JPH072802A - Production of optically active triazole derivative - Google Patents
Production of optically active triazole derivativeInfo
- Publication number
- JPH072802A JPH072802A JP6029390A JP2939094A JPH072802A JP H072802 A JPH072802 A JP H072802A JP 6029390 A JP6029390 A JP 6029390A JP 2939094 A JP2939094 A JP 2939094A JP H072802 A JPH072802 A JP H072802A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- triazole derivative
- derivative
- bromocamphor
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003852 triazoles Chemical class 0.000 title claims abstract description 59
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 4
- 239000013543 active substance Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000011833 salt mixture Substances 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 229960000846 camphor Drugs 0.000 claims description 2
- -1 camphor sulfone Chemical class 0.000 claims description 2
- MZWDAEVXPZRJTQ-WUXMJOGZSA-N 4-[(e)-(4-fluorophenyl)methylideneamino]-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound CC1=NNC(=S)N1\N=C\C1=CC=C(F)C=C1 MZWDAEVXPZRJTQ-WUXMJOGZSA-N 0.000 claims 2
- 241000723346 Cinnamomum camphora Species 0.000 claims 1
- 229930008380 camphor Natural products 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 34
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 abstract description 11
- 238000000926 separation method Methods 0.000 abstract description 6
- 238000011033 desalting Methods 0.000 abstract description 4
- 239000003429 antifungal agent Substances 0.000 abstract description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical class C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 abstract 1
- 238000004440 column chromatography Methods 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 125000001425 triazolyl group Chemical group 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- GFBVBBRNPGPROZ-ZVGXWIELSA-N azanium;[(1r,2s,4s,7r)-2-bromo-4,7-dimethyl-3-oxo-7-bicyclo[2.2.1]heptanyl]methanesulfonate Chemical compound [NH4+].C1C[C@]2(C)C(=O)[C@@H](Br)[C@H]1[C@]2(CS([O-])(=O)=O)C GFBVBBRNPGPROZ-ZVGXWIELSA-N 0.000 description 5
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- MFEDKMBNKNOUPA-UHFFFAOYSA-N (2-bromo-4,7-dimethyl-3-oxo-7-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(C)C(=O)C(Br)C1C2(CS(O)(=O)=O)C MFEDKMBNKNOUPA-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- GFBVBBRNPGPROZ-UHFFFAOYSA-N azanium;(2-bromo-4,7-dimethyl-3-oxo-7-bicyclo[2.2.1]heptanyl)methanesulfonate Chemical compound [NH4+].C1CC2(C)C(=O)C(Br)C1C2(CS([O-])(=O)=O)C GFBVBBRNPGPROZ-UHFFFAOYSA-N 0.000 description 3
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- XUJHKPSBHDQIOD-UHFFFAOYSA-N (2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C XUJHKPSBHDQIOD-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NZEBWFSFYQECNY-UHFFFAOYSA-N 3-methyl-3-methylsulfonyl-1-(1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]butan-2-ol Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(O)(C(C)(C)S(C)(=O)=O)CN1C=NC=N1 NZEBWFSFYQECNY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 208000002474 Tinea Diseases 0.000 description 2
- 241000130764 Tinea Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 208000024386 fungal infectious disease Diseases 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940091951 (+-)- 3-bromocamphor Drugs 0.000 description 1
- NJQADTYRAYFBJN-FWWHASMVSA-N (1s,2s,4r)-2-bromo-4,7,7-trimethylbicyclo[2.2.1]heptan-3-one Chemical compound C1C[C@@]2(C)C(=O)[C@@H](Br)[C@@H]1C2(C)C NJQADTYRAYFBJN-FWWHASMVSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- 229930007886 (R)-camphor Natural products 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- FEVALTJSQBFLEU-UHFFFAOYSA-N 1-methyl-4-methylsulfinylbenzene Chemical compound CC1=CC=C(S(C)=O)C=C1 FEVALTJSQBFLEU-UHFFFAOYSA-N 0.000 description 1
- RRYSNSDXICTJMV-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]butan-2-ol Chemical compound CCC(C)(O)C1=CC=C(C(F)(F)F)C=C1 RRYSNSDXICTJMV-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010027236 Meningitis fungal Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000005035 cutaneous candidiasis Diseases 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- MMSGWPLJAYFEQJ-UHFFFAOYSA-N ethanol;n-ethylethanamine;hexane Chemical compound CCO.CCNCC.CCCCCC MMSGWPLJAYFEQJ-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 201000010056 fungal meningitis Diseases 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([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
- 229920005615 natural polymer Polymers 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 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
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明は抗真菌剤として有用なト
リアゾール誘導体の光学活性体の製造法に関する。FIELD OF THE INVENTION The present invention relates to a method for producing an optically active triazole derivative useful as an antifungal agent.
【0002】[0002]
【従来の技術】アゾール系化合物の中には優れた抗真菌
作用を有するものが多く、そのいくつかは各種白癬、癩
癬、乾癬、皮膚カンジダ症、真菌性髄膜炎、真菌性呼吸
器感染症、真菌血症、尿路真菌症などの治療剤として広
く使用されている。ところで、次の一般式(1)BACKGROUND OF THE INVENTION Many azole compounds have excellent antifungal activity, some of which are various tinea, tinea, psoriasis, cutaneous candidiasis, fungal meningitis, fungal respiratory infection. It is widely used as a therapeutic agent for diseases such as infectious diseases, fungal diseases, and urinary mycosis. By the way, the following general formula (1)
【0003】[0003]
【化3】 [Chemical 3]
【0004】〔式中、R1 およびR2 は水素原子もしく
は低級アルキル基を示すか、またはR 1 とR2 が一緒に
なって低級アルキレン基を形成してもよい。R3 は低級
アルキル基を示し、nは0〜2の整数を示す。ただし、
R1 とR2 がともに水素原子となることはない。〕で表
されるトリアゾール誘導体は、優れた抗真菌作用を有す
ることが知られている。また、このトリアゾール誘導体
(1)の光学活性体は、そのラセミ体よりもさらに強い
抗真菌作用を有し、かつ安全性も高いので前記の各種真
菌症の治療剤として有用であることが知られている(特
開平3−223266号公報)。特に、トリアゾール誘
導体(1)のうち、R1 ,R2 ,R3 がともにメチル基
で、nが2である化合物の(−)体が有用である。[Wherein R1And R2Is a hydrogen atom
Represents a lower alkyl group, or R 1And R2Together
May form a lower alkylene group. R3Is low
It represents an alkyl group, and n represents an integer of 0 to 2. However,
R1And R2Are not both hydrogen atoms. ]
Triazole derivatives have excellent antifungal activity
It is known that Also, this triazole derivative
The optically active form (1) is stronger than its racemic form.
It has an antifungal action and is highly safe, so
It is known to be useful as a therapeutic agent for mycosis (special
Kaihei 3-223266). In particular, triazole
R of the conductor (1)1, R2, R3Are both methyl groups
And the (−) form of the compound where n is 2 is useful.
【0005】このトリアゾール誘導体(1)の光学異性
体の製造法としては、2−アルキルチオアセトフェノン
誘導体にS(−)メチル−p−トリルスルホキシド等の
光学活性スルフィニル化合物を反応させて二種のジアス
テレオマー混合物とし、この混合物よりシリカゲルカラ
ムクロマトグラフィーで光学活性体を得、さらに当該光
学活性体を酸化し、アセチルクロリドとヨウ化ナトリウ
ムを反応させ、次いでエポキシ化後、トリアゾールを反
応させることにより得る方法が知られている(特開平3
−223266号公報)。As a method for producing the optical isomer of the triazole derivative (1), two diastereomers are prepared by reacting a 2-alkylthioacetophenone derivative with an optically active sulfinyl compound such as S (-) methyl-p-tolyl sulfoxide. Mer mixture, an optically active substance is obtained from this mixture by silica gel column chromatography, the optically active substance is further oxidized, acetyl chloride is reacted with sodium iodide, and then epoxidation is performed, followed by reaction with triazole. Is known (Japanese Patent Application Laid-Open No. Hei 3
-223266 publication).
【0006】[0006]
【発明が解決しようとする課題】しかし、かかるトリア
ゾール誘導体(1)の光学活性体の製造法は、中間工程
である二種のジアステレオマーの分離効率が悪く、また
製造工程が長いため工業的な生産手段としては不利なる
を免れなかった。従って、本発明の目的は高純度の前記
トリアゾール誘導体(1)の光学活性体を工業的に有利
に製造するための方法を提供することにある。However, the method for producing an optically active substance of the triazole derivative (1) is industrially difficult because the separation efficiency of two diastereomers, which is an intermediate step, is poor and the production step is long. It was inevitable as a disadvantageous production method. Therefore, an object of the present invention is to provide a method for industrially producing a highly pure optically active isomer of the triazole derivative (1).
【0007】[0007]
【課題を解決するための手段】そこで、本発明者らは工
業的に有利に製造できるトリアゾール誘導体(1)のラ
セミ体の光学分割について種々検討してきたところ、従
来より光学分割剤として広く知られている酒石酸誘導体
等を用いても光学活性体は単離できなかったが、光学活
性カンファースルホン酸類を用いれば効率よく光学活性
体が単離できること、さらに光学異性体分離用カラムを
用いた光学分割でも光学活性体が効率よく分離できるこ
とを見出し、本発明を完成するに至った。Therefore, the present inventors have made various studies on the optical resolution of the racemate of the triazole derivative (1) which can be industrially advantageously produced, and have been widely known as an optical resolving agent. The optically active compound could not be isolated even with the use of tartaric acid derivatives, etc., but the optically active compound can be efficiently isolated by using optically active camphorsulfonic acid, and the optical resolution using a column for separation of optical isomers. However, they have found that the optically active substance can be efficiently separated, and have completed the present invention.
【0008】すなわち、本発明は前記一般式(1)で表
されるトリアゾール誘導体のラセミ体に光学活性カンフ
ァースルホン酸類を反応させて、当該トリアゾール誘導
体(1)と光学活性カンファースルホン酸類とのジアス
テレオマー塩混合物を形成せしめ、次いで当該混合物よ
り一方のジアステレオマー塩のみを晶析させた後、脱塩
することを特徴とする当該トリアゾール誘導体(1)の
光学活性体の製造法を提供するものである。That is, in the present invention, the optically active camphorsulfonic acid is reacted with the racemate of the triazole derivative represented by the general formula (1), and the diastereomer of the triazole derivative (1) and the optically active camphorsulfonic acid is reacted. Forming a mer salt mixture, and then crystallizing only one diastereomer salt from the mixture, followed by desalting, which provides a method for producing an optically active form of the triazole derivative (1). Is.
【0009】また、本発明は前記一般式(1)で表され
るトリアゾール誘導体のラセミ体を光学活性固定相を充
填したカラムを用いるクロマトグラフィーに付すことを
特徴とする当該トリアゾール誘導体(1)の光学活性体
の製造法を提供するものである。Further, the present invention is characterized in that the racemate of the triazole derivative represented by the general formula (1) is subjected to chromatography using a column packed with an optically active stationary phase. A method for producing an optically active substance is provided.
【0010】本発明方法に用いられるトリアゾール誘導
体を示す一般式(1)中、R1 ,R 2 およびR3 で示さ
れる低級アルキル基としては、炭素数1〜6の直鎖また
は分枝鎖のアルキル基が挙げられ、具体的にはメチル
基、エチル基、n−プロピル基、イソプロピル基、n−
ブチル基、イソブチル基、sec−ブチル基、tert
−ブチル基、n−ペンチル基、n−ヘキシル基等が挙げ
られ、いずれもメチル基が好ましい。また、R1 および
R2 により形成される低級アルキレン基としては、炭素
数2〜5のアルキレン基、たとえばエチレン基、トリメ
チレン基、テトラメチレン基等が挙げられる。かかるト
リアゾール誘導体(1)の中には、水酸基が結合してい
る炭素原子、R1 およびR2 が結合している炭素原子な
らびに硫黄原子に基づく異性体が存在するが、水酸基が
結合している炭素原子の不斉に基づく光学異性体以外は
特開平3−223266号公報記載の方法により容易に
立体異性体に分離できる。本発明方法により光学分割す
るのは、従来、容易になし得なかった水酸基が結合して
いる炭素原子の不斉に基づくラセミ体である。トリアゾ
ール誘導体(1)のラセミ体は、たとえば特開平3−2
23266号公報記載の方法に従い、容易に製造するこ
とができる。Triazole derivatization used in the method of the present invention
In the general formula (1) representing the body, R1, R 2And R3Indicated by
Examples of the lower alkyl group include a straight chain having 1 to 6 carbon atoms or
Is a branched chain alkyl group, specifically methyl
Group, ethyl group, n-propyl group, isopropyl group, n-
Butyl group, isobutyl group, sec-butyl group, tert
-Butyl group, n-pentyl group, n-hexyl group, etc.
And a methyl group is preferable in each case. Also, R1and
R2The lower alkylene group formed by
An alkylene group having a number of 2 to 5, for example, an ethylene group, a trimer
Examples thereof include a ethylene group and a tetramethylene group. Such
A hydroxyl group is bonded to the lyazole derivative (1).
Carbon atom, R1And R2Is the carbon atom to which
There are isomers based on sulfur atoms, but hydroxyl groups are
Except for optical isomers based on the asymmetry of the carbon atoms attached
Easily by the method described in JP-A-3-223266
It can be separated into stereoisomers. Optical resolution by the method of the present invention
The reason for this is that the hydroxyl group,
It is a racemic body based on the asymmetry of existing carbon atoms. Triazo
The racemate of the diol derivative (1) is described in, for example, JP-A-3-2
It can be easily manufactured according to the method described in Japanese Patent No. 23266.
You can
【0011】本発明方法に用いられる光学分割剤である
光学活性カンファースルホン酸類としては、たとえばハ
ロゲン原子が置換していてもよい光学活性カンファース
ルホン酸又はその塩、具体的には(+)−カンファー−
10−スルホン酸、(−)−カンファー−10−スルホ
ン酸、(+)−3−ブロモカンファー−8−スルホン
酸、(+)−3−ブロモカンファー−10−スルホン
酸、(−)−3−ブロモカンファー−8−スルホン酸、
(−)−3−ブロモカンファー−10−スルホン酸、
(+)−3−ブロモカンファー−8−スルホン酸アンモ
ニウム塩、(−)−3−ブロモカンファー−8−スルホ
ン酸アンモニウム塩等が挙げられるが、就中(+)−3
−ブロモカンファー−8−スルホン酸、(−)−3−ブ
ロモカンファー−8−スルホン酸、(+)−3−ブロモ
カンファー−8−スルホン酸アンモニウム塩、(−)−
3−ブロモカンファー−8−スルホン酸アンモニウム塩
が好ましい。Examples of the optically active camphorsulfonic acid which is an optical resolving agent used in the method of the present invention include, for example, optically active camphorsulfonic acid which may be substituted with a halogen atom or a salt thereof, specifically (+)-camphor. −
10-sulfonic acid, (-)-camphor-10-sulfonic acid, (+)-3-bromocamphor-8-sulfonic acid, (+)-3-bromocamphor-10-sulfonic acid, (-)-3- Bromocamphor-8-sulfonic acid,
(−)-3-bromocamphor-10-sulfonic acid,
(+)-3-Bromocamphor-8-sulfonic acid ammonium salt, (−)-3-bromocamphor-8-sulfonic acid ammonium salt and the like can be mentioned, among which (+)-3.
-Bromocamphor-8-sulfonic acid, (-)-3-bromocamphor-8-sulfonic acid, (+)-3-bromocamphor-8-sulfonic acid ammonium salt, (-)-
3-Bromocamphor-8-sulfonic acid ammonium salt is preferred.
【0012】トリアゾール誘導体(1)のラセミ体と光
学活性カンファースルホン酸類との反応は、この反応に
より生成するジアステレオマー塩混合物から一方のジア
ステレオマー塩のみを晶析させるのに適した溶媒中で行
うのが好ましい。かかる溶媒としては、メタノール、エ
タノール、プロパノール、イソプロパノール、ブタノー
ル、イソブタノール、t−ブタノール等のアルコール
類;ベンゼン、トルエン、キシレン等の炭化水素類、テ
トラヒドロフラン、ジオキサン、ジメトキシエタン、ジ
エチレングリコールジメチルエーテル等のエーテル類;
ジクロルメタン、クロロホルム、ジクロルエタン等のハ
ロゲン化炭化水素類;アセトン、アセトニトリル、ジメ
チルホルムアミド、ジメチルスルホキシド等が挙げられ
る。The reaction between the racemate of the triazole derivative (1) and the optically active camphorsulfonic acid is carried out in a solvent suitable for crystallizing only one of the diastereomeric salts from the diastereomeric salt mixture produced by this reaction. It is preferable to carry out. Examples of such a solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and t-butanol; hydrocarbons such as benzene, toluene, xylene, and ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. ;
Halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane; acetone, acetonitrile, dimethylformamide, dimethylsulfoxide and the like.
【0013】この反応は、トリアゾール誘導体(1)の
ラセミ体1モルに対し、光学活性カンファースルホン酸
類0.5〜1モルを使用し、上記溶媒中に溶解し、室温
から溶媒の沸点までの温度で行われる。この反応によ
り、トリアゾール誘導体(1)の光学活性体と光学活性
カンファースルホン酸類のジアステレオマー塩混合物が
生成する。In this reaction, 0.5 to 1 mol of optically active camphorsulfonic acid is used per 1 mol of the racemate of the triazole derivative (1), the compound is dissolved in the above solvent, and the temperature is from room temperature to the boiling point of the solvent. Done in. By this reaction, a mixture of an optically active substance of the triazole derivative (1) and a diastereomer salt of optically active camphorsulfonic acid is produced.
【0014】このジアステレオマー塩混合物から一方の
ジアステレオマー塩のみを晶析させるには、ジアステレ
オマー塩の溶媒に対する溶解度の差が利用される。たと
えば、反応混合物を冷却することにより行われる。ま
た、あらかじめ用意しておいた光学純度の高い種結晶を
少量添加するのが好ましい。析出した一方のジアステレ
オマー塩をさらに再結晶すれば光学純度が向上する。In order to crystallize only one of the diastereomeric salts from this diastereomeric salt mixture, the difference in the solubility of the diastereomeric salts in the solvent is utilized. For example, by cooling the reaction mixture. Further, it is preferable to add a small amount of seed crystals having high optical purity prepared in advance. Further recrystallization of one of the precipitated diastereomeric salts improves the optical purity.
【0015】得られたジアステレオマー塩を脱塩するに
は、たとえば有機溶媒とアルカリ水溶液の混液中で処理
することにより行われる。かくすることにより、目的の
トリアゾール誘導体(1)の光学活性体は、有機溶媒中
に移行するので、当該有機層から目的物を容易に分離精
製することができる。ここで用いられる有機溶媒として
は酢酸エチル、クロロホルム、塩化メチレン等が好まし
い。アルカリ水溶液としては水酸化ナトリウム、水酸化
カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナ
トリウム、炭酸水素カリウム等の水溶液が用いられる。
また、有機層から目的物の分離精製は、たとえば再結晶
によるのがよく、当該再結晶溶媒としては、水、メタノ
ール、エタノール、プロパノール、イソプロパノール、
エーテル、イソプロピルエーテル、テトラヒドロフラ
ン、ジオキサン等を単独あるいは混合溶媒として用いる
ことができる。Desalination of the obtained diastereomeric salt is carried out, for example, by treating in a mixed solution of an organic solvent and an aqueous alkaline solution. By doing so, the optically active substance of the target triazole derivative (1) is transferred to the organic solvent, and thus the target substance can be easily separated and purified from the organic layer. The organic solvent used here is preferably ethyl acetate, chloroform, methylene chloride or the like. As the alkaline aqueous solution, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or the like is used.
Further, the separation and purification of the target substance from the organic layer may be carried out, for example, by recrystallization, and as the recrystallization solvent, water, methanol, ethanol, propanol, isopropanol,
Ether, isopropyl ether, tetrahydrofuran, dioxane and the like can be used alone or as a mixed solvent.
【0016】さらに、トリアゾール誘導体(1)の光学
活性体は、光学分割剤として(+)−または(−)−3
−ブロモカンファー−8−スルホン酸アンモニウム塩を
用いることによって、より工業的に有利に製造される。
この方法は、特に(−)−3−メチル−3−メチルスル
ホニル−1−(1,2,4−トリアゾール−1−イル)
−2−〔4−(トリフルオロメチル)フェニル〕ブタン
−2−オールの製造に用いるのが有利である。Further, the optically active substance of the triazole derivative (1) is (+)-or (-)-3 as an optical resolving agent.
By using -bromocamphor-8-sulfonic acid ammonium salt, it is more industrially advantageously produced.
This method is particularly suitable for (-)-3-methyl-3-methylsulfonyl-1- (1,2,4-triazol-1-yl).
Preference is given to using it for the production of 2- [4- (trifluoromethyl) phenyl] butan-2-ol.
【0017】すなわち、ラセミ体に硫酸、メタンスルホ
ン酸等の存在下に(−)−3−ブロモカンファー−8−
スルホン酸アンモニウム塩を用いて光学活性な塩、すな
わちトリアゾール誘導体(1)の(−)体の(−)−3
−ブロモカンファー−8−スルホン酸塩を形成させ、つ
いで脱塩、精製処理等を行うことによって、光学純度の
高いトリアゾール誘導体(1)の(−)体が高収率で容
易に得られる。また、(+)−3−ブロモカンファー−
8−スルホン酸アンモニウム塩を用いることも可能であ
り、この場合はトリアゾール誘導体(1)の(−)体の
(+)−3−ブロモカンファー−8−スルホン酸塩が生
成し、上記と同様に処理することによって、光学純度の
高いトリアゾール誘導体(1)の(−)体が高収率で容
易に得られる。これら光学活性な塩は、アルコール(メ
タノール、エタノール、イソプロピルアルコール等)等
の溶媒中、約0℃から約30℃の間の温度の条件下で生
成させることができる。アンモニウムイオンは、硫酸、
メタンスルホン酸等を共存させることにより、酸のアン
モニウム塩として除去できる。光学活性な塩の脱塩は、
たとえば炭酸カリウム、炭酸ナトリウム、炭酸水素ナト
リウム、アンモニウム等のアルカリまたはトリエチルア
ミン等の有機塩基を用いることによって行われる。精製
は再結晶法等それ自体公知の方法を採用できる。なお、
光学活性な塩を晶出させる際には、高純度なトリアゾー
ル誘導体(1)の(−)体の(−)−3−ブロモカンフ
ァー−8−スルホン酸塩またはトリアゾール誘導体
(1)の(−)体の(+)−3−ブロモカンファー−8
−スルホン酸塩の種結晶を添加するのが好ましい。That is, (-)-3-bromocamphor-8- in the presence of racemic compound such as sulfuric acid and methanesulfonic acid.
Optically active salt using ammonium sulfonate, that is, (−)-3 of (−) form of triazole derivative (1)
By forming -bromocamphor-8-sulfonate, followed by desalting, purification treatment and the like, the triazole derivative (1) (-) having high optical purity can be easily obtained in high yield. In addition, (+)-3-bromocamphor-
It is also possible to use ammonium 8-sulfonate, in which case (+)-3-bromocamphor-8-sulfonate of the (−) form of the triazole derivative (1) is produced, and in the same manner as above. By the treatment, the (−) form of the triazole derivative (1) having high optical purity can be easily obtained in high yield. These optically active salts can be formed in a solvent such as alcohol (methanol, ethanol, isopropyl alcohol, etc.) under the condition of the temperature between about 0 ° C and about 30 ° C. Ammonium ion is sulfuric acid,
By coexisting with methanesulfonic acid or the like, it can be removed as an ammonium salt of the acid. Desalting of optically active salts
For example, it is carried out by using an alkali such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate or ammonium or an organic base such as triethylamine. For the purification, a method known per se such as a recrystallization method can be adopted. In addition,
When crystallizing an optically active salt, the (−)-3-bromocamphor-8-sulfonate of the (−) form of the high-purity triazole derivative (1) or the (−) of the triazole derivative (1) is used. (+)-3-Bromocamphor-8 in the body
-Preference is given to adding sulfonate seed crystals.
【0018】光学分割剤として(+)−3−ブロモカン
ファー−8−スルホン酸アンモニウム塩を、また種結晶
として高純度のトリアゾール誘導体(1)の(+)体の
(+)−3−ブロモカンファー−8−スルホン酸塩を用
いることにより、結晶としてトリアゾール(1)の
(+)体の(+)−3−ブロモカンファー−8−スルホ
ン酸塩が得られ、その母液からトリアゾール誘導体
(1)の(−)体の粗結晶が得られることから、これに
結晶化剤として(+)−カンファー−10−スルホン酸
を、また種結晶として高純度のトリアゾール誘導体
(1)の(−)体の(+)−10−カンファースルホン
酸塩を用いることにより、光学純度の高いトリアゾール
誘導体(1)の(−)体の(+)−カンファー−10−
スルホン酸塩が得られる。この塩を上記と同様に処理す
ることにより、遊離のトリアゾール誘導体(1)の
(−)体が高収率で得られる。(+)-3-Bromocamphor-8-sulfonic acid ammonium salt as an optical resolving agent, and (+)-form (+)-3-bromocamphor of the high-purity triazole derivative (1) as a seed crystal. By using -8-sulfonic acid salt, (+)-form (+)-3-bromocamphor-8-sulfonic acid salt of triazole (1) is obtained as crystals, and the triazole derivative (1) of the triazole derivative (1) is obtained from the mother liquor. Since crude crystals of the (-) form are obtained, (+)-camphor-10-sulfonic acid is used as a crystallization agent, and (-) form of the (-) form of the high-purity triazole derivative (1) is used as a seed crystal. By using +)-10-camphor sulfonate, the (+)-camphor-10- of the (−) form of the triazole derivative (1) having high optical purity is obtained.
A sulfonate salt is obtained. By treating this salt in the same manner as above, the free triazole derivative (1) (-) form is obtained in high yield.
【0019】次に、光学異性体分離用カラムを用いる方
法について説明する。光学活性固定相としては、合成光
学活性ポリマー、天然高分子、アミノ酸の金属錯体等が
挙げられるが、セルロース誘導体をコーティングしたシ
リカゲルが好ましい。当該セルロース誘導体をコーティ
ングしたシリカゲルを充填したカラムとしては、キラル
セルOJ光学異性体分離用カラム(ダイセル化学工業
(株)製)等の市販品を用いることができる。また、ク
ロマトグラフィーの形式としては液体クロマトグラフィ
ーが好ましい。この場合、移動相としての溶離液は、た
とえばヘキサン−エタノール−ジエチルアミン、ヘキサ
ン−イソプロパノール等を用いることができる。Next, a method of using a column for separating optical isomers will be described. Examples of the optically active stationary phase include synthetic optically active polymers, natural polymers, metal complexes of amino acids, and the like, and silica gel coated with a cellulose derivative is preferable. As the column packed with the silica gel coated with the cellulose derivative, a commercially available product such as a column for chiral cell OJ optical isomer separation (manufactured by Daicel Chemical Industries, Ltd.) can be used. Liquid chromatography is preferred as the format of chromatography. In this case, the eluent as the mobile phase can be, for example, hexane-ethanol-diethylamine, hexane-isopropanol or the like.
【0020】[0020]
【発明の効果】本発明方法によれば、各種真菌症治療剤
として有用なトリアゾール誘導体(1)の光学活性体
が、簡便かつ工業的に有利に製造できる。According to the method of the present invention, an optically active substance of the triazole derivative (1) useful as a therapeutic agent for various fungal diseases can be produced easily and industrially advantageously.
【0021】[0021]
【実施例】次に実施例を挙げて本発明を詳細に説明する
が、本発明はこれら実施例に限定されるものではない。EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.
【0022】実施例1 (−)−3−メチル−3−メチルスルホニル−1−
(1,2,4−トリアゾール−1−イル)−2−〔4−
(トリフルオロメチル)フェニル〕ブタン−2−オール
〔以下、「目的(−)体」という〕の合成: (1)(±)−3−メチル−3−メチルスルホニル−1
−(1,2,4−トリアゾール−1−イル)−2−〔4
−(トリフルオロメチル)フェニル〕ブタン−2−オー
ル100gにイソプロパノール1.8lを加え、65℃
で攪拌下溶解した。同温で(+)−3−ブロモカンファ
ー−8−スルホン酸82.5gのイソプロピルアルコー
ル溶液0.6lを加え、80℃で30分攪拌した。50
℃まで放冷後、純度の高い種結晶を接種し、25℃で3
日間静置した。析出した結晶を濾取し、イソプロパノー
ル0.2lで洗浄し、乾燥して目的(−)体の(+)−
3−ブロモカンファー−8−スルホン酸塩を98.3g
得た(光学純度53.8%e.e.)。Example 1 (-)-3-Methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
Synthesis of (trifluoromethyl) phenyl] butan-2-ol [hereinafter referred to as the "target (-) form"]: (1) (±) -3-methyl-3-methylsulfonyl-1
-(1,2,4-triazol-1-yl) -2- [4
To 100 g of-(trifluoromethyl) phenyl] butan-2-ol was added 1.8 l of isopropanol, and the mixture was heated to 65 ° C.
Dissolved under stirring. At the same temperature, 0.61 of an isopropyl alcohol solution containing 82.5 g of (+)-3-bromocamphor-8-sulfonic acid was added, and the mixture was stirred at 80 ° C for 30 minutes. Fifty
After allowing to cool to ℃, seed with high-purity seed crystals and
Let stand for days. The precipitated crystals were collected by filtration, washed with 0.2 l of isopropanol, and dried to obtain (+)-of the desired (-) form.
98.3 g of 3-bromocamphor-8-sulfonate
Obtained (optical purity 53.8% ee).
【0023】(2)得られた目的(−)体の塩にイソプ
ロパノール2lを加え、80℃で40分攪拌溶解した
後、純度の高い種結晶を接種し、25℃で2日間静置し
た。析出した結晶を濾取し、イソプロパノール0.2l
で洗浄し、乾燥して目的(−)体の(+)−3−ブロモ
カンファー−8−スルホン酸塩を70.0g得た(光学
純度96.4%e.e.)。さらに、この塩をイソプロ
パノール1.5lに加温溶解し、同様の操作を行い、目
的(−)体の(+)−3−ブロモカンファー−8−スル
ホン酸塩を62.2g得た(光学純度99.5%e.
e.)。(2) 2 liters of isopropanol was added to the obtained salt of the target (-) form, and the mixture was stirred and dissolved at 80 ° C for 40 minutes, inoculated with a highly pure seed crystal, and allowed to stand at 25 ° C for 2 days. The precipitated crystals were collected by filtration, and 0.2 liter of isopropanol
After washing with water and drying, 70.0 g of (+)-3-bromocamphor-8-sulfonate of the objective (-) form was obtained (optical purity 96.4% ee). Further, this salt was dissolved in 1.5 liter of isopropanol with heating, and the same operation was performed to obtain 62.2 g of (+)-3-bromocamphor-8-sulfonate of the objective (-) form (optical purity 99.5% e.
e. ).
【0024】(3)上記の塩、酢酸エチル0.7lおよ
び10%炭酸カリウム0.25lの混合物を攪拌し、有
機層を水洗し、無水硫酸マグネシウムで乾燥した。溶媒
留去し、残渣を40%エタノールで再結晶すると目的
(−)体を25.9g得た。光学純度99.5%e.
e.、融点145〜147℃、〔α〕D 25−9.4°
(c=0.5、アセトン)(3) A mixture of the above salt, 0.7 l of ethyl acetate and 0.25 l of 10% potassium carbonate was stirred, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from 40% ethanol to obtain 25.9 g of the target (-) form. Optical purity 99.5% e.
e. , Melting point 145 to 147 ° C., [α] D 25 −9.4 °
(C = 0.5, acetone)
【0025】実施例2 (±)−3−メチル−3−メチルスルホニル−1−
(1,2,4−トリアゾール−1−イル)−2−〔4−
(トリフルオロメチル)フェニル〕ブタン−2−オール
200mg、(+)−カンファー−10−スルホン酸6
1.6mgにイソプロパノール3mlを加え、加温し、
溶解した。種結晶を接種し、室温で終夜静置した。析出
した結晶を濾取し、イソプロパノール1mlで洗浄した
後、乾燥し、目的(−)体の(+)−カンファー−10
−スルホン酸塩80mgを得た(光学純度82.0%
e.e.)。この塩を実施例1と同様に再結晶後、脱塩
したところ、高純度の目的(−)体が得られた。Example 2 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
(Trifluoromethyl) phenyl] butan-2-ol 200 mg, (+)-camphor-10-sulfonic acid 6
3 ml of isopropanol was added to 1.6 mg and heated,
Dissolved. Seed crystals were inoculated and left at room temperature overnight. The precipitated crystals were collected by filtration, washed with 1 ml of isopropanol, and then dried to obtain (+)-camphor-10 of the desired (-) form.
80 mg of sulfonate were obtained (optical purity 82.0%
e. e. ). This salt was recrystallized and then desalted in the same manner as in Example 1 to obtain a highly pure target (-) form.
【0026】実施例3 (±)−3−メチル−3−メチルスルホニル−1−
(1,2,4−トリアゾール−1−イル)−2−〔4−
(トリフルオロメチル)フェニル〕ブタン−2−オール
をキラルセルOJ光学異性体分離用カラムを用い、移動
相(ヘキサン:エタノール:ジエチルアミン=800:
200:1)によりそれぞれの光学異性体に分離し、目
的(−)体(光学純度99%e.e.)と(+)−3−
メチル−3−メチルスルホニル−1−(1,2,4−ト
リアゾール−1−イル)−2−〔4−(トリフルオロメ
チル)フェニル〕ブタン−2−オール(光学純度99%
e.e.)を得た。Example 3 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
The (trifluoromethyl) phenyl] butan-2-ol was used as a mobile phase (hexane: ethanol: diethylamine = 800 :) using a chiralcel OJ optical isomer separation column.
200: 1) to separate the respective optical isomers, and the target (-) isomer (optical purity 99% ee) and (+)-3-
Methyl-3-methylsulfonyl-1- (1,2,4-triazol-1-yl) -2- [4- (trifluoromethyl) phenyl] butan-2-ol (optical purity 99%
e. e. ) Got.
【0027】実施例4 (±)−3−メチル−3−メチルスルホニル−1−
(1,2,4−トリアゾール−1−イル)−2−〔4−
(トリフルオロメチル)フェニル〕ブタン−2−オール
10gおよび(−)−3−ブロモカンファー−8−スル
ホン酸アンモニウム塩6.3gをメタノール100ml
に溶解し、水冷下、濃硫酸1.33gを加えた後、メタ
ノールを減圧留去する。残留物にイソプロパノール15
0mlを加え、加温溶解させる。不溶物を濾去した後、
高純度の目的(−)体の(−)−3−ブロモカンファー
−8−スルホン酸塩を接種し、室温で一夜放置する。析
出した結晶を濾取、乾燥すると目的(−)体の(−)−
3−ブロモカンファー−8−スルホン酸塩が白色結晶と
して8.2g得られた(光学純度96%e.e.)。こ
れをさらにイソプロパノール82mlから再結晶すると
光学純度99.5%e.e.以上の目的(−)体の
(−)−3−ブロモカンファー−8−スルホン酸塩7.
8gが得られた。この塩を水150mlに懸濁し炭酸カ
リウムでアルカリ性とした後、酢酸エチルで抽出し、水
洗、乾燥した。濃縮後、残留物を含水エタノールから再
結晶すると目的(−)体が白色結晶として4.1g得ら
れた。融点145〜147℃、収率82%。〔α〕D 25
−10.7°(c=0.5、アセトン)。Example 4 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
10 g of (trifluoromethyl) phenyl] butan-2-ol and 6.3 g of (−)-3-bromocamphor-8-sulfonic acid ammonium salt were added to 100 ml of methanol.
Was dissolved in water, 1.33 g of concentrated sulfuric acid was added under water cooling, and methanol was distilled off under reduced pressure. Isopropanol 15 in the residue
Add 0 ml and dissolve by heating. After filtering off the insoluble matter,
Inoculation with (-)-3-bromocamphor-8-sulfonate of the objective (-) form of high purity is performed, and the mixture is allowed to stand at room temperature overnight. The precipitated crystals are collected by filtration and dried to obtain the desired (-) form (-)-
8.2 g of 3-bromocamphor-8-sulfonate was obtained as white crystals (optical purity 96% ee). When recrystallized from 82 ml of isopropanol, the optical purity was 99.5% e.p. e. (-)-3-Bromocamphor-8-sulfonate of the above objective (-) form 7.
8 g was obtained. This salt was suspended in 150 ml of water, made alkaline with potassium carbonate, extracted with ethyl acetate, washed with water and dried. After concentration, the residue was recrystallized from hydrous ethanol to obtain 4.1 g of the target (-) form as white crystals. Melting point 145-147 ° C, yield 82%. [Α] D 25
-10.7 ° (c = 0.5, acetone).
【0028】実施例5 (±)−3−メチル−3−メチルスルホニル−1−
(1,2,4−トリアゾール−1−イル)−2−〔4−
(トリフルオロメチル)フェニル〕ブタン−2−オール
10gおよび(+)−3−ブロモカンファー−8−スル
ホン酸アンモニウム塩6.3gをメタノール100ml
に溶解し、水冷下、濃硫酸1.33gを加えた後、メタ
ノールを減圧留去する。残留物にイソプロパノール15
0mlを加え、加温溶解させる。不溶物を濾去した後、
高純度の目的(−)体の(+)−3−ブロモカンファー
−8−スルホン酸塩を接種し、室温で一夜放置する。析
出した結晶を濾取、乾燥すると目的(−)体の(+)−
3−ブロモカンファー−8−スルホン酸塩が白色結晶と
して8.3g得られた。光学純度53%e.e.。これ
をさらにイソプロパノールから2回再結晶すると、光学
純度99.5%e.e.以上の目的(−)体の(+)−
3−ブロモカンファー−8−スルホン酸塩5.5gが得
られた。この塩を実施例4と同様に処理して目的(−)
体2.8gを得た。融点145〜147℃、収率56
%。〔α〕D 25−10.8°(c=0.5、アセト
ン)。Example 5 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
10 g of (trifluoromethyl) phenyl] butan-2-ol and 6.3 g of (+)-3-bromocamphor-8-sulfonic acid ammonium salt were added to 100 ml of methanol.
Was dissolved in water, 1.33 g of concentrated sulfuric acid was added under water cooling, and methanol was distilled off under reduced pressure. Isopropanol 15 in the residue
Add 0 ml and dissolve by heating. After filtering off the insoluble matter,
A high-purity (-)-form (+)-3-bromocamphor-8-sulfonate is inoculated and left overnight at room temperature. The precipitated crystals are collected by filtration and dried to give the desired (-) form (+)-
8.3 g of 3-bromocamphor-8-sulfonate was obtained as white crystals. Optical purity 53% e. e. . This was recrystallized twice from isopropanol to give an optical purity of 99.5% e.p. e. (+)-Of the above purpose (-) body
5.5 g of 3-bromocamphor-8-sulfonate was obtained. This salt was treated in the same manner as in Example 4 to obtain the objective (-).
2.8 g of body was obtained. Melting point 145 to 147 ° C, yield 56
%. [Α] D 25 -10.8 ° (c = 0.5, acetone).
【0029】実施例6 (±)−3−メチル−3−メチルスルホニル−1−
(1,2,4−トリアゾール−1−イル)−2−〔4−
(トリフルオロメチル)フェニル〕ブタン−2−オール
9.1gおよび(+)−3−ブロモカンファー−8−ス
ルホン酸アンモニウム塩5.7gをメタノール90ml
に溶解し、水冷下、濃硫酸1.21gを得た後、メタノ
ールを減圧留去する。残留物にイソプロパノール136
mlを加え、加温溶解させる。不溶物を濾去した後、高
純度の(+)−3−メチル−3−メチルスルホニル−1
−(1,2,4−トリアゾール−1−イル)−2−〔4
−(トリフルオロメチル)フェニル〕ブタン−2−オー
ルの(+)−3−ブロモカンファー−8−スルホン酸塩
を接種し、室温で一夜放置する。析出した結晶を濾取、
乾燥すると、(+)−3−メチル−3−メチルスルホニ
ル−1−(1,2,4−トリアゾール−1−イル)−2
−〔4−(トリフルオロメチル)フェニル〕ブタン−2
−オールの(+)−3−ブロモカンファー−8−スルホ
ン酸塩が白色結晶として7.1g得られた。光学純度9
9%e.e.。この母液より得た粗目的(−)体5.4
gをイソプロパノール80mlに溶解させ、(+)−カ
ンファー−10−スルホン酸3.3gを加えて、加温溶
解させる。これに高純度の目的(−)体の(+)−カン
ファー−10−スルホン酸塩を接種し、室温で一夜放置
後、析出した結晶を濾取、イソプロパノールから再結晶
すると、光学純度99.5%e.e.以上の目的(−)
体の(+)−カンファー−10−スルホン酸塩6.1g
が得られた。この塩を実施例4と同様に処理して目的
(−)体3.6gを得た。融点145〜147℃、収率
79%。〔α〕D 25−10.8°(c=0.5、アセト
ン)。Example 6 (±) -3-methyl-3-methylsulfonyl-1-
(1,2,4-triazol-1-yl) -2- [4-
9.1 g of (trifluoromethyl) phenyl] butan-2-ol and 5.7 g of (+)-3-bromocamphor-8-sulfonic acid ammonium salt were added to 90 ml of methanol.
Was dissolved in water and 1.21 g of concentrated sulfuric acid was obtained under water cooling, and then methanol was distilled off under reduced pressure. Isopropanol 136 on residue
Add ml and dissolve by heating. After filtering off the insoluble matter, highly pure (+)-3-methyl-3-methylsulfonyl-1
-(1,2,4-triazol-1-yl) -2- [4
Inoculate (+)-3-bromocamphor-8-sulfonate of-(trifluoromethyl) phenyl] butan-2-ol and leave at room temperature overnight. The precipitated crystals are collected by filtration,
When dried, (+)-3-methyl-3-methylsulfonyl-1- (1,2,4-triazol-1-yl) -2
-[4- (trifluoromethyl) phenyl] butane-2
7.1 g of (-)-3-bromocamphor-8-sulfonate of -ol was obtained as white crystals. Optical purity 9
9% e. e. . The crude (-) form 5.4 obtained from this mother liquor
g is dissolved in 80 ml of isopropanol, 3.3 g of (+)-camphor-10-sulfonic acid is added, and dissolved by heating. A high-purity (+)-form (+)-camphor-10-sulfonate was inoculated into this, and after standing at room temperature overnight, the precipitated crystals were collected by filtration and recrystallized from isopropanol to give an optical purity of 99.5. % E. e. Purpose of the above (-)
6.1 g of (+)-camphor-10-sulfonate of the body
was gotten. This salt was treated in the same manner as in Example 4 to obtain 3.6 g of the desired (-) form. Melting point 145-147 ° C, yield 79%. [Α] D 25 -10.8 ° (c = 0.5, acetone).
───────────────────────────────────────────────────── フロントページの続き (72)発明者 中澤 等 千葉県成田市橋賀台3−5−23−102 (72)発明者 松田 秀明 千葉県我孫子市東我孫子2−29−8 (72)発明者 倉石 忠幸 千葉県習志野市香澄2−5−4 (72)発明者 鶴田 峯生 福岡県築上郡吉富町大字小祝955番地 吉 富製薬株式会社創薬研究センター内 (72)発明者 川崎 和幸 福岡県築上郡吉富町大字小祝955番地 吉 富製薬株式会社創薬研究センター内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Nakazawa et al. 3-5-23-102 Hashigadai, Narita City, Chiba Prefecture (72) Inventor Hideaki Matsuda 2-29-8 Higashi Abiko, Abiko City, Chiba Prefecture Inventor Tadayuki Kuraishi 2-5-4 Kasumi, Narashino City, Chiba Prefecture (72) Minoru Tsuruta, Inoue, 955 Address, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Research Center (72) Kazuyuki Kawasaki, Yoshitomi, Chikami-gun, Fukuoka Prefecture Machizai Ozawari 955 Address Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Research Center
Claims (2)
ル基を示すか、またはR 1 とR2 が一緒になって低級ア
ルキレン基を形成してもよい。R3 は低級アルキル基を
示し、nは0〜2の整数を示す。ただし、R1 とR2 が
ともに水素原子になることはない。〕で表されるトリア
ゾール誘導体のラセミ体に光学活性カンファースルホン
酸類を反応させて当該トリアゾール誘導体と光学活性カ
ンファースルホン酸類とのジアステレオマー塩混合物を
形成せしめ、次いで当該混合物より一方のジアステレオ
マー塩のみを晶析させた後、脱塩することを特徴とする
トリアゾール誘導体の光学活性体の製造法。1. A compound represented by the general formula (1):[In the formula, R1And R2Is a hydrogen atom or lower alk
Represents a radical or R 1And R2Together with
A alkylene group may be formed. R3Is a lower alkyl group
It shows and n shows the integer of 0-2. However, R1And R2But
Neither becomes a hydrogen atom. ] Represented by
Optically active camphor sulfone as racemate of sol derivative
The triazole derivative and the optically active carboxylic acid are reacted with an acid.
Diastereomeric salt mixture with
Formed and then one diastereomer from the mixture.
It is characterized in that only the mer salt is crystallized and then desalted.
Process for producing optically active triazole derivative.
ル基を示すか、またはR 1 とR2 が一緒になって低級ア
ルキレン基を形成してもよい。R3 は低級アルキル基を
示し、nは0〜2の整数を示す。ただし、R1 とR2 が
ともに水素原子になることはない。〕で表されるトリア
ゾール誘導体のラセミ体を光学活性固定相を充填したカ
ラムを用いるクロマトグラフィーに付すことを特徴とす
る当該トリアゾール誘導体の光学活性体の製造法。2. A compound represented by the general formula (1):[In the formula, R1And R2Is a hydrogen atom or lower alk
Represents a radical or R 1And R2Together with
A alkylene group may be formed. R3Is a lower alkyl group
It shows and n shows the integer of 0-2. However, R1And R2But
Neither becomes a hydrogen atom. ] Represented by
The racemic sol derivative is packed with an optically active stationary phase.
Characterized by being subjected to chromatography using ram
A method for producing an optically active substance of the triazole derivative.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP02939094A JP3503832B2 (en) | 1993-03-01 | 1994-02-28 | Method for producing optically active triazole derivative |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3984593 | 1993-03-01 | ||
JP5-39845 | 1993-03-01 | ||
JP02939094A JP3503832B2 (en) | 1993-03-01 | 1994-02-28 | Method for producing optically active triazole derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH072802A true JPH072802A (en) | 1995-01-06 |
JP3503832B2 JP3503832B2 (en) | 2004-03-08 |
Family
ID=26367587
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP02939094A Expired - Fee Related JP3503832B2 (en) | 1993-03-01 | 1994-02-28 | Method for producing optically active triazole derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP3503832B2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005534693A (en) * | 2002-07-30 | 2005-11-17 | クラリアント(フランス) | Preparation of primary amines |
WO2013077265A1 (en) | 2011-11-25 | 2013-05-30 | 株式会社クレハ | Azole derivative and use thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6651107B1 (en) * | 1999-09-21 | 2003-11-18 | Intel Corporation | Reduced hardware network adapter and communication |
-
1994
- 1994-02-28 JP JP02939094A patent/JP3503832B2/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005534693A (en) * | 2002-07-30 | 2005-11-17 | クラリアント(フランス) | Preparation of primary amines |
WO2013077265A1 (en) | 2011-11-25 | 2013-05-30 | 株式会社クレハ | Azole derivative and use thereof |
Also Published As
Publication number | Publication date |
---|---|
JP3503832B2 (en) | 2004-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH0529216B2 (en) | ||
US20070100149A1 (en) | Process for preparing letrozole | |
JPH0674243B2 (en) | Optically active atenolol salt with high optical purity and process for producing atenolol | |
JP5255765B2 (en) | Method and intermediate for producing entitabine | |
JPH072802A (en) | Production of optically active triazole derivative | |
CN111777554A (en) | Method for synthesizing cisatracurium besilate | |
JP3018296B2 (en) | Method for producing glycidyl ether | |
KR20040018275A (en) | Process for the preparation of racemic and enantiomerically pure derivatives of 1,5-diaryl-3-trifluoromethyl-delta2-pyrazoliines | |
JPH07330732A (en) | Optically active 3-amino-1-benzylpiperidine derivative | |
JPH06122686A (en) | Method for optical resolution of racemic modification | |
US8569322B2 (en) | Lamivudine oxalate and preparation method thereof | |
JPS5846045A (en) | Resolution of racemic compound (1rs,2sr)-2- amino-1-phenyl-propan-1-ol | |
JP3157117B2 (en) | Optical resolution method of piperidine derivative | |
JP2013095725A (en) | Method for producing enantiomer of triazole compound | |
JP3225107B2 (en) | Method for producing optically active 2-propanol derivative | |
JP4109446B2 (en) | Process for producing pure trans-2-[(α-methylbenzyl) amino] cyclopentanol as a diastereoisomer | |
JP2002371060A (en) | Method for producing optically active aminopiperidine derivative | |
JPH0570439A (en) | Production of optically active azole derivative | |
JPH07258215A (en) | Production of optically active 1-(4-chloropyridin-2-yl)-2-(pyridin-2-yl)ethylamine | |
JPH09241227A (en) | New optical resolution agent | |
JP2001131157A (en) | Method for producing optically active 2-methylpiperazine | |
JPH07215955A (en) | Production of optically active erythro-3-amino-1,2-epoxy form | |
JPH023627A (en) | Production of optically active 1-methyl-3-phenylpropylamine | |
JPH0436279A (en) | Production of optically active benzoxepin derivative | |
CN115210223A (en) | Tricyclic compound and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20031203 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20031205 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20071219 Year of fee payment: 4 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
LAPS | Cancellation because of no payment of annual fees |