｍ），7.58（１Ｈ，ｄ，Ｊ＝１４H
z），8.10〜8.62（１Ｈ，ｍ），10.32（１Ｈ，ｂｓ） 同様にして、つぎの化合物を得る。IR (KBr) cm -1 ; ν c = o 1670 NMR (CDCl 3 ) δ value; 1.58 to 2.27 (2H, m), 6.57 ~ 7.12 (2H, m), 7.58 (1H, d, J = 14H
z), 8.10 to 8.62 (1H, m), 10.32 (1H, bs) In the same manner, the following compound is obtained.
６−（４−アセチル−１−ピペラジニル）−２−（2,
4−ジフルオロフエニルアミノ）−５−フルオロニコチ
ン酸メチルエステル 融点；172〜173℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1680，1650 ＮＭＲ（ＣＤＣｌ3）δ値； 2.13（３Ｈ，ｓ）， 6.57〜7.07（２Ｈ，ｍ），7.68（１Ｈ，ｄ，Ｊ＝１３H
z），7.77〜8.18（１Ｈ，ｍ），10.05（１Ｈ，ｂｓ） 実施例９ ６−（３−アミノ−１−ピロリジニル）−２−（2,4−
ジフルオロフエニルアミノ）−５−フルオロニコチン酸
メチルエステル0.65ｇをクロロホルム6.5ｍに溶解さ
せ、無水酢酸0.19ｇを加え、室温で１０分間反応させた
後、減圧下に溶媒を留去する。得られた結晶をジエチル
エーテル２ｍで洗浄すれば、融点199〜200℃を示す６
−（３−アセチルアミノ−１−ピロリジニル）−２−
（2,4−ジフルオロフエニルアミノ）−５−フルオロニ
コチン酸メチルエステル0.72ｇ（収率99.4％）を得る。6- (4-acetyl-1-piperazinyl) -2- (2,
4-difluorophenylamino) -5-fluoronicotinic acid methyl ester melting point; 172-173 ° C (resolving solvent; ethyl acetate) IR (KBr) cm -1 ; ν c = o 1680,1650 NMR (CDCl 3 ) δ Value; 2.13 (3H, s), 6.57 ~ 7.07 (2H, m), 7.68 (1H, d, J = 13H
z), 7.77 to 8.18 (1H, m), 10.05 (1H, bs) Example 9 6- (3-Amino-1-pyrrolidinyl) -2- (2,4-
0.65 g of methyl difluorophenylamino) -5-fluoronicotinate was dissolved in 6.5 m of chloroform, 0.19 g of acetic anhydride was added, the mixture was reacted at room temperature for 10 minutes, and then the solvent was distilled off under reduced pressure. When the obtained crystals are washed with 2 m of diethyl ether, they show a melting point of 199-200 ° C.
-(3-Acetylamino-1-pyrrolidinyl) -2-
0.72 g (yield 99.4%) of (2,4-difluorophenylamino) -5-fluoronicotinic acid methyl ester is obtained.
融点；202〜203℃（再結溶媒；酢酸エチル） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1675 ＮＭＲ（ＣＤＣｌ3−ＤＭＳＯ−d6）δ値； 6.63〜7.17（２Ｈ，ｍ），7.62（１Ｈ，ｄ，Ｊ＝１４H
z），7.83〜8.60（２Ｈ，ｍ），10.30（１Ｈ，ｂｓ） 実施例１０ ３−アミノピロリジンの二塩酸塩0.12ｇをＮ，Ｎ−ジメ
チルホルムアミド３ｍに懸濁させ、トリエチルアミン
0.25ｇを加え、室温で５分間反応させた後、２−（2,4
−ジフルオロフエニルアミノ）−５−フルオロ−６−
（2,4,6−トリメチルベンゼンスルホニルオキシ）ニコ
チン酸メチルエステル0.30ｇを加え、室温で1.5時間反
応させる。反応液にクロロホルム１０ｍおよび水１０
ｍを加え、有機層を分取し、水１０ｍおよび飽和食
塩水１０ｍで順次洗浄した後、無水硫酸マグネシウム
で乾燥させる。ついで無水酢酸0.10ｇを加え、室温で１
０分間反応させた後、減圧下に溶媒を留去する。得られ
た結晶をジエチルエーテル５ｍで洗浄すれば、６−
（３−アセチルアミノ−１−ピロリジニル）−２−（2,
4−ジフルオロフエニルアミノ）−５−フルオロニコチ
ン酸メチルエステル0.21ｇ（収率82.4％）を得る。この
ものの物性は実施例９で得られたものと一致した。Melting point; 202 to 203 ° C. (resolving solvent; ethyl acetate) IR (KBr) cm −1 ; ν c = o 1675 NMR (CDCl 3 -DMSO-d 6 ) δ value; 6.63 ~ 7.17 (2H, m), 7.62 (1H, d, J = 14H
z), 7.83 to 8.60 (2H, m), 10.30 (1H, bs) Example 10 0.12 g of 3-aminopyrrolidine dihydrochloride was suspended in 3 m of N, N-dimethylformamide to give triethylamine.
After adding 0.25g and reacting at room temperature for 5 minutes, 2- (2,4
-Difluorophenylamino) -5-fluoro-6-
0.30 g of (2,4,6-trimethylbenzenesulfonyloxy) nicotinic acid methyl ester is added, and the mixture is reacted at room temperature for 1.5 hours. Chloroform 10m and water 10 in reaction liquid
m is added, the organic layer is separated, washed successively with 10 m of water and 10 m of saturated saline, and then dried over anhydrous magnesium sulfate. Then add 0.10 g of acetic anhydride, and add 1 at room temperature.
After reacting for 0 minutes, the solvent is distilled off under reduced pressure. If the obtained crystals are washed with 5 m of diethyl ether, 6-
(3-Acetylamino-1-pyrrolidinyl) -2- (2,
0.21 g (yield 82.4%) of 4-difluorophenylamino) -5-fluoronicotinic acid methyl ester is obtained. The physical properties of this product were the same as those obtained in Example 9.
実施例１１ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−ヒドロキシニコチン酸メチルエステル3.00ｇを
メタノール３０ｍに懸濁させ、室温で２Ｎ−水酸化ナ
トリウム水溶液16.1ｍを加えた後、加熱還流下で４時
間反応させる。ついで反応液を酢酸エチル６０ｍおよ
び水６０ｍの混合液に加え、水層を分取する。水層を
６Ｎ−塩酸でpH1.0に調整し、析出晶を取した後、水1
5ｍおよびイソプロパノール１５ｍで順次洗浄すれ
ば、融点213〜216℃を示す２−（2,4−ジフルオロフエ
ニルアミノ）−５−フルオロ−６−ヒドロキシニコチン
酸2.68ｇ（収率93.7％）を得る。Example 11 3.00 g of methyl 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinate was suspended in 30 m of methanol, and 16.1 m of 2N-sodium hydroxide aqueous solution was added at room temperature. Then, the mixture is reacted under heating under reflux for 4 hours. Then, the reaction solution is added to a mixed solution of 60 m of ethyl acetate and 60 m of water, and the aqueous layer is separated. The aqueous layer was adjusted to pH 1.0 with 6N-hydrochloric acid, and the precipitated crystals were collected, followed by water 1
If washed successively with 5 m and 15 m of isopropanol, 2.68 g (yield 93.7%) of 2- (2,4-difluorophenylamino) -5-fluoro-6-hydroxynicotinic acid having a melting point of 213 to 216 ° C is obtained.
融点；215〜216℃（再結溶媒；アセトン：エタノール＝
１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1700 ＮＭＲ（ＤＭＳＯ−d6）δ値； 6.65〜7.58（２Ｈ，ｍ），7.86（１Ｈ，ｄ，Ｊ＝１１H
z），8.12〜8.68（１Ｈ，ｍ），10.49（１Ｈ，ｂｓ） 同様にして、つぎの化合物を得る。Melting point: 215 to 216 ° C (resolving solvent; acetone: ethanol =
1: 1) IR (KBr) cm −1 ; ν c = o 1700 NMR (DMSO-d 6 ) δ value; 6.65 to 7.58 (2H, m), 7.86 (1H, d, J = 11H)
z), 8.12 to 8.68 (1H, m), 10.49 (1H, bs) Similarly, the following compound is obtained.
５−フルオロ−２−（４−フルオロフエニルアミノ）
−６−ヒドロキシニコチン酸 融点；216〜217℃（再結溶媒；アセトン：エタノール＝
１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1685（ｓｈ） ＮＭＲ（ＤＭＳＯ−d6）δ値； 6.84〜7.94（５Ｈ，ｍ），10.33（１Ｈ，ｂｓ） 実施例１２ ２−（2,4−ジフルオロフエニルアミノ）−５−フルオ
ロ−６−メトキシニコチン酸メチルエステル2.00ｇをテ
トラヒドロフラン６０ｍに溶解させ、室温で１Ｎ−水
酸化ナトリウム水溶液25.5ｍを加え、加熱還流下で７
時間反応させる。ついで、減圧下に溶媒を留去し、得ら
れた残留物に酢酸エチル100ｍおよび水100ｍを加
え、２Ｎ−塩酸でpH2.0に調整する。有機層を水５０ｍ
および飽和食塩水５０ｍで順次洗浄し、無水硫酸マ
グネシウムで乾燥させ、減圧下に溶媒を留去する。得ら
れた結晶をジエチルエーテル１０ｍで洗浄すれば、融
点237〜240℃を示す２−（2,4−ジフルオロフエニルア
ミノ）−５−フルオロ−６−メトキシニコチン酸1.40ｇ
（収率73.3％）を得る。5-fluoro-2- (4-fluorophenylamino)
-6-Hydroxynicotinic acid Melting point; 216-217 ° C (reconstitution solvent; acetone: ethanol =
1: 1) IR (KBr) cm -1 ; ν c = o 1685 (sh) NMR (DMSO-d 6 ) δ value; 6.84 to 7.94 (5H, m), 10.33 (1H, bs) Example 122 2- (2,4-Difluorophenylamino) -5-fluoro-6-methoxynicotinic acid methyl ester (2.00 g) was dissolved in tetrahydrofuran (60 m), 1N-aqueous sodium hydroxide solution (25.5 m) was added at room temperature, and the mixture was heated under reflux to give 7
React for hours. Then, the solvent is distilled off under reduced pressure, 100 m of ethyl acetate and 100 m of water are added to the obtained residue, and the pH is adjusted to 2.0 with 2N-hydrochloric acid. 50m water organic layer
Then, the extract is washed successively with 50 m of saturated saline and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained crystals are washed with 10 m of diethyl ether to give 2- (2,4-difluorophenylamino) -5-fluoro-6-methoxynicotinic acid (1.40 g) having a melting point of 237-240 ° C.
(Yield 73.3%) is obtained.
融点；239〜240℃（再結溶媒；アセトン） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1665 ＮＭＲ（ＤＭＳＯ−d6）δ値； 3.98（３Ｈ，ｓ），6.76〜7.48（２Ｈ，ｍ），7.86（１
Ｈ，ｄ，Ｊ＝１１Hz），8.10〜8.60（１Ｈ，ｍ），10.5
1（１Ｈ，ｂｓ） 同様にして、つぎの化合物を得る。Melting point: 239 to 240 ° C. (resolving solvent; acetone) IR (KBr) cm −1 ; ν c = o 1665 NMR (DMSO-d 6 ) δ value; 3.98 (3H, s), 6.76 to 7.48 (2H, m) ), 7.86 (1
H, d, J = 11Hz), 8.10 to 8.60 (1H, m), 10.5
1 (1H, bs) Similarly, the following compound is obtained.
６−クロロ−２−（2,4−ジフルオロフエニルアミ
ノ）−５−フルオロニコチン酸 融点；226〜228℃（再結溶媒；ベンゼン） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1680 ＮＭＲ（アセトン−d6）δ値； 6.60〜7.41（２Ｈ，ｍ）， 10.30（１Ｈ，ｂｓ），10.64（１Ｈ，ｂｓ） ２−（2,4−ジフルオロフエニルアミノ）−５−フル
オロ−６−（2,4,6−トリメチルベンゼンスルホニルオ
キシ）ニコチン酸 融点；179〜180℃（再結溶媒；ベンゼン） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1665 ＮＭＲ（アセトン−d6）δ値； 2.32（３Ｈ，ｓ），2.55（６Ｈ，ｓ）， 10.37（１Ｈ，ｂｓ） ６−エチルチオ−２−（2,4−ジフルオロフエニルア
ミノ）−５−フルオロニコチン酸 融点；209〜210℃（再結溶媒；ベンゼン） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1665 ＮＭＲ（アセトン−d6）δ値； 1.30（３Ｈ，ｔ，Ｊ＝７Hz），3.14（２Ｈ，ｑ，Ｊ＝７
Hz），6.70〜7.50（２Ｈ，ｍ）， 9.70（１Ｈ，ｂｓ），10.27（１Ｈ，ｂｓ） ２−（2,4−ジフルオロフエニルアミノ）−５−フル
オロ−６−フエニルチオニコチン酸 融点；264〜265℃（再結溶媒；酢酸エチル：エタノール
＝１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1660 ＮＭＲ（ＤＭＳＯ−d6）δ値； 6.00〜7.73（８Ｈ，ｍ），7.85（１Ｈ，ｄ，Ｊ＝１０H
z），10.58（１Ｈ，ｂｓ） 実施例１３ ６−（３−アセチルアミノ−１−ピロリジニル）−２−
（2,4−ジフルオロフエニルアミノ）−５−フルオロニ
コチン酸メチルエステル0.98ｇをテトラヒドロフラン３
０ｍ、メタノール１０ｍおよび水４ｍの混合液に
懸濁させ、１Ｎ−水酸化ナトリウム水溶液5.3ｍを加
え、６５℃で３時間反応させる。ついで反応液を酢酸エ
チル５０ｍおよび水５０ｍの混合液に加え、水層を
分取した後１Ｎ−塩酸でpH2.0に調整する。析出結晶を
取し、水２ｍおよびエタノール２ｍで順次洗浄す
れば、融点232〜234℃を示す６−（３−アセチルアミノ
−１−ピロリジニル）−２−（2,4−ジフルオロフエニ
ルアミノ）−５−フルオロニコチン酸0.88ｇ（収率９
３．０％）を得る。6-chloro-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid Melting point; 226 to 228 ° C (resolving solvent; benzene) IR (KBr) cm -1 ; ν c = o 1680 NMR ( Acetone-d 6 ) δ value; 6.60 to 7.41 (2H, m), 10.30 (1H, bs), 10.64 (1H, bs) 2- (2,4-difluorophenylamino) -5-fluoro-6- (2,4,6-trimethylbenzenesulfonyloxy) nicotinic acid Melting point; 179- 180 ° C (resolving solvent; benzene) IR (KBr) cm -1 ; ν c = o 1665 NMR (acetone-d 6 ) δ value; 2.32 (3H, s), 2.55 (6H, s), 10.37 (1H, bs) 6-Ethylthio-2- (2,4-difluorophenylamino) -5-fluoronicotinic acid Melting point; 209 to 210 ° C (resolving solvent; benzene) IR (KBr) cm -1 ; ν c = o 1665 NMR (acetone-d 6 ) δ value; 1.30 (3H, t, J = 7Hz), 3.14 (2H, q, J = 7)
Hz), 6.70 ~ 7.50 (2H, m), 9.70 (1H, bs), 10.27 (1H, bs) 2- (2,4-difluorophenylamino) -5-fluoro-6-phenylthionicotinic acid Melting point: 264 to 265 ° C (resolving solvent; ethyl acetate) : Ethanol = 1: 1) IR (KBr) cm −1 ; ν c = o 1660 NMR (DMSO-d 6 ) δ value; 6.00 to 7.73 (8H, m), 7.85 (1H, d, J = 10H
z), 10.58 (1H, bs) Example 13 6- (3-Acetylamino-1-pyrrolidinyl) -2-
0.98 g of (2,4-difluorophenylamino) -5-fluoronicotinic acid methyl ester was added to tetrahydrofuran 3
It is suspended in a mixed solution of 0 m, 10 m of methanol and 4 m of water, 5.3 m of 1N-sodium hydroxide aqueous solution is added, and the mixture is reacted at 65 ° C. for 3 hours. Then, the reaction solution is added to a mixed solution of 50 m of ethyl acetate and 50 m of water, the aqueous layer is separated, and then adjusted to pH 2.0 with 1N-hydrochloric acid. The precipitated crystals were collected and washed successively with 2 m of water and 2 m of ethanol to give 6- (3-acetylamino-1-pyrrolidinyl) -2- (2,4-difluorophenylamino)-having a melting point of 232 to 234 ° C. 0.88 g of 5-fluoronicotinic acid (yield 9
3.0%).
融点；233.5〜236℃（再結溶媒；アセトン：メタノール
＝１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1645 ＮＭＲ（ＴＦＡ−d1）δ値； 3.62〜5.03（５Ｈ，ｍ），6.82〜7.80（３Ｈ，ｍ），8.
27（１Ｈ，ｄ，Ｊ＝１３Hz） 同様にして、つぎの化合物を得る。Melting point: 233.5 to 236 ° C. (resolving solvent; acetone: methanol = 1: 1) IR (KBr) cm −1 ; ν c = o 1645 NMR (TFA-d 1 ) δ value; 3.62 to 5.03 (5H, m), 6.82 to 7.80 (3H, m), 8.
27 (1H, d, J = 13 Hz) Similarly, the following compound is obtained.
６−（４−アセチル−１−ピペラジニル）−２−（2,
4−ジフルオロフエニルアミノ）−５−フルオロニコチ
ン酸 融点；243〜244℃（再結溶媒；酢酸エチル：エタノール
＝１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1670，1635（ｓｈ） ＮＭＲ（ＴＦＡ−d1）δ値； 2.48（３Ｈ，ｓ），3.47〜4.40（８Ｈ，ｍ），6.83〜7.
82（３Ｈ，ｍ），8.47（１Ｈ，ｄ，Ｊ＝１３Hz） 実施例１４ ６−（４−アセチル−１−ピペラジニル）−２−（2,4
−ジフルオロフエニルアミノ）−５−フルオロニコチン
酸メチルエステル0.13ｇをメタノール3.9ｍに懸濁さ
せ、２Ｎ−水酸化ナトリウム水溶液3.33ｍを加え、加
熱還流下で２時間反応させる。反応液に水２ｍを加
え、１Ｎ−塩酸でpH8.5に調整した後、析出結晶を取
し水２ｍで洗浄すれば、融点279〜281℃を示す２−
（2,4−ジフルオロフエニルアミノ）−５−フルオロ−
６−（１−ピペラジニル）ニコチン酸0.11ｇ（収率98.2
％）を得る。6- (4-acetyl-1-piperazinyl) -2- (2,
4-difluorophenylamino) -5-fluoronicotinic acid Melting point: 243 to 244 ° C. (resolving solvent; ethyl acetate: ethanol = 1: 1) IR (KBr) cm −1 ; ν c = o 1670, 1635 (sh ) NMR (TFA-d 1 ) δ value; 2.48 (3H, s), 3.47 to 4.40 (8H, m), 6.83 to 7.
82 (3H, m), 8.47 (1H, d, J = 13Hz) Example 14 6- (4-acetyl-1-piperazinyl) -2- (2,4)
-Difluorophenylamino) -5-fluoronicotinic acid methyl ester 0.13 g was suspended in methanol 3.9 m, 2N-sodium hydroxide aqueous solution 3.33 m was added, and the mixture was reacted under heating reflux for 2 hours. After adding 2 m of water to the reaction solution and adjusting the pH to 8.5 with 1N-hydrochloric acid, the precipitated crystals are collected and washed with 2 m of water to give a melting point of 279 to 281 ° C.
(2,4-difluorophenylamino) -5-fluoro-
6- (1-Piperazinyl) nicotinic acid 0.11 g (yield 98.2
%).
ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1625 ＮＭＲ（ＴＦＡ−d1）δ値； 3.53〜4.33（８Ｈ，ｍ），6,87〜7.77（３Ｈ，ｍ），8.
53（１Ｈ，ｄ，Ｊ＝１３Hz） 同様にして、つぎの化合物を得る。IR (KBr) cm -1 ; ν c = o 1625 NMR (TFA-d 1 ) δ value; 3.53 to 4.33 (8H, m), 6,87 to 7.77 (3H, m), 8.
53 (1H, d, J = 13 Hz) Similarly, the following compound is obtained.
６−（３−アミノ−１−ピロリジニル）−２−（2,4
−ジフルオロフエニルアミノ）−５−フルオロニコチン
酸 融点；249〜250℃ ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1630 ＮＭＲ（ＴＦＡ−d1）δ値； 2.47〜2.92（２Ｈ，ｍ），3.72〜4.23（２Ｈ，ｍ），4.
23〜4.73（３Ｈ，ｍ），6.95〜7.77（３Ｈ，ｍ），8.36
（１Ｈ，ｄ，Ｊ＝１３Hz） 参考例１ β−イミノ−β−フエノキシプロピオン酸エチルエステ
ルの塩酸塩５０ｇおよび2,4−ジフルオロアニリン27.8
ｇを酢酸エチル300ｍに懸濁させ、加熱還流下で２時
間反応させる。析出結晶を取し、酢酸エチル200ｍ
で２回洗浄すれば、融点196〜197℃を示すＮ−（2,4−
ジフルオロフエニル）アミジノ酢酸エチルエステルの塩
酸塩47ｇ（収率82.2％）を得る。6- (3-amino-1-pyrrolidinyl) -2- (2,4
-Difluorophenylamino) -5-fluoronicotinic acid melting point; 249 to 250 ° C IR (KBr) cm -1 ; ν c = o 1630 NMR (TFA-d 1 ) δ value; 2.47 to 2.92 (2H, m), 3.72 to 4.23 (2H, m), 4.
23 ~ 4.73 (3H, m), 6.95 ~ 7.77 (3H, m), 8.36
(1 H, d, J = 13 Hz) Reference Example 1 50 g of β-imino-β-phenoxypropionic acid ethyl ester hydrochloride and 2,4-difluoroaniline 27.8
g is suspended in 300 m of ethyl acetate and reacted under heating under reflux for 2 hours. Precipitated crystals are collected and ethyl acetate 200m
If washed twice with N- (2,4-
47 g (yield 82.2%) of the hydrochloride of difluorophenyl) amidinoacetic acid ethyl ester are obtained.
ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1730 ＮＭＲ（ＤＭＳＯ−d6）δ値； 1.26（３Ｈ，ｔ，Ｊ＝７Hz），4.07（２Ｈ，ｓ），4.19
（２Ｈ，ｑ，Ｊ＝７Hz），7.02〜7,78（３Ｈ，ｍ），9.
11（１Ｈ，ｂｓ），10.26（１Ｈ，ｂｓ），12.28（１
Ｈ，ｂｓ） 同様にして、つぎの化合物を得る。IR (KBr) cm -1 ; ν c = o 1730 NMR (DMSO-d 6 ) δ value; 1.26 (3H, t, J = 7Hz), 4.07 (2H, s), 4.19
(2H, q, J = 7Hz), 7.02 to 7,78 (3H, m), 9.
11 (1H, bs), 10.26 (1H, bs), 12.28 (1
H, bs) Similarly, the following compound is obtained.
Ｎ−（2,4−ジフルオロフエニル）アミジノ酢酸メチ
ルエステルの塩酸塩 融点；192〜193℃ ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1735 ＮＭＲ（ＤＭＳＯ−d6）δ値； 3.74（３Ｈ，ｓ），4.09（２Ｈ，ｓ），6.91〜7.73（３
Ｈ，ｍ），9.15（１Ｈ，ｂｓ），10.31（１Ｈ，ｂ
ｓ），12.29（１Ｈ，ｂｓ） Ｎ−（４−フルオロフエニル）アミジノ酢酸メチルエ
ステルの塩酸塩 融点；134〜135℃ ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1730 ＮＭＲ（ＤＭＳＯ−d6）δ値； 3.74（３Ｈ，ｓ），4.05（２Ｈ，ｓ），7.01〜7.59（４
Ｈ，ｍ），8.96（１Ｈ，ｂｓ），10.06（１Ｈ，ｂ
ｓ），12.26（１Ｈ，ｂｓ） 参考例２ ６−（３−アセチルアミノ−１−ピロリジニル）−２−
（2,4−ジフルオロフエニルアミノ）−５−フルオロニ
コチン酸0.93ｇを無水テトラヒドロフラン３７ｍに懸
濁させ、氷冷下でカルボニルジイミダゾール0.76ｇを添
加し、室温で１２時間反応させる。ついで、エトキシカ
ルボニル酢酸のマグネシウム塩0.67ｇを添加し、６０℃
で２時間反応させる。反応液を酢酸エチル100ｍおよ
び水５０ｍの混合液に加え、２Ｎ−塩酸でpH2.0に調
整し、有機層を分取する。有機層に水５０ｍを加え、
飽和炭酸水素ナトリウム水溶液でpH7.0に調整する。有
機層を分取し、水５０ｍおよび飽和食塩水５０ｍで
順次洗浄し、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：エタノール（容量比２００：１）〕で精製す
れば、融点182〜184℃を示す６−（３−アセチルアミノ
−１−ピロリジニル）−２−（2,4−ジフルオロフエニ
ルアミノ）−５−フルオロニコチノイル酢酸エチルエス
テル0.61ｇ（収率55.7％）を得る。Hydrochloride of N- (2,4-difluorophenyl) amidinoacetic acid methyl ester Melting point; 192-193 ° C IR (KBr) cm -1 ; ν c = o 1735 NMR (DMSO-d 6 ) δ value; 3.74 (3H , S), 4.09 (2H, s), 6.91 to 7.73 (3
H, m), 9.15 (1H, bs), 10.31 (1H, b)
s), 12.29 (1H, bs) N- (4-fluorophenyl) amidinoacetic acid methyl ester hydrochloride Melting point; 134-135 ° C IR (KBr) cm -1 ; ν c = o 1730 NMR (DMSO-d 6 ) Δ value; 3.74 (3H, s), 4.05 (2H, s), 7.01 to 7.59 (4
H, m), 8.96 (1H, bs), 10.06 (1H, b)
s), 12.26 (1H, bs) Reference Example 2 6- (3-Acetylamino-1-pyrrolidinyl) -2-
0.93 g of (2,4-difluorophenylamino) -5-fluoronicotinic acid is suspended in 37 m of anhydrous tetrahydrofuran, 0.76 g of carbonyldiimidazole is added under ice cooling, and the mixture is reacted at room temperature for 12 hours. Next, 0.67 g of magnesium salt of ethoxycarbonylacetic acid was added, and the temperature was 60 ° C.
React for 2 hours. The reaction solution is added to a mixed solution of 100 m of ethyl acetate and 50 m of water, adjusted to pH 2.0 with 2N-hydrochloric acid, and the organic layer is separated. Add 50m of water to the organic layer,
Adjust to pH 7.0 with saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed successively with 50 m of water and 50 m of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, eluting solvent: chloroform: ethanol (volume ratio 200: 1)] to give a melting point of 182-184 ° C. 6- (3-acetylamino-1-pyrrolidinyl) -2- (2,4-difluorophenylamino) -5-fluoronicotinoyl acetic acid ethyl ester (0.61 g, yield 55.7%) is obtained.
融点；184〜185℃（再結溶媒；酢酸エチル：エタノール
＝１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1735，1670 ＮＭＲ（ＣＤＣｌ３）δ値； 1.27（３Ｈ，ｔ，Ｊ＝７Hz）， 8.00〜8.38（１Ｈ，ｍ），11.25（１Ｈ，ｂｓ） 参考例３ ６−（３−アセチルアミノ−１−ピロリジニル）−２−
（2,4−ジフルオロフエニルアミノ）−５−フルオロニ
コチノイル酢酸エチルエステル0.20ｇをベンゼン２ｍ
に懸濁させ、Ｎ，Ｎ−ジメチルホルムアミドジメチルア
セタール0.10ｇを加え、加熱還流下で７時間反応させ
る。ついで、析出結晶を取し、ジエチルエーテル２ｍ
で洗浄すれば、融点233〜236℃を示す７−（３−アセ
チルアミノ−１−ピロリジニル）−１−（2,4−ジフル
オロフエニル）−６−フルオロ−1,4−ジヒドロ−４−
オキソ−1.8−ナフチリジン−３−カルボン酸エチルエ
ステル0.18ｇ（収率88.1％）を得る。Melting point: 184 to 185 ° C. (resolving solvent; ethyl acetate: ethanol = 1: 1) IR (KBr) cm −1 ; ν c = o 1735,1670 NMR (CDCl 3 ) δ value; 1.27 (3H, t, J = 7Hz), 8.00 to 8.38 (1H, m), 11.25 (1H, bs) Reference Example 3 6- (3-Acetylamino-1-pyrrolidinyl) -2-
(2,4-difluorophenylamino) -5-fluoronicotinoyl acetic acid ethyl ester 0.20 g was added to benzene 2 m.
Then, 0.10 g of N, N-dimethylformamide dimethylacetal is added, and the mixture is reacted under heating under reflux for 7 hours. Then, the precipitated crystals were collected and 2m of diethyl ether
7- (3-acetylamino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-, which shows a melting point of 233-236 ° C.
0.18 g (yield 88.1%) of oxo-1.8-naphthyridine-3-carboxylic acid ethyl ester is obtained.
融点；234〜236℃（再結溶媒；アセトン：メタノール＝
１：１） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1725，1700，1670 ＮＭＲ（ＣＤＣｌ３）δ値； 1.33（３Ｈ，ｔ，Ｊ＝７Hz）， 3.13〜4.02（４Ｈ，ｍ）， 6.78〜7.70（４Ｈ，ｍ），8.10（１Ｈ，ｄ，Ｊ＝８H
z），8.31（１Ｈ，ｓ） 参考例４ ７−（３−アセチルアミノ−１−ピロリジニル）−１−
（2,4−ジフルオロフエニル）−６−フルオロ−1,4−ジ
ヒドロ−４−オキソ−1.8−ナフチリジン−３−カルボ
ン酸エチルエステル0.50ｇを６Ｎ−塩酸５ｍに溶解さ
せ、加熱還流下で４時間反応させる。ついで、析出結晶
を取し、水１ｍで洗浄すれば、融点247〜250℃（分
解）を示す７−（３−アミノ−１−ピロリジニル）−１
−（2,4−ジフルオロフエニル）−６−フルオロ−1,4−
ジヒドロ−４−オキソ−1,8−ナフチリジン−３−カル
ボン酸の塩酸塩0.39ｇ（収率84.0％）を得る。Melting point: 234 to 236 ° C (resolving solvent; acetone: methanol =
1: 1) IR (KBr) cm -1 ; ν c = o 1725, 1700, 1670 NMR (CDCl 3 ) δ value; 1.33 (3H, t, J = 7Hz), 3.13 ~ 4.02 (4H, m), 6.78 to 7.70 (4H, m), 8.10 (1H, d, J = 8H
z), 8.31 (1H, s) Reference Example 4 7- (3-Acetylamino-1-pyrrolidinyl) -1-
(2,4-Difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acid ethyl ester (0.50 g) was dissolved in 6N-hydrochloric acid (5 m) and heated under reflux to give 4 React for hours. Then, the precipitated crystals are collected and washed with 1 m of water to give 7- (3-amino-1-pyrrolidinyl) -1 having a melting point of 247 to 250 ° C. (decomposition).
-(2,4-Difluorophenyl) -6-fluoro-1,4-
0.39 g (yield 84.0%) of the hydrochloride of dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained.
融点；247〜250℃（分解）（再結溶媒；濃塩酸：エタノ
ール＝１：３） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1730 ＮＭＲ（ＴＦＡ−d1）δ値； 2.23〜2.95（２Ｈ，ｍ），3.38〜4.83（５Ｈ，ｍ），6.
95〜7.90（３Ｈ，ｍ），8.22（１Ｈ，ｄ，Ｊ＝１１H
z），9.18（１Ｈ，ｓ） 参考例５ 参考例２〜４と同様にして、１−（2,4−ジフルオロフ
エニル）−６−フルオロ−７−（１−ピペラジニル）−
1,4−ジヒドロ−４−オキソ−1,8−ナフチリジン−３−
カルボン酸の塩酸塩を得る。Melting point: 247 to 250 ° C. (decomposition) (resolving solvent; concentrated hydrochloric acid: ethanol = 1: 3) IR (KBr) cm −1 ; ν c = o 1730 NMR (TFA-d 1 ) δ value; 2.23 to 2.95 ( 2H, m), 3.38-4.83 (5H, m), 6.
95 ~ 7.90 (3H, m), 8.22 (1H, d, J = 11H
z), 9.18 (1H, s) Reference Example 5 1- (2,4-difluorophenyl) -6-fluoro-7- (1-piperazinyl) -in the same manner as in Reference Examples 2 to 4.
1,4-dihydro-4-oxo-1,8-naphthyridine-3-
The carboxylic acid hydrochloride is obtained.
融点；249〜252℃（分解）（再結溶媒；濃塩酸：メタノ
ール＝１：２） ＩＲ（ＫＢｒ）cm-1；νｃ＝ｏ 1730 ＮＭＲ（ＴＦＡ−d1）δ値； 3.33〜3.92（４Ｈ，ｍ），3.92〜4.50（４Ｈ，ｍ），6.
90〜7.90（３Ｈ，ｍ），8.30（１Ｈ，ｄ，Ｊ＝１２H
z），9.18（１Ｈ，ｓ）Melting point: 249 to 252 ° C. (decomposition) (resolving solvent; concentrated hydrochloric acid: methanol = 1: 2) IR (KBr) cm −1 ; ν c = o 1730 NMR (TFA-d 1 ) δ value; 3.33 to 3.92 ( 4H, m), 3.92 to 4.50 (4H, m), 6.
90 ~ 7.90 (3H, m), 8.30 (1H, d, J = 12H
z), 9.18 (1H, s)
───────────────────────────────────────────────────── フロントページの続き (72)発明者 小西 義憲 富山県高岡市佐加野（佐加野新町）1000― 72 (72)発明者 成田 弘和 富山県富山市奥田本町６―40 (72)発明者 高野 俊太郎 富山県富山市稲荷元町３丁目８―44 (72)発明者 才川 勇 富山県富山市大泉中町７―52 審査官 赤坂 信一 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yoshinori Konishi Sano (Takaoka Shinmachi), Takaoka City, Toyama 1000-72 (72) Inventor Hirokazu Narita 6-40, Okudahonmachi, Toyama City, Toyama (72) Inventor Takano Shuntaro 3-8-44, Inarimoto-cho, Toyama-shi, Toyama (72) Inventor Isamu Saikawa 7-52 Oizumi-naka-cho, Toyama-shi, Toyama Examiner Shinichi Akasaka
Claims (1)
塩。1. A general formula A 5-fluoronicotinic acid derivative represented by and a salt thereof.
Priority Applications (52)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60009191A JPH0629247B2 (en) | 1985-01-23 | 1985-01-23 | 5-fluoronicotinic acid derivative and its salt |
| AT72/86A AT392789B (en) | 1985-01-23 | 1986-01-14 | METHOD FOR PRODUCING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES |
| GB8601045A GB2170804B (en) | 1985-01-23 | 1986-01-16 | Novel process for producing 1-substituted aryl-1, 4-dihydro-4-oxonaphthyridine derivative, intermediates thereof and processes for producing the intermediates |
| US06/819,821 US4704459A (en) | 1985-01-23 | 1986-01-17 | Process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives, and processes for producing the intermediates |
| DE3637679A DE3637679C1 (en) | 1985-01-23 | 1986-01-20 | 2- (5-fluoronicotinoyl) acetic acid derivatives and process for their preparation |
| DE19863601517 DE3601517A1 (en) | 1985-01-23 | 1986-01-20 | NEW METHOD FOR PRODUCING 1-SUBST.-ARYL-1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES, INTERMEDIATE PRODUCTS THEREOF AND METHOD FOR PRODUCING THE INTERIM PRODUCTS |
| FI860250A FI83313C (en) | 1985-01-23 | 1986-01-20 | New process for the preparation of 1- (substituted aryl) -1,4-dihydro-4-oxo-1,8-naphthyridine derivatives and intermediates useful in the process |
| DE3641633A DE3641633C2 (en) | 1985-01-23 | 1986-01-20 | New 5-fluoronicotinic acid derivatives, their salts and reactive derivatives of the carboxyl group thereof |
| AU52543/86A AU576657B2 (en) | 1985-01-23 | 1986-01-21 | Naphthyridine and pyridine derivatives |
| CH235/86A CH667456A5 (en) | 1985-01-23 | 1986-01-22 | METHOD FOR PRODUCING 1,4-DIHYDRO-4-OXONAPHTHYRIDINE DERIVATIVES CARRYING A SUBSTITUTED ARYL REST IN 1-POSITION. |
| CN 91102757 CN1027067C (en) | 1985-01-23 | 1986-01-22 | Process for producing 5-fluoronicotinic acids or derivatives, or reactive derivatives in carboxyl group thereof, or their salts |
| NZ214901A NZ214901A (en) | 1985-01-23 | 1986-01-22 | Naphthyridine derivatives and nicotinic acid derivative intermediates |
| CN 86100879 CN1019012B (en) | 1985-01-23 | 1986-01-22 | Process for producing 1-substituted aryl-1, 4-dihydro-4-oxonaphthyridine derivative intermediates |
| NL8600138A NL192986C (en) | 1985-01-23 | 1986-01-22 | Process for preparing 1,4-dihydro-4-oxo-naphthyridine derivatives. |
| ES551134A ES8702362A1 (en) | 1985-01-23 | 1986-01-22 | 1-Fluoro:phenyl-1,8-naphthyridine-3-carboxylic acid derivs. prodn. |
| NO860226A NO163227C (en) | 1985-01-23 | 1986-01-22 | PROCEDURE TE FOR PREPARATION OF 1-SUBSTITUTED-ARYI HYDRO-4-OXONAFTYRIDINE DERIVATIVES. |
| ZA86475A ZA86475B (en) | 1985-01-23 | 1986-01-22 | Process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative,intermediates therefor and processes for producing the intermediates |
| SE8600274A SE462164B (en) | 1985-01-23 | 1986-01-22 | PROCEDURES FOR PREPARING 1-SUBSTITUTED ARYL-1,4-DIHYDRO-4-OXONAFTYRIDE DERIVATIVES |
| PH33316A PH22711A (en) | 1985-01-23 | 1986-01-22 | Novel process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative, intermediates thereof and processes for producing the intermediates |
| BE0/216165A BE904086A (en) | 1985-01-23 | 1986-01-22 | NOVEL PROCESS FOR THE MANUFACTURE OF A DERIVATIVE OF (SUBSTITUTED ARYL) -1 DIHYDRO-1,4 OXO-4 NAPHTYRIDINE INTERMEDIATE SUBSTANCES USED FOR THIS MANUFACTURE AND METHODS OF MANUFACTURE OF INTERMEDIATE SUBSTANCES. |
| CA000500107A CA1340706C (en) | 1985-01-23 | 1986-01-22 | Process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative, intermediates therefor and processes for producing the intermediates |
| KR1019860000388A KR880001078B1 (en) | 1985-01-23 | 1986-01-22 | Process for the preparation of 1-substituted arye-1,4-dihydro-4-oxonaphthyridine derivatives |
| IT47562/86A IT1190193B (en) | 1985-01-23 | 1986-01-22 | PROCEDURE FOR THE PRODUCTION OF AN ARIL-1,4-DIHYDRO-4-OSSONAFTYRIDINE 1-SUBSTITUTE DERIVATIVE, INTERMEDIATE FOR THE SAME, AND PROCEDURES FOR THE PRODUCTION OF INTERMEDIATES |
| CH643/88A CH671957A5 (en) | 1985-01-23 | 1986-01-22 | |
| PT81889A PT81889B (en) | 1985-01-23 | 1986-01-22 | PROCESS FOR THE PREPARATION OF POSITION 1 SUBSTITUTED ARIL-1,4-DIHIDRO-4-OXONETHRIDIDINE DERIVATIVES AND INTERMEDIATE COMPOUNDS USED IN THAT PROCESS |
| DK032286A DK169570B1 (en) | 1985-01-23 | 1986-01-22 | Process for the preparation of 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives |
| FR868600871A FR2576305B1 (en) | 1985-01-23 | 1986-01-22 | NOVEL PROCESS FOR THE MANUFACTURE OF A DERIVATIVE OF (SUBSTITUTED ARYL) -1 DIHYDRO-1,4 OXO-4 NAPHTYRIDINE, INTERMEDIATE SUBSTANCES USED FOR THIS MANUFACTURE AND METHODS OF MANUFACTURE OF INTERMEDIATE SUBSTANCES |
| IL9240186A IL92401A (en) | 1985-01-23 | 1986-01-23 | Process for producing 7-halogeno-1-(4-fluoro or 2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivative |
| LU86264A LU86264A1 (en) | 1985-01-23 | 1986-01-23 | NOVEL PROCESS FOR THE PREPARATION OF A DERIVATIVE OF ARYL-1,4-DIHYDRO 4-OXONAPHTYRIDINE 1-SUBSTITUTED INTERMEDIATE PRODUCTS FOR THIS DERIVATIVE AND PROCESS FOR THE PREPARATION OF INTERMEDIATE PRODUCTS |
| IL77688A IL77688A (en) | 1985-01-23 | 1986-01-23 | Process for producing 7-substituted-6-fluoro-1-(4-fluoro or 2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives and some new such derivatives produced thereby |
| IL88468A IL88468A (en) | 1985-01-23 | 1986-01-23 | 2-(4-fluoro or 2,4-difluorophenylamino)-5-fluoro-6-substituted nicotinic acid and nicotinyl acetic acid and their preparation |
| ES557078A ES8707715A1 (en) | 1985-01-23 | 1986-09-19 | 1-Fluoro:phenyl-1,8-naphthyridine-3-carboxylic acid derivs. prodn. |
| ES557077A ES8707730A1 (en) | 1985-01-23 | 1986-09-19 | 1-Fluoro:phenyl-1,8-naphthyridine-3-carboxylic acid derivs. prodn. |
| PH35456A PH23202A (en) | 1985-01-23 | 1987-06-25 | 2-(5-fluoronicotinoyl) acetic acid derivatives and process of preparation thereof |
| PH35456A PH22956A (en) | 1985-01-23 | 1987-06-25 | Fluoronicotinic avid derivatives and process of preparing said compounds |
| US06/067,264 US4851535A (en) | 1985-01-23 | 1987-06-29 | Nicotinic acid derivatives |
| CH642/88A CH669378A5 (en) | 1985-01-23 | 1988-01-22 | 1-Fluoro:phenyl-1,8-naphthyridine-3-carboxylic acid derivs. prodn. |
| GB8811645A GB2204040B (en) | 1985-01-23 | 1988-05-17 | 2-(5-fluoronicotinoyl)-acetic acid intermediates |
| CA 568266 CA1340648C (en) | 1985-01-23 | 1988-05-31 | Process for producing 1-substituted aryl-1, 4-dihydro-4-oxonaphthyridine derivative, intermediates therefor and porcesses for producing the intermediates |
| CA000568265A CA1340783C (en) | 1985-01-23 | 1988-05-31 | Process for producing 1-substituted aryl-1, 4-dihydro-4-oxonaphthyridine derivative, intermediates therefor and processes for producing the intermediates |
| SE8902265A SE469984B (en) | 1985-01-23 | 1989-06-21 | 5-Fluoronicotinic acid derivative and process for its preparation |
| SE8902264A SE469983B (en) | 1985-01-23 | 1989-06-21 | 2- (5-Fluoronicotinoyl) -acetic acid derivatives and process for their preparation |
| FI893075A FI87647C (en) | 1985-01-23 | 1989-06-22 | FAR OIL FRAMSTERING AV NYA 5-FLUORNICOTIN SYROR ELLER FOR CARBOXYL GROUP DETERMINING REACTIVE DERIVATIVES DAERAV ELLER SALTER DAERAV OCH DERAS MELLANPRODUKTER |
| FI893074A FI85703C (en) | 1985-01-23 | 1989-06-22 | FOERFARANDE FOER FRAMSTAELLNING AV 1,4 -DIHYDRO-4-OXONAFTYRIDINDERIVAT. |
| NO892693A NO167804C (en) | 1985-01-23 | 1989-06-28 | PROCEDURE FOR THE PREPARATION OF 1-SUBSTITUTED-PHENYL-1,4-DIHYDRO-4-OXONAFTYRIDINE DERIVATIVES. |
| NO892692A NO174888C (en) | 1985-01-23 | 1989-06-28 | New 2- (5-fluoro-nicotinoyl) -acetic acid derivatives |
| AT0200289A AT394193B (en) | 1985-01-23 | 1989-08-24 | Process for the preparation of novel 5-fluoronicotinic acids or derivatives and salts thereof |
| AT2003/89A AT392791B (en) | 1985-01-23 | 1989-08-24 | Process for the preparation of 1-substituted aryl-1,4- dihydro-4-oxonaphthyridine derivatives |
| DK285190A DK170857B1 (en) | 1985-01-23 | 1990-11-30 | 2- (5-Fluornicotinoyl) acetic acid derivative and process for its preparation |
| DK285290A DK170532B1 (en) | 1985-01-23 | 1990-11-30 | 5-Fluornicotinic acid derivative or salt thereof or reactive derivative in the carboxyl group thereof |
| NO924181A NO178574C (en) | 1985-01-23 | 1992-10-29 | New 5-fluoronicotinic acid derivatives |
| NL9700011A NL193540C (en) | 1985-01-23 | 1997-11-06 | Method for preparing nicotinic acid derivatives. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60009191A JPH0629247B2 (en) | 1985-01-23 | 1985-01-23 | 5-fluoronicotinic acid derivative and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61171469A JPS61171469A (en) | 1986-08-02 |
| JPH0629247B2 true JPH0629247B2 (en) | 1994-04-20 |
Family
ID=11713630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60009191A Expired - Lifetime JPH0629247B2 (en) | 1985-01-23 | 1985-01-23 | 5-fluoronicotinic acid derivative and its salt |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH0629247B2 (en) |
| ZA (1) | ZA86475B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200528106A (en) * | 2003-11-10 | 2005-09-01 | Synta Pharmaceuticals Corp | Pyridine compounds |
| SA08280783B1 (en) * | 2007-01-11 | 2011-04-24 | استرازينيكا ايه بي | Pyridopyrimidine Derivatives as PDE4 Inhibitors |
-
1985
- 1985-01-23 JP JP60009191A patent/JPH0629247B2/en not_active Expired - Lifetime
-
1986
- 1986-01-22 ZA ZA86475A patent/ZA86475B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61171469A (en) | 1986-08-02 |
| ZA86475B (en) | 1986-09-24 |
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