JP5679102B2 - Optically active form and diastereomeric salt of dihydroisoxazole-substituted benzoic acid compound and method for producing the same - Google Patents
Optically active form and diastereomeric salt of dihydroisoxazole-substituted benzoic acid compound and method for producing the same Download PDFInfo
- Publication number
- JP5679102B2 JP5679102B2 JP2010174135A JP2010174135A JP5679102B2 JP 5679102 B2 JP5679102 B2 JP 5679102B2 JP 2010174135 A JP2010174135 A JP 2010174135A JP 2010174135 A JP2010174135 A JP 2010174135A JP 5679102 B2 JP5679102 B2 JP 5679102B2
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- JP
- Japan
- Prior art keywords
- group
- alkyl
- haloalkyl
- diastereomeric salt
- dihydroisoxazol
- 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.)
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- -1 benzoic acid compound Chemical class 0.000 title claims description 192
- 150000003839 salts Chemical class 0.000 title claims description 61
- 238000004519 manufacturing process Methods 0.000 title claims description 17
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title description 6
- 239000005711 Benzoic acid Substances 0.000 title description 5
- 235000010233 benzoic acid Nutrition 0.000 title description 5
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 11
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 5
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 5
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 37
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 125000001424 substituent group Chemical group 0.000 description 20
- 239000007787 solid Substances 0.000 description 17
- 238000004296 chiral HPLC Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 11
- KBWVSPGZOPXKRR-KRWDZBQOSA-N 4-[(5s)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-methylbenzoic acid Chemical compound C1=C(C(O)=O)C(C)=CC(C=2C[C@](ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 KBWVSPGZOPXKRR-KRWDZBQOSA-N 0.000 description 10
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- 239000013543 active substance Substances 0.000 description 10
- KBWVSPGZOPXKRR-UHFFFAOYSA-N 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-methylbenzoic acid Chemical compound C1=C(C(O)=O)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 KBWVSPGZOPXKRR-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 150000007514 bases Chemical class 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- KBWVSPGZOPXKRR-QGZVFWFLSA-N 4-[(5r)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-methylbenzoic acid Chemical compound C1=C(C(O)=O)C(C)=CC(C=2C[C@@](ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 KBWVSPGZOPXKRR-QGZVFWFLSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- 229960004365 benzoic acid Drugs 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 4
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- VDMAQVANUGNDOM-UHFFFAOYSA-N 3-methyl-2-phenylbutan-1-amine Chemical compound CC(C)C(CN)C1=CC=CC=C1 VDMAQVANUGNDOM-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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 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
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- NWYYWIJOWOLJNR-UHFFFAOYSA-N 2-Amino-3-methyl-1-butanol Chemical compound CC(C)C(N)CO NWYYWIJOWOLJNR-UHFFFAOYSA-N 0.000 description 2
- 125000006024 2-pentenyl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- 150000007513 acids Chemical class 0.000 description 2
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- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012776 electronic material Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
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- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
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- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
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- 239000000575 pesticide Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 229960000948 quinine Drugs 0.000 description 2
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- RAFFEHDNCQXIQG-UHFFFAOYSA-N 2-[(1,3-dimethyl-4,5-diphenylimidazolidin-2-ylidene)amino]-3-phenylpropan-1-ol Chemical compound CN1C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)N(C)C1=NC(CO)CC1=CC=CC=C1 RAFFEHDNCQXIQG-UHFFFAOYSA-N 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 125000001973 tert-pentyl group Chemical group [H]C([H])([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
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
本発明は、医農薬あるいは電子材料等の機能性材料として、もしくはその製造中間体として有用な４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物のジアステレオマー塩法による光学活性体とその製造方法、４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体と光学活性な塩基性化合物とを構成成分として有するジアステレオマー塩の製造方法とそのジアステレオマー塩に関するものである。 The present invention is based on a diastereomeric salt method of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound useful as a functional material such as a medical pesticide or an electronic material, or as an intermediate for its production. Optically active substance and production method thereof, and production of diastereomeric salt having optically active substance of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound and optically active basic compound as constituents The method and its diastereomeric salts.
従来、４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体を製造する方法としては、特許文献１が知られている。 Conventionally, Patent Document 1 is known as a method for producing an optically active substance of a 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound.
また、一般的な方法として、ラセミ体の４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物を光学活性な担体を担持したカラムによる光学分割により光学活性体とする方法が考えられるが、生産性が高くなく、工業的生産には改善の余地があると考えられる。 Further, as a general method, there is a method in which a racemic 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound is converted into an optically active substance by optical resolution using a column carrying an optically active carrier. Although it can be considered, productivity is not high and there is room for improvement in industrial production.
ジアステレオマー塩法による４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体の製造方法と、４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体と光学活性な塩基性化合物とを構成成分として有するジアステレオマー塩の製造方法及びそのジアステレオマー塩を提供することである。 Process for producing optically active form of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound by diastereomeric salt method, and 4- (4,5-dihydroisoxazol-3-yl) It is to provide a method for producing a diastereomeric salt having an optically active form of a benzoic acid compound and an optically active basic compound as constituents, and a diastereomeric salt thereof.
本発明者らは、このような状況に鑑み、鋭意検討した結果、４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体と光学活性な塩基性化合物とを構成成分として有するジアステレオマー塩を見出し、このジアステレオマー塩を分解することにより、４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体を簡便に製造する方法を完成させるに至った。
すなわち、本発明は、
〔１〕
一般式（１）：
As a result of intensive studies in view of such circumstances, the present inventors have determined that an optically active substance of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound and an optically active basic compound are obtained. An optically active form of a 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound is easily produced by finding a diastereomeric salt having a constituent component and decomposing the diastereomeric salt. It came to complete the method.
That is, the present invention
[1]
General formula (1):
［式中、R1は、C1〜C6ハロアルキル又はC3〜C8ハロシクロアルキルを表し、
A1、A2、A3及びA4は、それぞれ独立にN又はC-Yを表し、
A5、A6および及びA7は、それぞれ独立にN又はC-Xを表し、
Xは、水素原子、ハロゲン原子、シアノ、ニトロ、-SF5、C1〜C6アルキル、C1〜C6ハロアルキル、ヒドロキシ（C1〜C6）ハロアルキル、C1〜C6アルコキシ(C1〜C6)ハロアルキル、C1〜C6ハロアルコキシ(C1〜C6)ハロアルキル、C3〜C8ハロシクロアルキル、-OR2、-OSO2R2又は-S(O)rR2を表し、各々のXは互いに同一であっても又は互いに相異なっていてもよく、
R2は、C1〜C6アルキル、C1〜C4アルコキシ(C1〜C4)アルキル、C1〜C6ハロアルキル又はC1〜C3ハロアルコキシ(C1〜C3)ハロアルキルを表し、
Yは、水素原子、ハロゲン原子、シアノ、ニトロ、C1〜C4アルキル、C1〜C4ハロアルキル、C1〜C4アルコキシ、C1〜C4ハロアルコキシ、C1〜C6アルキルチオ、C1〜C6ハロアルキルチオ、C1〜C6アルキルスルホニル、C1〜C6ハロアルキルスルホニル、-NH2、-N(R4)R3を表し、各々のYは互いに同一であっても又は互いに相異なっていてもよく、
隣接する２つのYが一緒になって、A8=A9-A10=A11を形成していても良く、
A8、A9、A10及びA11は、それぞれ独立にN又はC-Y1を表し、
Y1は、水素原子、ハロゲン原子、シアノ、ニトロ、C1〜C4アルキル、C1〜C4ハロアルキル、C1〜C4アルコキシ、C1〜C4ハロアルコキシ、C1〜C6アルキルチオ、C1〜C6ハロアルキルチオ、C1〜C6アルキルスルホニル、C1〜C6ハロアルキルスルホニル、-NH2、-N(R4)R3を表し、各々のY1は互いに同一であっても又は互いに相異なっていてもよく、
R3は、C1〜C6アルキル、-CHO、C1〜C6アルキルカルボニル、C1〜C6ハロアルキルカルボニル、C1〜C6アルコキシカルボニル、C1〜C6アルキルチオカルボニル、C1〜C6アルコキシチオカルボニル、C1〜C6アルキルジチオカルボニル、C1〜C6アルキルスルホニル又はC1〜C6ハロアルキルスルホニルを表し、
R4は、水素原子又はC1〜C6アルキルを表し、
rは、０〜２の整数を表す] で表される４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物と、光学活性なα−フェニルエチルアミンと溶液中で反応させ、次に晶析により一方のジアステレオマー塩を析出させ分離する、前記溶液に対して低溶解性のジアステレオマー塩の製造方法
〔２〕
前記〔１〕に記載のジアステレオマー塩を酸により分解することによる、式（１）で表される４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体の製造方法。
[Wherein R 1 represents C 1 -C 6 haloalkyl or C 3 -C 8 halocycloalkyl,
A 1 , A 2 , A 3 and A 4 each independently represent N or CY,
A 5 , A 6 and A 7 each independently represent N or CX;
X is a hydrogen atom, a halogen atom, cyano, nitro, -SF 5, C 1 ~C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6) haloalkyl, C 1 -C 6 alkoxy (C 1 -C 6) haloalkyl, C 1 -C 6 haloalkoxy (C 1 ~C 6) haloalkyl, C 3 -C 8 halocycloalkyl, the -OR 2, -OSO 2 R 2, or -S (O) r R 2 Each X may be the same as or different from each other;
R 2 represents C 1 -C 6 alkyl, C 1 -C 4 alkoxy (C 1 -C 4 ) alkyl, C 1 -C 6 haloalkyl or C 1 -C 3 haloalkoxy (C 1 -C 3 ) haloalkyl. ,
Y is a hydrogen atom, a halogen atom, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 6 alkylthio, C 1 to C 6 haloalkylthio, C 1 to C 6 alkylsulfonyl, C 1 to C 6 haloalkylsulfonyl, —NH 2 , —N (R 4 ) R 3 , each Y may be the same as each other or They may be different,
Two adjacent Ys may be joined together to form A 8 = A 9 -A 10 = A 11
A 8 , A 9 , A 10 and A 11 each independently represent N or CY 1
Y 1 is a hydrogen atom, a halogen atom, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, -NH 2 , -N (R 4 ) R 3 , each Y 1 may be the same as each other Or they may be different from each other,
R 3 is, C 1 -C 6 alkyl, -CHO, C 1 ~C 6 alkyl carbonyl, C 1 -C 6 haloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthiocarbonyl, C 1 -C 6 alkoxythiocarbonyl, C 1 -C 6 alkyl dithio carbonyl, represents C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl,
R 4 represents a hydrogen atom or C 1 -C 6 alkyl,
r represents an integer of 0 to 2] and a 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound represented by the following reaction with optically active α-phenylethylamine in solution: Next, a method for producing a diastereomeric salt having low solubility in the solution, wherein one diastereomeric salt is precipitated and separated by crystallization [2]
Optically active substance of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound represented by formula (1) obtained by decomposing the diastereomeric salt of [1] with an acid Manufacturing method.
〔３〕
前記〔１〕記載のジアステレオマー塩
[3]
The diastereomeric salt according to the above [1]
〔４〕
溶媒和分子を含む前記〔３〕記載のジアステレオマー塩
[4]
Diastereomeric salts of the [3] Symbol mounting including solvated molecules
本発明の製造方法により、医農薬あるいは電子材料等の機能性材料の製造中間体の合成に有用な４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体と４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体と光学活性な塩基性化合物とを構成成分として有するジアステレオマー塩を製造することができ、それをもって４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体の工業的生産に有益な方法を提供できる。 According to the production method of the present invention, an optically active substance of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound useful for the synthesis of a production intermediate of a functional material such as a medical pesticide or an electronic material, and A diastereomeric salt having an optically active form of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound and an optically active basic compound as constituents can be produced. A useful method can be provided for industrial production of an optically active substance of-(4,5-dihydroisoxazol-3-yl) benzoic acid compound.
さらに、本発明は農薬、特に国際公開第０５／０８５２１６号パンフレット記載の農業害虫、ハダニ類、哺乳動物又は鳥類の内部もしくは外部寄生虫に対して優れた殺虫・殺ダニ活性を有する化合物及びその製造中間体の製造方法を提供することができる。 Furthermore, the present invention relates to agricultural chemicals, in particular compounds having excellent insecticidal / miticidal activity against internal or ectoparasites of agricultural pests, spider mites, mammals or birds described in WO05 / 085216 and their production A method for producing an intermediate can be provided.
本発明に係る反応を実施するには、例えば、反応器に式（１）で表される４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物と、トルエンに代表される溶媒と、光学活性な塩基性化合物とを仕込み、生じた固体を濾取し、ジアステレオマー塩を得ればよい。また、ろ液を濃縮し、該ジアステレオマー塩中の光学活性な４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物とは逆の立体化学をもつ光学活性な４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物を得ればよい。さらには、該ジアステレオマーを塩酸に代表される酸を用いて分解して、光学活性な４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物を得ればよい。 For carrying out the reaction according to the present invention, for example, 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound represented by the formula (1) in a reactor and toluene are representative. A solvent and an optically active basic compound are charged, and the resulting solid is collected by filtration to obtain a diastereomeric salt. Further, the filtrate is concentrated, and the optically active 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound in the diastereomeric salt has an opposite stereochemistry to that of the optically active 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound. What is necessary is just to obtain (4,5-dihydroisoxazol-3-yl) benzoic acid compound. Furthermore, the diastereomer may be decomposed with an acid typified by hydrochloric acid to obtain an optically active 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound.
なお、本願記載の４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物は、例えば、国際特許出願公開WO2009/001942号公報などに記載の方法で製造することができる。 The 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound described in the present application can be produced, for example, by the method described in International Patent Application Publication No. WO2009 / 001942.
本願記載の式（１）で表される化合物は置換基によっては、E-体及びZ-体の幾何異性体が存在するが、本発明はこれらE-体、Z-体又はE-体及びZ-体を任意の割合で含む混合物を包含するものである。また、本願記載の化合物には、１個又は２個以上の不斉炭素原子の存在に起因する光学活性体が存在するが、本願記載の化合物は全ての光学活性体又はラセミ体を包含する。 The compound represented by the formula (1) described in the present application has an E-form and a Z-form geometric isomer depending on a substituent, and the present invention includes these E-form, Z-form or E-form and It includes a mixture containing Z-isomers in an arbitrary ratio. Moreover, although the optically active substance resulting from presence of 1 or 2 or more asymmetric carbon atoms exists in the compound described in this application, the compound described in this application includes all the optically active substances or a racemic body.
或いは、本願記載の式（１）で表される化合物のうちで、常法に従って金属塩にすることができるものは、例えば、リチウム、ナトリウム、カリウムといったアルカリ金属の塩、カルシウム、バリウム、マグネシウムといったアルカリ土類金属の塩又はアルミニウムの塩とすることができる。 Alternatively, among the compounds represented by the formula (1) described in the present application, those that can be converted into a metal salt according to a conventional method include, for example, alkali metal salts such as lithium, sodium, and potassium, calcium, barium, and magnesium. It can be an alkaline earth metal salt or an aluminum salt.
或いは、本願記載の式（１）で表される化合物のうちで、常法に従ってアミン塩にすることができるものは、例えば、アンモニア、メチルアミン、エチルアミン、プロピルアミン、ブチルアミン、ペンチルアミン、ベンジルアミン、アニリン、ジメチルアミン、ジエチルアミン、ジプロピルアミン、ジブチルアミン、ジペンチルアミン、ピロリジン、ピペリジン、ピペラジン、モルホリン、ジベンジルアミン、トリメチルアミン、トリエチルアミン、トリプロピルアミン、トリブチルアミン、トリペンチルアミン、トリベンジルアミンなどの塩とすることができる。 Alternatively, among the compounds represented by the formula (1) described in the present application, those that can be converted into an amine salt according to a conventional method include, for example, ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, and benzylamine. Aniline, dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, pyrrolidine, piperidine, piperazine, morpholine, dibenzylamine, trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine, tribenzylamine, etc. It can be a salt.
次に、本明細書において示した各置換基の具体例を以下に示す。ここで、n-はノルマル、i-はイソ、s-はセカンダリー及びt-はターシャリーを各々意味し、Phはフェニルを意味する。 Next, specific examples of each substituent shown in the present specification are shown below. Here, n- represents normal, i- represents iso, s- represents secondary, and t- represents tertiary, and Ph represents phenyl.
本願記載の化合物におけるハロゲン原子としては、フッ素原子、塩素原子、臭素原子及びヨウ素原子が挙げられる。尚、本明細書中「ハロ」の表記もこれらのハロゲン原子を表す。 Examples of the halogen atom in the compounds described in the present application include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the present specification, the notation “halo” also represents these halogen atoms.
本明細書におけるCa〜Cbアルキルの表記は、炭素原子数がa〜b個よりなる直鎖状又は分岐鎖状の炭化水素基を表し、例えばメチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、i-ブチル基、s-ブチル基、t-ブチル基、n-ペンチル基、1-メチルブチル基、2-メチルブチル基、3-メチルブチル基、1-エチルプロピル基、1,1-ジメチルプロピル基、1,2-ジメチルプロピル基、2,2-ジメチルプロピル基、n-ヘキシル基、1-メチルペンチル基、2-メチルペンチル基、1,1-ジメチルブチル基、1,3-ジメチルブチル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a to C b alkyl in the present specification represents a linear or branched hydrocarbon group having a carbon number of a to b , for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 1,1-dimethylbutyl group, Specific examples include 1,3-dimethylbutyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group and the like, and each is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbハロアルキルの表記は、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa〜b個よりなる直鎖状又は分岐鎖状の炭化水素基を表し、このとき、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、又は互いに相異なっていてもよい。例えばフルオロメチル基、クロロメチル基、ブロモメチル基、ヨードメチル基、ジフルオロメチル基、クロロフルオロメチル基、ジクロロメチル基、ブロモフルオロメチル基、トリフルオロメチル基、クロロジフルオロメチル基、ジクロロフルオロメチル基、トリクロロメチル基、ブロモジフルオロメチル基、ブロモクロロフルオロメチル基、ジブロモフルオロメチル基、2-フルオロエチル基、2-クロロエチル基、2-ブロモエチル基、2,2-ジフルオロエチル基、2-クロロ-2-フルオロエチル基、2,2-ジクロロエチル基、2-ブロモ-2-フルオロエチル基、2,2,2-トリフルオロエチル基、2-クロロ-2,2-ジフルオロエチル基、2,2-ジクロロ-2-フルオロエチル基、2,2,2-トリクロロエチル基、2-ブロモ-2,2-ジフルオロエチル基、2-ブロモ-2-クロロ-2-フルオロエチル基、2-ブロモ-2,2-ジクロロエチル基、1,1,2,2-テトラフルオロエチル基、ペンタフルオロエチル基、1-クロロ-1,2,2,2-テトラフルオロエチル基、2-クロロ-1,1,2,2-テトラフルオロエチル基、1,2-ジクロロ-1,2,2-トリフルオロエチル基、2-ブロモ-1,1,2,2-テトラフルオロエチル基、2-フルオロプロピル基、2-クロロプロピル基、2-ブロモプロピル基、2-クロロ-2-フルオロプロピル基、2,3-ジクロロプロピル基、2-ブロモ-3-フルオロプロピル基、3-ブロモ-2-クロロプロピル基、2,3-ジブロモプロピル基、3,3,3-トリフルオロプロピル基、3-ブロモ-3,3-ジフルオロプロピル基、2,2,3,3-テトラフルオロプロピル基、2-クロロ-3,3,3-トリフルオロプロピル基、2,2,3,3,3-ペンタフルオロプロピル基、1,1,2,3,3,3-ヘキサフルオロプロピル基、ヘプタフルオロプロピル基、2,3-ジクロロ-1,1,2,3,3-ペンタフルオロプロピル基、2-フルオロ-1-メチルエチル基、2-クロロ-1-メチルエチル基、2-ブロモ-1-メチルエチル基、2,2,2-トリフルオロ-1-(トリフルオロメチル)エチル基、1,2,2,2-テトラフルオロ-1-(トリフルオロメチル)エチル基、2-フルオロブチル基、2-クロロブチル基、2,2,3,3,4,4-ヘキサフルオロブチル基、2,2,3,4,4,4-ヘキサフルオロブチル基、2,2,3,3,4,4-ヘキサフルオロブチル基、2,2,3,3,4,4,4-ヘプタフルオロブチル基、1,1,2,2,3,3,4,4-オクタフルオロブチル基、ノナフルオロブチル基、4-クロロ-1,1,2,2,3,3,4,4-オクタフルオロブチル基、2-フルオロ-2-メチルプロピル基、1,2,2,3,3,3-ヘキサフルオロ-1-(トリフルオロメチル)プロピル基、2-クロロ-1,1-ジメチルエチル基、2-ブロモ-1,1-ジメチルエチル基、5-クロロ-2,2,3,4,4,5,5-ヘプタフルオロペンチル基、トリデカフルオロヘキシル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b haloalkyl is represented by a linear or branched chain consisting of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. Represents a hydrocarbon group, and when substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, chlorofluoromethyl group, dichloromethyl group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethyl group, trichloromethyl Group, bromodifluoromethyl group, bromochlorofluoromethyl group, dibromofluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl Group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2 -Fluoroethyl group, 2,2,2-trichloroethyl group, 2-bromo-2,2-difluoroethyl group, 2-bromo-2-chloro-2-fluoroethyl group, 2-butyl Lomo-2,2-dichloroethyl group, 1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1 1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2-trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, 2-fluoropropyl Group, 2-chloropropyl group, 2-bromopropyl group, 2-chloro-2-fluoropropyl group, 2,3-dichloropropyl group, 2-bromo-3-fluoropropyl group, 3-bromo-2-chloropropyl group Group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group, 3-bromo-3,3-difluoropropyl group, 2,2,3,3-tetrafluoropropyl group, 2-chloro- 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group, heptafluoropropyl group, 2, 3-dichloro-1,1,2,3,3-pentaph Oropropyl group, 2-fluoro-1-methylethyl group, 2-chloro-1-methylethyl group, 2-bromo-1-methylethyl group, 2,2,2-trifluoro-1- (trifluoromethyl) ethyl Group, 1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl group, 2-fluorobutyl group, 2-chlorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group 2,2,3,4,4,4-hexafluorobutyl group, 2,2,3,3,4,4-hexafluorobutyl group, 2,2,3,3,4,4,4-hepta Fluorobutyl group, 1,1,2,2,3,3,4,4-octafluorobutyl group, nonafluorobutyl group, 4-chloro-1,1,2,2,3,3,4,4- Octafluorobutyl group, 2-fluoro-2-methylpropyl group, 1,2,2,3,3,3-hexafluoro-1- (trifluoromethyl) propyl group, 2-chloro-1,1-dimethylethyl Group, 2-bromo-1,1-dimethylethyl group, 5-chloro-2,2,3,4,4,5,5-heptafluoropentyl group, tridecafluorohexyl Group, etc. As a specific example, it may be selected from the range of the specified number of carbon atoms.
本明細書におけるシアノ(Ca〜Cb)アルキルの表記は、炭素原子に結合した水素原子が、シアノ基によって任意に置換された、炭素原子数がa〜b個よりなる直鎖状又は分岐鎖状のアルキル基を表し、例えばシアノメチル基、1-シアノエチル基、2-シアノエチル基、2-シアノプロピル基、3-シアノプロピル基、2-シアノブチル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of cyano (C a -C b ) alkyl in the present specification is linear or branched having a carbon number of a to b , wherein a hydrogen atom bonded to a carbon atom is optionally substituted with a cyano group Represents a chain alkyl group, for example, cyanomethyl group, 1-cyanoethyl group, 2-cyanoethyl group, 2-cyanopropyl group, 3-cyanopropyl group, 2-cyanobutyl group, etc. Selected in the range of the number of carbon atoms.
本明細書におけるCa〜Cbシクロアルキルの表記は、炭素原子数がa〜b個よりなる環状の炭化水素基を表し、３員環から６員環までの単環又は複合環構造を形成することが出来る。また、各々の環は指定の炭素原子数の範囲でアルキル基によって任意に置換されていてもよい。例えばシクロプロピル基、1-メチルシクロプロピル基、2-メチルシクロプロピル基、2,2-ジメチルシクロプロピル基、2,2,3,3-テトラメチルシクロプロピル基、シクロブチル基、シクロペンチル基、2-メチルシクロペンチル基、3-メチルシクロペンチル基、シクロヘキシル基、2-メチルシクロヘキシル基、3-メチルシクロヘキシル基、4-メチルシクロヘキシル基、ビシクロ[2.2.1]ヘプタン-2-イル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b cycloalkyl represents a cyclic hydrocarbon group having a to b carbon atoms, and forms a monocyclic or complex ring structure having 3 to 6 members. I can do it. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms. For example, cyclopropyl group, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, 2- Specific examples include methylcyclopentyl group, 3-methylcyclopentyl group, cyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, bicyclo [2.2.1] heptan-2-yl group, etc. , Each selected range of carbon atoms.
本明細書におけるCa〜Cbハロシクロアルキルの表記は、炭素原子に結合した水素原子が、ハロゲン原子によって任意に置換された、炭素原子数がa〜b個よりなる環状の炭化水素基を表し、３員環から６員環までの単環又は複合環構造を形成することが出来る。また、各々の環は指定の炭素原子数の範囲でアルキル基によって任意に置換されていてもよく、ハロゲン原子による置換は環構造部分であっても、側鎖部分であっても、或いはそれらの両方であってもよく、さらに、２個以上のハロゲン原子によって置換されている場合、それらのハロゲン原子は互いに同一でも、又は互いに相異なっていてもよい。例えば2,2-ジフルオロシクロプロピル基、2,2-ジクロロシクロプロピル基、2,2-ジブロモシクロプロピル基、2,2-ジフルオロ-1-メチルシクロプロピル基、2,2-ジクロロ-1-メチルシクロプロピル基、2,2-ジブロモ-1-メチルシクロプロピル基、2,2,3,3-テトラフルオロシクロブチル基、2-(トリフルオロメチル)シクロヘキシル基、3-(トリフルオロメチル)シクロヘキシル基、4-(トリフルオロメチル)シクロヘキシル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b halocycloalkyl represents a cyclic hydrocarbon group composed of a to b carbon atoms in which a hydrogen atom bonded to a carbon atom is optionally substituted with a halogen atom. And can form monocyclic or complex ring structures from 3 to 6-membered rings. Each ring may be optionally substituted with an alkyl group within the range of the specified number of carbon atoms, and the substitution with a halogen atom may be a ring structure part, a side chain part, They may be both, and when they are substituted by two or more halogen atoms, the halogen atoms may be the same as or different from each other. For example, 2,2-difluorocyclopropyl group, 2,2-dichlorocyclopropyl group, 2,2-dibromocyclopropyl group, 2,2-difluoro-1-methylcyclopropyl group, 2,2-dichloro-1-methyl Cyclopropyl group, 2,2-dibromo-1-methylcyclopropyl group, 2,2,3,3-tetrafluorocyclobutyl group, 2- (trifluoromethyl) cyclohexyl group, 3- (trifluoromethyl) cyclohexyl group , 4- (trifluoromethyl) cyclohexyl group and the like can be mentioned as specific examples, and each is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbアルケニルの表記は、炭素原子数がa〜b個よりなる直鎖状又は分岐鎖状で、且つ分子内に１個又は２個以上の二重結合を有する不飽和炭化水素基を表し、例えばビニル基、1-プロペニル基、2-プロペニル基、1-メチルエテニル基、2-ブテニル基、1-メチル-2-プロペニル基、2-メチル-2-プロペニル基、2-ペンテニル基、2-メチル-2-ブテニル基、3-メチル-2-ブテニル基、2-エチル-2-プロペニル基、1,1-ジメチル-2-プロペニル基、2-ヘキセニル基、2-メチル-2-ペンテニル基、2,4-ジメチル-2,6-ヘプタジエニル基、3,7-ジメチル-2,6-オクタジエニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a to C b alkenyl is a linear or branched chain composed of a to b carbon atoms and has one or more double bonds in the molecule. Represents a saturated hydrocarbon group, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-methylethenyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2 -Pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 2-ethyl-2-propenyl group, 1,1-dimethyl-2-propenyl group, 2-hexenyl group, 2-methyl Specific examples include 2-pentenyl group, 2,4-dimethyl-2,6-heptadienyl group, 3,7-dimethyl-2,6-octadienyl group, etc. Is done.
本明細書におけるCa〜Cbアルキニルの表記は、炭素原子数がa〜b個よりなる直鎖状又は分岐鎖状で、且つ分子内に１個又は２個以上の三重結合を有する不飽和炭化水素基を表し、例えばエチニル基、1-プロピニル基、2-プロピニル基、2-ブチニル基、1-メチル-2-プロピニル基、2-ペンチニル基、1-メチル-2-ブチニル基、1,1-ジメチル-2-プロピニル基、2-ヘキシニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, C a -C b alkynyl is a linear or branched chain having a carbon number of a to b , and is unsaturated having one or more triple bonds in the molecule. Represents a hydrocarbon group, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 2-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 1-methyl-2-butynyl group, 1, Specific examples include a 1-dimethyl-2-propynyl group, a 2-hexynyl group, and the like, and each is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbアルコキシの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-O-基を表し、例えばメトキシ基、エトキシ基、n-プロピルオキシ基、i-プロピルオキシ基、n-ブチルオキシ基、i-ブチルオキシ基、s-ブチルオキシ基、t-ブチルオキシ基、n-ペンチルオキシ基、n-ヘキシルオキシ基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkoxy in the present specification represents an alkyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methoxy group, ethoxy group, n-propyloxy group, Specific examples include i-propyloxy group, n-butyloxy group, i-butyloxy group, s-butyloxy group, t-butyloxy group, n-pentyloxy group, n-hexyloxy group, etc. It is selected in the range of the number of atoms.
本明細書におけるCa〜Cbハロアルコキシの表記は、炭素原子数がa〜b個よりなる前記の意味であるハロアルキル-O-基を表し、例えばジフルオロメトキシ基、トリフルオロメトキシ基、クロロジフルオロメトキシ基、ブロモジフルオロメトキシ基、2-フルオロエトキシ基、2-クロロエトキシ基、2,2,2-トリフルオロエトキシ基、1,1,2,2,-テトラフルオロエトキシ基、2-クロロ-1,1,2-トリフルオロエトキシ基、2-ブロモ-1,1,2-トリフルオロエトキシ基、ペンタフルオロエトキシ基、2,2-ジクロロ-1,1,2-トリフルオロエトキシ基、2,2,2-トリクロロ-1,1-ジフルオロエトキシ基、2-ブロモ-1,1,2,2-テトラフルオロエトキシ基、2,2,3,3-テトラフルオロプロピルオキシ基、1,1,2,3,3,3-ヘキサフルオロプロピルオキシ基、2,2,2-トリフルオロ-1-(トリフルオロメチル)エトキシ基、ヘプタフルオロプロピルオキシ基、2-ブロモ-1,1,2,3,3,3-ヘキサフルオロプロピルオキシ基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b haloalkoxy in the present specification represents a haloalkyl-O— group having the above-mentioned meaning consisting of a to b carbon atoms, for example, difluoromethoxy group, trifluoromethoxy group, chlorodifluoro Methoxy group, bromodifluoromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2, -tetrafluoroethoxy group, 2-chloro-1 , 1,2-trifluoroethoxy group, 2-bromo-1,1,2-trifluoroethoxy group, pentafluoroethoxy group, 2,2-dichloro-1,1,2-trifluoroethoxy group, 2,2 , 2-trichloro-1,1-difluoroethoxy group, 2-bromo-1,1,2,2-tetrafluoroethoxy group, 2,2,3,3-tetrafluoropropyloxy group, 1,1,2, 3,3,3-hexafluoropropyloxy group, 2,2,2-trifluoro-1- (trifluoromethyl) ethoxy group, Data fluoropropyl group, 2-bromo-1,1,2,3,3,3-hexafluoro-propyloxy group, etc. As a specific example, may be selected from the range of the specified number of carbon atoms.
本明細書におけるCa〜Cbアルキルチオの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-S-基を表し、例えばメチルチオ基、エチルチオ基、n-プロピルチオ基、i-プロピルチオ基、n-ブチルチオ基、i-ブチルチオ基、s-ブチルチオ基、t-ブチルチオ基、n-ペンチルチオ基、n-ヘキシルチオ基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkylthio in the present specification represents an alkyl-S-group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylthio group, ethylthio group, n-propylthio group, i Specific examples include -propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group, n-pentylthio group, n-hexylthio group, etc. Selected.
本明細書におけるCa〜Cbハロアルキルチオの表記は、炭素原子数がa〜b個よりなる前記の意味であるハロアルキル-S-基を表し、例えばジフルオロメチルチオ基、トリフルオロメチルチオ基、クロロジフルオロメチルチオ基、ブロモジフルオロメチルチオ基、2,2,2-トリフルオロエチルチオ基、1,1,2,2-テトラフルオロエチルチオ基、2-クロロ-1,1,2-トリフルオロエチルチオ基、ペンタフルオロエチルチオ基、2-ブロモ-1,1,2,2-テトラフルオロエチルチオ基、1,1,2,3,3,3-ヘキサフルオロプロピルチオ基、ヘプタフルオロプロピルチオ基、1,2,2,2-テトラフルオロ-1-(トリフルオロメチル)エチルチオ基、ノナフルオロブチルチオ基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b haloalkylthio in the present specification represents a haloalkyl-S-group having the above-mentioned meaning consisting of a to b carbon atoms, for example, difluoromethylthio group, trifluoromethylthio group, chlorodifluoro Methylthio group, bromodifluoromethylthio group, 2,2,2-trifluoroethylthio group, 1,1,2,2-tetrafluoroethylthio group, 2-chloro-1,1,2-trifluoroethylthio group, Pentafluoroethylthio group, 2-bromo-1,1,2,2-tetrafluoroethylthio group, 1,1,2,3,3,3-hexafluoropropylthio group, heptafluoropropylthio group, 1, Specific examples include 2,2,2-tetrafluoro-1- (trifluoromethyl) ethylthio group, nonafluorobutylthio group and the like, and each is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbアルキルスルホニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-SO2-基を表し、例えばメチルスルホニル基、エチルスルホニル基、n-プロピルスルホニル基、i-プロピルスルホニル基、n-ブチルスルホニル基、i-ブチルスルホニル基、s-ブチルスルホニル基、t-ブチルスルホニル基、n-ペンチルスルホニル基、n-ヘキシルスルホニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkylsulfonyl in the present specification represents an alkyl-SO 2 -group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylsulfonyl group, ethylsulfonyl group, n- Specific examples include propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group and the like. Each of which is selected for each specified number of carbon atoms.
本明細書におけるCa〜Cbハロアルキルスルホニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるハロアルキル-SO2-基を表し、例えばジフルオロメチルスルホニル基、トリフルオロメチルスルホニル基、クロロジフルオロメチルスルホニル基、ブロモジフルオロメチルスルホニル基、2,2,2-トリフルオロエチルスルホニル基、1,1,2,2-テトラフルオロエチルスルホニル基、2-クロロ-1,1,2-トリフルオロエチルスルホニル基、2-ブロモ-1,1,2,2-テトラフルオロエチルスルホニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b haloalkylsulfonyl in the present specification represents a haloalkyl-SO 2 — group having the above-mentioned meaning consisting of a to b carbon atoms, such as a difluoromethylsulfonyl group or a trifluoromethylsulfonyl group. Chlorodifluoromethylsulfonyl group, bromodifluoromethylsulfonyl group, 2,2,2-trifluoroethylsulfonyl group, 1,1,2,2-tetrafluoroethylsulfonyl group, 2-chloro-1,1,2-trimethyl Specific examples include a fluoroethylsulfonyl group, a 2-bromo-1,1,2,2-tetrafluoroethylsulfonyl group, and the like, and each is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbアルキルカルボニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-C(O)-基を表し、例えばアセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、2-メチルブタノイル基、ピバロイル基、ヘキサノイル基、ヘプタノイル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkylcarbonyl in the present specification represents an alkyl-C (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, acetyl group, propionyl group, butyryl group. Specific examples thereof include isobutyryl group, valeryl group, isovaleryl group, 2-methylbutanoyl group, pivaloyl group, hexanoyl group, heptanoyl group and the like, and each is selected in the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbハロアルキルカルボニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるハロアルキル-C(O)-基を表し、例えばフルオロアセチル基、クロロアセチル基、ジフルオロアセチル基、ジクロロアセチル基、トリフルオロアセチル基、クロロジフルオロアセチル基、ブロモジフルオロアセチル基、トリクロロアセチル基、ペンタフルオロプロピオニル基、ヘプタフルオロブタノイル基、3-クロロ-2,2-ジメチルプロパノイル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b haloalkylcarbonyl in the present specification represents a haloalkyl-C (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, such as a fluoroacetyl group, a chloroacetyl group, Difluoroacetyl group, dichloroacetyl group, trifluoroacetyl group, chlorodifluoroacetyl group, bromodifluoroacetyl group, trichloroacetyl group, pentafluoropropionyl group, heptafluorobutanoyl group, 3-chloro-2,2-dimethylpropanoyl group Etc. are given as specific examples, and each is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbアルコキシカルボニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-O-C(O)-基を表し、例えばメトキシカルボニル基、エトキシカルボニル基、 n-プロピルオキシカルボニル基、i-プロピルオキシカルボニル基、n-ブトキシカルボニル基、i-ブトキシカルボニル基、t-ブトキシカルボニル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkoxycarbonyl in the present specification represents an alkyl-OC (O) — group having the above-mentioned meaning consisting of a to b carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, Specific examples include n-propyloxycarbonyl group, i-propyloxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, t-butoxycarbonyl group, etc., selected within the range of each designated number of carbon atoms Is done.
本明細書におけるCa〜Cbアルキルチオカルボニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-S-C(O)-基を表し、例えばメチルチオ-C(O)-基、エチルチオ-C(O)-基、n-プロピルチオ-C(O)-基、i-プロピルチオ-C(O)-基、n-ブチルチオ-C(O)-基、i-ブチルチオ-C(O)-基、t-ブチルチオ-C(O)-基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkylthiocarbonyl in the present specification represents an alkyl-SC (O) -group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylthio-C (O) -group , Ethylthio-C (O)-group, n-propylthio-C (O)-group, i-propylthio-C (O)-group, n-butylthio-C (O)-group, i-butylthio-C (O ) -Group, t-butylthio-C (O) -group and the like are listed as specific examples, and each group is selected within the range of the designated number of carbon atoms.
本明細書におけるCa〜Cbアルコキシチオカルボニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-O-C(S)-基を表し、例えばメトキシ-C(S)-基、エトキシ-C(S)-基、n-プロピルオキシ-C(S)-基、i-プロピルオキシ-C(S)-基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkoxythiocarbonyl in the present specification represents an alkyl-OC (S) — group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methoxy-C (S) — Groups, ethoxy-C (S) -groups, n-propyloxy-C (S) -groups, i-propyloxy-C (S) -groups, etc. Selected by range.
本明細書におけるCa〜Cbアルキルジチオカルボニルの表記は、炭素原子数がa〜b個よりなる前記の意味であるアルキル-S-C(S)-基を表し、例えばメチルチオ-C(S)-基、エチルチオ-C(S)-基、n-プロピルチオ-C(S)-基、i-プロピルチオ-C(S)-基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, the expression C a -C b alkyldithiocarbonyl represents an alkyl-SC (S) -group having the above-mentioned meaning consisting of a to b carbon atoms, for example, methylthio-C (S) — Group, ethylthio-C (S)-group, n-propylthio-C (S)-group, i-propylthio-C (S)-group, etc. Selected.
本明細書におけるCa〜Cbアルコキシ(Cd〜Ce)アルキルの表記は、前記の意味である任意のCa〜Cbアルコキシ基によって、炭素原子に結合した水素原子が任意に置換された炭素原子数がd〜e個よりなる直鎖状又は分岐鎖状の炭化水素基を表し、各々の指定の炭素原子数の範囲で選択される。 The notation of C a -C b alkoxy (C d -C e ) alkyl in the present specification indicates that a hydrogen atom bonded to a carbon atom is optionally substituted by any C a -C b alkoxy group having the above meaning. It represents a linear or branched hydrocarbon group consisting of d to e carbon atoms, and is selected within the range of the respective designated number of carbon atoms.
本明細書におけるヒドロキシ(Cd〜Ce)ハロアルキル、Ca〜Cbアルコキシ(Cd〜Ce)ハロアルキル又はCa〜Cbハロアルコキシ(Cd〜Ce)ハロアルキルの表記は、それぞれ前記の意味である任意のCa〜Cbアルコキシ基、Ca〜Cbハロアルコキシ基又は水酸基によって炭素原子に結合した水素原子又はハロゲン原子が任意に置換された炭素原子数がd〜e個よりなる前記の意味であるハロアルキル基を表し、例えば2,2,2-トリフルオロ-1-ヒドロキシ-1-(トリフルオロメチル)エチル基、ジフルオロ(メトキシ)メチル基、2,2,2-トリフルオロ-1-メトキシ-1-(トリフルオロメチル)エチル基、ジフルオロ(2,2,2-トリフルオロエトキシ)メチル基、2,2,2-トリフルオロ-1-(2,2,2-トリフルオロエトキシ)-1-(トリフルオロメチル)エチル基、3-(1,2-ジクロロ-1,2,2-トリフルオロエトキシ)-1,1,2,2,3,3-ヘキサフルオロプロピル基等が具体例として挙げられ、各々の指定の炭素原子数の範囲で選択される。 In the present specification, the notation of hydroxy (C d -C e ) haloalkyl, C a -C b alkoxy (C d -C e ) haloalkyl or C a -C b haloalkoxy (C d -C e ) haloalkyl is as described above. The number of carbon atoms in which a hydrogen atom or a halogen atom bonded to a carbon atom is arbitrarily substituted by any C a -C b alkoxy group, C a -C b haloalkoxy group or hydroxyl group, A haloalkyl group as defined above, for example 2,2,2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl group, difluoro (methoxy) methyl group, 2,2,2-trifluoro -1-methoxy-1- (trifluoromethyl) ethyl group, difluoro (2,2,2-trifluoroethoxy) methyl group, 2,2,2-trifluoro-1- (2,2,2-trifluoro group) Ethoxy) -1- (trifluoromethyl) ethyl group, 3- (1,2-dichloro-1,2,2-trifluoroethoxy)- Specific examples include 1,1,2,2,3,3-hexafluoropropyl group and the like, and each is selected within the range of the designated number of carbon atoms.
本願記載の化合物において、Xで表される置換基としては、好ましくは水素原子、ハロゲン原子及びC1〜C4ハロアルキルが挙げられ、より好ましくは水素原子、塩素原子、臭素原子、ヨウ素原子及びトリフルオロメチルが挙げられる。このときXで表される置換基の数を表すmが２以上の整数を表すとき、各々のXは互いに同一であっても又は互いに相異なっていてもよい。 In the compounds described in the present, the substituents represented by X, is preferably a hydrogen atom, halogen atom and C 1 -C 4 haloalkyl, more preferably a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom and tri Fluoromethyl is mentioned. At this time, when m representing the number of substituents represented by X represents an integer of 2 or more, each X may be the same as or different from each other.
本願記載の化合物において、Xで表される置換基の数を表すmとしては、好ましくは１、２及び３が挙げられる。 In the compounds described in the present application, examples of m representing the number of substituents represented by X include 1, 2, and 3.
本願記載の化合物において、Xで表される置換基の位置としては、より好ましくはR1が結合する炭素との結合位置に対して、メタ位及びパラ位が挙げられる。 In the compounds described in the present application, the position of the substituent represented by X preferably includes a meta position and a para position with respect to the bonding position with the carbon to which R 1 is bonded.
本願記載の化合物において、Yで表される置換基としては、好ましくはハロゲン原子、ニトロ、C1〜C4アルキル及びC1〜C4ハロアルキルが挙げられ、より好ましくはフッ素原子、塩素原子、臭素原子、ヨウ素原子、ニトロ、メチル、エチル及びトリフルオロメチルが挙げられる。このとき、nが２の整数を表すとき、各々のYは互いに同一であっても又は互いに相異なっていてもよい。 In the compounds described in the present, the substituents represented by Y, preferably a halogen atom, nitro, include C 1 -C 4 alkyl and C 1 -C 4 haloalkyl, more preferably fluorine atom, chlorine atom, bromine Atoms, iodine atoms, nitro, methyl, ethyl and trifluoromethyl are mentioned. At this time, when n represents an integer of 2, each Y may be the same as or different from each other.
本願記載の化合物において、Yで表される置換基の数を表すnとしては、より好ましくは０及び1が挙げられる。 In the compounds described in the present application, n representing the number of substituents represented by Y is more preferably 0 or 1.
本願記載の化合物において、Yで表される置換基の位置としては、より好ましくは−COOHとの結合位置に対して、オルト位が挙げられる。 In the compounds described in the present application, the position of the substituent represented by Y is more preferably an ortho position with respect to the bonding position with —COOH.
本願記載の化合物において、Y1で表される置換基としては、好ましくは水素原子が挙げられる。 In the compounds described in the present application, the substituent represented by Y 1 is preferably a hydrogen atom.
本願記載の化合物において、R1で表される置換基としては、好ましくはC1〜C4ハロアルキルが挙げられ、より好ましくはジフルオロメチル、クロロジフルオロメチル、ブロモジフルオロメチル及びトリフルオロメチルが挙げられ、極めて好ましくはクロロジフルオロメチル及びトリフルオロメチルが挙げられる。 In the compounds described in the present application, the substituent represented by R 1 preferably includes C 1 to C 4 haloalkyl, more preferably difluoromethyl, chlorodifluoromethyl, bromodifluoromethyl, and trifluoromethyl. Very particular preference is given to chlorodifluoromethyl and trifluoromethyl.
本願記載の化合物において、R2で表される置換基としては、好ましくはC1〜C4アルキル、C1〜C4アルコキシ(C1〜C4)アルキル及びC1〜C4ハロアルキルが挙げられ、より好ましくは、メチル、エチル、メトキシメチル、メトキシエチル、エトキシメチル及びトリフルオロメチルが挙げられる。 In the compounds described in the present, the substituents represented by R 2, preferably include C 1 -C 4 alkyl, C 1 -C 4 alkoxy (C 1 ~C 4) alkyl and C 1 -C 4 haloalkyl More preferably, methyl, ethyl, methoxymethyl, methoxyethyl, ethoxymethyl and trifluoromethyl are mentioned.
本願記載の化合物において、R3で表される置換基としては、好ましくは-CHO、C1〜C4アルキルカルボニル及びC1〜C4アルコキシカルボニルが挙げられ、より好ましくは、ホルミル、アセチル、プロピオニル、メトキシカルボニル及びエトキシカルボニルが挙げられる。 In the compounds described in the present application, the substituent represented by R 3 preferably includes —CHO, C 1 -C 4 alkylcarbonyl and C 1 -C 4 alkoxycarbonyl, more preferably formyl, acetyl, propionyl. , Methoxycarbonyl and ethoxycarbonyl.
本願記載の化合物において、R4で表される置換基としては、好ましくは水素原子が挙げられる。 In the compounds described in the present application, the substituent represented by R 4 is preferably a hydrogen atom.
本願記載の化合物において、R5で表される置換基としては、好ましくはメチル、エチル及びイソプロピルが挙げられる。
本願記載の化合物において、R6で表される置換基としては、好ましくは水素原子、メチル、エチル、ヒドロキシメチル、メトキシカルボニル及びエトキシカルボニルが挙げられる。
本願記載の化合物において、R7で表される置換基としては、好ましくは水素原子、メチル、エチル及びシクロプロピルが挙げられる。
本願記載の化合物において、Zで表される置換基としては、好ましくは水素原子、ハロゲン原子及びC1〜C4ハロアルキルが挙げられ、より好ましくは水素原子、塩素原子、臭素原子、ヨウ素原子及びトリフルオロメチルが挙げられる。このときZで表される置換基の数を表すpが２以上の整数を表すとき、各々のZは互いに同一であっても又は互いに相異なっていてもよい。
In the compounds described in the present application, the substituent represented by R 5 preferably includes methyl, ethyl and isopropyl.
In the compounds described in the present application, examples of the substituent represented by R 6 include a hydrogen atom, methyl, ethyl, hydroxymethyl, methoxycarbonyl and ethoxycarbonyl.
In the compounds described in the present application, examples of the substituent represented by R 7 include a hydrogen atom, methyl, ethyl, and cyclopropyl.
In the compounds described in the present, as the substituent represented by Z, preferably a hydrogen atom, halogen atom and C 1 -C 4 haloalkyl, more preferably a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom and tri Fluoromethyl is mentioned. At this time, when p representing the number of substituents represented by Z represents an integer of 2 or more, each Z may be the same as or different from each other.
本願記載の化合物において、Zで表される置換基の数を表すpとしては、好ましくは１、２及び３が挙げられる。 In the compounds described in the present application, p, which represents the number of substituents represented by Z, preferably includes 1, 2 and 3.
本願記載の式（２）で表される光学活性な塩基性化合物としては、リシン、アルギニン、ヒスチジン等の塩基性アミノ酸類、α−フェニルエチルアミン、３−メチル−２−フェニルブチルアミン、フェニルアラニノール、バリノール、シンコニン、シンコニジン、キニン、キニジン等のアミン類、２−（１−メトキシエチル）ピリジン、２−（１，２−ジメチルプロピル）ピリジン等のピリジン類、N−(６，７−ジヒドロ−３H−ジナフト[２，１−e：１´，２´−ｇ][１，３]ジアゾニン−５(４H)−イリデン)−１，１−ジフェニルメタナミン、２−(１，３−ジメチル−４，５−ジフェニルイミダゾリジン−２−イリデンアミノ)−３−フェニルプロパン−１−オール、（１R，２S，２aS，４R，７R，８aS）−１，２−ジメトキシ−４，７−（６´−メチル−２´−テトラヒドロピラニル）−２，２a，３，４，５，７，８，８a−オクタヒドロ−１H−５，６，８ｂ−トリアザアセナフチレン ハイドロクロライド等のグアニジン類が挙げられ、α−フェニルエチルアミン、３−メチル−２−フェニルブチルアミン、フェニルアラニノール、バリノール、シンコニン、シンコニジン、キニン、キニジン等のアミン類が好ましく、中でもα−フェニルエチルアミン、３−メチル−２−フェニルブチルアミン等が好ましい。 Examples of the optically active basic compound represented by the formula (2) described in the present application include basic amino acids such as lysine, arginine, and histidine, α-phenylethylamine, 3-methyl-2-phenylbutylamine, phenylalaninol, Amines such as valinol, cinchonine, cinchonidine, quinine, quinidine, pyridines such as 2- (1-methoxyethyl) pyridine, 2- (1,2-dimethylpropyl) pyridine, N- (6,7-dihydro-3H Dinaphtho [2,1-e: 1 ′, 2′-g] [1,3] diazonin-5 (4H) -ylidene) -1,1-diphenylmethanamine, 2- (1,3-dimethyl-4 , 5-Diphenylimidazolidin-2-ylideneamino) -3-phenylpropan-1-ol, (1R, 2S, 2aS, 4R, 7R, 8aS) -1,2-dimethoxy-4,7- (6'-me 2'-tetrahydropyranyl) -2,2a, 3,4,5,7,8,8a-octahydro-1H-5,6,8b-triazaacenaphthylene hydrochloride and other guanidines , Α-phenylethylamine, 3-methyl-2-phenylbutylamine, phenylalaninol, valinol, cinchonine, cinchonidine, quinine, quinidine and other amines are preferable, among which α-phenylethylamine, 3-methyl-2-phenylbutylamine, etc. Is preferred.
本発明のジアステレオマー塩を析出させる工程、該ジアステレオマー塩を分離する工程、及び該分離したジアステレオマー塩を分解する工程に使用できる溶媒としては、例えば、ベンゼン、トルエン、キシレン、クロロベンゼン、o-ジクロロベンゼン又はメシチレン等のハロゲン原子で置換されてもよい芳香族炭化水素類、若しくはｎ−ペンタン、ｎ−ヘキサン、ｎ−ヘプタン、ｎ−オクタン、シクロペンタン、シクロヘキサン、メチルシクロヘキサン、塩化メチレン又は１，２−ジクロロエタン等のハロゲン原子で置換されてもよい脂肪族炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、シクロペンチルメチルエーテル、ｔ−ブチルメチルエーテル等のエーテル類、アセトニトリル、プロピオニトリル等のニトリル類、酢酸エチル、酢酸ブチル等のエステル類、メタノール、エタノール、イソプロパノール等のアルコール類、N, N−ジメチルホルムアミド、N, N−ジメチルアセトアミド、N−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒、トリエチルアミン、トリブチルアミン、ピリジン等のアミン類、ニトロメタン、ニトロエタン、水、超臨界流体等が挙げられる。これらは単独で使用しても良いし、２種以上を混合して使用しても良い。 Examples of the solvent that can be used in the step of precipitating the diastereomeric salt of the present invention, the step of separating the diastereomeric salt, and the step of decomposing the separated diastereomeric salt include benzene, toluene, xylene, and chlorobenzene. , Aromatic hydrocarbons optionally substituted with a halogen atom such as o-dichlorobenzene or mesitylene, or n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, methylcyclohexane, methylene chloride Or aliphatic hydrocarbons which may be substituted with halogen atoms such as 1,2-dichloroethane, ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether and t-butyl methyl ether, nitriles such as acetonitrile and propionitrile , Ethyl acetate , Esters such as butyl acetate, alcohols such as methanol, ethanol and isopropanol, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide, triethylamine, Examples include amines such as butylamine and pyridine, nitromethane, nitroethane, water, and supercritical fluid. These may be used singly or in combination of two or more.
斯かる溶媒の使用量は特に限定されないが、ジアステレオマー塩を析出させる工程においては４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物１重量部に対して、該ジアステレオマー塩を分離する工程、及び該分離したジアステレオマー塩を分解する工程においてはジアステレオマー塩１重量部に対して、通常０．０１〜１００重量部、好ましくは０．０５〜５０重量部、特に好ましくは０．１〜１５重量部である。 The amount of such solvent to be used is not particularly limited, but in the step of precipitating the diastereomeric salt, the diastereomer salt is used with respect to 1 part by weight of 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound. In the step of separating the stereomeric salt and the step of decomposing the separated diastereomeric salt, usually 0.01 to 100 parts by weight, preferably 0.05 to 50 parts by weight per 1 part by weight of the diastereomeric salt. Parts, particularly preferably 0.1 to 15 parts by weight.
本発明のジアステレオマー塩を分解する反応に使用できる酸としては、例えば、フッ化水素酸、塩酸、臭化水素酸、沃化水素酸等のハロゲン化水素酸、硝酸、硫酸、燐酸、塩素酸、過塩素酸等の無機酸、メタンスルホン酸、エタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等のスルホン酸、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、フマール酸、酒石酸、蓚酸、マレイン酸、リンゴ酸、コハク酸、安息香酸、マンデル酸、アスコルビン酸、乳酸、グルコン酸、クエン酸等のカルボン酸又はグルタミン酸、アスパラギン酸等のアミノ酸等が挙げられる。これらは単独で使用しても良いし、２種以上を混合して使用しても良い。 Examples of the acid that can be used in the reaction for decomposing the diastereomeric salt of the present invention include hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and chlorine. Acids, inorganic acids such as perchloric acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, sulfonic acid such as p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid Carboxylic acids such as tartaric acid, succinic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid, and amino acids such as glutamic acid and aspartic acid. These may be used singly or in combination of two or more.
斯かる酸の使用量は特に限定されないが、ジアステレオマー塩１モルに対して、通常０．０１〜１００倍モル、好ましくは０．０５〜５０倍モル、特に好ましくは０．５〜１０倍モルである。 The amount of such an acid used is not particularly limited, but is usually 0.01 to 100 times mol, preferably 0.05 to 50 times mol, particularly preferably 0.5 to 10 times the mol of diastereomeric salt. Is a mole.
以下に本発明の実施例を示すが、本発明はこれらのみによって限定されるものではない。 Examples of the present invention are shown below, but the present invention is not limited to these examples.
また各実施例で得られた化合物の絶対配置は、実施例３に記載したX線結晶構造解析によって確認した（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸を標準物質として、そのHPLCでの保持時間の比較で決定した。 The absolute configuration of the compound obtained in each example was confirmed by X-ray crystal structure analysis described in Example 3 (S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl. -4,5-Dihydroisoxazol-3-yl] -2-methylbenzoic acid was used as a standard substance, and the determination was made by comparing the retention times by HPLC.
〔実施例１〕
（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（L）−（−）−α−フェニルエチルアミンのジアステレオマー塩の合成
ラセミ体の４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸２．０９g、トルエン１０ｇ、酢酸エチル５ｇを仕込み、５４℃で撹拌した。そこに（L）−（−）−α−フェニルエチルアミン０．３０４ｇを加え、１時間で４℃まで冷却した。生じた固体を減圧下濾取し、固体をトルエン／酢酸エチル＝５／１の溶液５ｍｌで洗浄した。減圧下乾燥し、白色固体として（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（L）−（−）−α−フェニルエチルアミンのジアステレオマー塩１．０３ｇを得た。1H-NMRより白色固体は４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸とα−フェニルエチルアミンの１対１の塩であることがわかった。
[Example 1]
(S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (L)-(-) Synthesis of diastereomeric salts of -α-phenylethylamine Racemic 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2- Methylbenzoic acid (2.09 g), toluene (10 g) and ethyl acetate (5 g) were charged, and the mixture was stirred at 54 ° C. Thereto was added 0.304 g of (L)-(−)-α-phenylethylamine, and the mixture was cooled to 4 ° C. over 1 hour. The resulting solid was collected by filtration under reduced pressure, and the solid was washed with 5 ml of a toluene / ethyl acetate = 5/1 solution. Dry under reduced pressure and (S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid as a white solid And 1.03 g of a diastereomeric salt of (L)-(−)-α-phenylethylamine. From 1 H-NMR, white solid was 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and α-phenyl. It was found to be a 1: 1 salt of ethylamine.
得られたジアステレオマー塩とろ液を、キラルHPLCカラムを付けた高速液体クロマトグラフィーで分析し、ジアステレオマー塩では（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸が保持時間12.9分／24.8分＝95／5であり、ろ液では保持時間12.9分／23.4分＝19／81であることを確認した（分析条件は、キラルHPLCカラム：Chiralpak AD-H 4.6×250mm、溶離液：ヘキサン／エタノール＝４／１、流速：0.40mL/min、オーブン温度：３０℃、検出：254nmの波長によるUV検出器）。
1H NMR (CDCl3, Me4Si, 300MHz) δ 7.96 (d, J=9.0Hz, 1H), 7.52 (m, 4H), 7.43 (t, J=1.8Hz, 1H), 7.23-7.36 (m, 5H), 4.16 (q, J=6.6Hz, 1H), 4.12 (d, J=17.7Hz, 1H), 3.75 (d, J=17.4Hz, 1H), 2.63 (s, 3H) , 1.43 (d, J=6.6Hz, 3H)。
The obtained diastereomeric salt and filtrate were analyzed by high performance liquid chromatography with a chiral HPLC column. For diastereomeric salts, (S) -4- [5- (3,5-dichlorophenyl) -5-tri Fluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5- Dihydroisoxazol-3-yl] -2-methylbenzoic acid was confirmed to have a retention time of 12.9 minutes / 24.8 minutes = 95/5, and the filtrate had a retention time of 12.9 minutes / 23.4 minutes = 19/81. (Analysis conditions are: chiral HPLC column: Chiralpak AD-H 4.6 × 250 mm, eluent: hexane / ethanol = 4/1, flow rate: 0.40 mL / min, oven temperature: 30 ° C., detection: UV detector with a wavelength of 254 nm. ).
1 H NMR (CDCl 3 , Me 4 Si, 300 MHz) δ 7.96 (d, J = 9.0Hz, 1H), 7.52 (m, 4H), 7.43 (t, J = 1.8Hz, 1H), 7.23-7.36 (m , 5H), 4.16 (q, J = 6.6Hz, 1H), 4.12 (d, J = 17.7Hz, 1H), 3.75 (d, J = 17.4Hz, 1H), 2.63 (s, 3H), 1.43 (d , J = 6.6Hz, 3H).
〔実施例２〕
（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（D）−（＋）−α−フェニルエチルアミンのジアステレオマー塩の合成
〔実施例２−１〕
ラセミ体の４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸０．２０９g、トルエン２ｍL、酢酸エチル１ｍLを仕込み、室温で撹拌した。そこに（D）−（＋）−α−フェニルエチルアミン０．０１３６ｇを加え、一晩撹拌した。生じた固体を減圧下濾取し、固体をヘキサン１ｍLで洗浄した。減圧下乾燥し、白色固体として（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（D）−（＋）−α−フェニルエチルアミンのジアステレオマー塩０．０４０５ｇを得た。1H-NMRより白色固体は４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸とα−フェニルエチルアミンの１対１の塩であることがわかった。
[Example 2]
(R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (D)-(+) Synthesis of diastereomeric salt of -α-phenylethylamine [Example 2-1]
Racemic 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid 0.209 g, toluene 2 mL, ethyl acetate 1 mL was charged and stirred at room temperature. Thereto was added 0.0136 g of (D)-(+)-α-phenylethylamine, and the mixture was stirred overnight. The resulting solid was collected by filtration under reduced pressure, and the solid was washed with 1 mL of hexane. Dry under reduced pressure and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid as a white solid And 0.0405 g of a diastereomeric salt of (D)-(+)-α-phenylethylamine. From 1 H-NMR, white solid was 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and α-phenyl. It was found to be a 1: 1 salt of ethylamine.
得られたジアステレオマー塩とろ液を、キラルHPLCカラムを付けた高速液体クロマトグラフィーで分析し、ジアステレオマー塩では（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸が保持時間13.5分／22.5分＝1.6／98.4であり、ろ液では保持時間12.4分／22.3分＝63／37であることを確認した（分析条件は、キラルHPLCカラム：Chiralpak AD-H 4.6×250mm、溶離液：ヘキサン／エタノール＝４／１、流速：0.40mL/min、オーブン温度：３０℃、検出：254nmの波長によるUV検出器）。 The obtained diastereomeric salt and filtrate were analyzed by high performance liquid chromatography with a chiral HPLC column. For diastereomeric salts, (S) -4- [5- (3,5-dichlorophenyl) -5-tri Fluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5- Dihydroisoxazol-3-yl] -2-methylbenzoic acid was confirmed to have a retention time of 13.5 minutes / 22.5 minutes = 1.6 / 98.4, and the filtrate had a retention time of 12.4 minutes / 22.3 minutes = 63/37. (Analysis conditions are: chiral HPLC column: Chiralpak AD-H 4.6 × 250 mm, eluent: hexane / ethanol = 4/1, flow rate: 0.40 mL / min, oven temperature: 30 ° C., detection: UV detector with a wavelength of 254 nm. ).
〔実施例２−２〕
ラセミ体の４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸０．２０９g、トルエン２ｍL、酢酸エチル１ｍLを仕込み、室温で撹拌した。そこに（D）−（＋）−α−フェニルエチルアミン０．０３６０ｇを加え、一晩撹拌した。生じた固体を減圧下濾取し、固体をヘキサン１ｍLで洗浄した。減圧下乾燥し、白色固体として（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（D）−（＋）−α−フェニルエチルアミンのジアステレオマー塩０．１５８８ｇを得た。1H-NMRより白色固体は４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸とα−フェニルエチルアミンの１対１の塩であることがわかった。
[Example 2-2]
Racemic 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid 0.209 g, toluene 2 mL, ethyl acetate 1 mL was charged and stirred at room temperature. Thereto was added 0.0360 g of (D)-(+)-α-phenylethylamine, and the mixture was stirred overnight. The resulting solid was collected by filtration under reduced pressure, and the solid was washed with 1 mL of hexane. Dry under reduced pressure and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid as a white solid And 0.1588 g of a diastereomeric salt of (D)-(+)-α-phenylethylamine. From 1 H-NMR, white solid was 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and α-phenyl. It was found to be a 1: 1 salt of ethylamine.
得られたジアステレオマー塩とろ液を、キラルHPLCカラムを付けた高速液体クロマトグラフィーで分析し、ジアステレオマー塩では（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸が保持時間13.2分／22.7分＝6／94であり、ろ液では保持時間12.3分／22.5分＝89／11であることを確認した（分析条件は、キラルHPLCカラム：Chiralpak AD-H 4.6×250mm、溶離液：ヘキサン／エタノール＝４／１、流速：0.40mL/min、オーブン温度：３０℃、検出：254nmの波長によるUV検出器）。 The obtained diastereomeric salt and filtrate were analyzed by high performance liquid chromatography with a chiral HPLC column. For diastereomeric salts, (S) -4- [5- (3,5-dichlorophenyl) -5-tri Fluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5- It was confirmed that dihydroisoxazol-3-yl] -2-methylbenzoic acid had a retention time of 13.2 minutes / 22.7 minutes = 6/94, and the filtrate had a retention time of 12.3 minutes / 22.5 minutes = 89/11. (Analysis conditions are: chiral HPLC column: Chiralpak AD-H 4.6 × 250 mm, eluent: hexane / ethanol = 4/1, flow rate: 0.40 mL / min, oven temperature: 30 ° C., detection: UV detector with a wavelength of 254 nm. ).
〔実施例２−３〕
ラセミ体の４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸０．２０９g、トルエン２ｍL、酢酸エチル１ｍLを仕込み、室温で撹拌した。そこに（D）−（＋）−α−フェニルエチルアミン０．０４２６ｇを加え、一晩撹拌した。生じた固体を減圧下濾取し、固体をヘキサン１ｍLで洗浄した。減圧下乾燥し、白色固体として（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（D）−（＋）−α−フェニルエチルアミンのジアステレオマー塩０．１８５６ｇを得た。1H-NMRより白色固体は４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸とα−フェニルエチルアミンの１対１の塩であることがわかった。
[Example 2-3]
Racemic 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid 0.209 g, toluene 2 mL, ethyl acetate 1 mL was charged and stirred at room temperature. Thereto was added 0.0426 g of (D)-(+)-α-phenylethylamine, and the mixture was stirred overnight. The resulting solid was collected by filtration under reduced pressure, and the solid was washed with 1 mL of hexane. Dry under reduced pressure and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid as a white solid And 0.1856 g of a diastereomeric salt of (D)-(+)-α-phenylethylamine. From 1 H-NMR, white solid was 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and α-phenyl. It was found to be a 1: 1 salt of ethylamine.
得られたジアステレオマー塩とろ液を、キラルHPLCカラムを付けた高速液体クロマトグラフィーで分析し、ジアステレオマー塩では（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸が保持時間12.8分／22.7分＝20／80であり、ろ液では保持時間12.3分／22.9分＝90／10であることを確認した（分析条件は、キラルHPLCカラム：Chiralpak AD-H 4.6×250mm、溶離液：ヘキサン／エタノール＝４／１、流速：0.40mL/min、オーブン温度：３０℃、検出：254nmの波長によるUV検出器）。 The obtained diastereomeric salt and filtrate were analyzed by high performance liquid chromatography with a chiral HPLC column. For diastereomeric salts, (S) -4- [5- (3,5-dichlorophenyl) -5-tri Fluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5- It was confirmed that dihydroisoxazol-3-yl] -2-methylbenzoic acid had a retention time of 12.8 minutes / 22.7 minutes = 20/80, and the filtrate had a retention time of 12.3 minutes / 22.9 minutes = 90/10. (Analysis conditions are: chiral HPLC column: Chiralpak AD-H 4.6 × 250 mm, eluent: hexane / ethanol = 4/1, flow rate: 0.40 mL / min, oven temperature: 30 ° C., detection: UV detector with a wavelength of 254 nm. ).
〔実施例３〕
（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（L）−（−）−α−フェニルエチルアミンのジアステレオマー塩の再晶析
実施例１で得た（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（L）−（−）−α−フェニルエチルアミンのジアステレオマー塩０．５０ｇに酢酸エチル８ｍLとエタノール６ｍLを加え、50℃に加熱し、均一な溶液とした。撹拌しながら温度を下げていき、析出した結晶を氷冷下で10分間撹拌した後、ろ過した。結晶は乾燥後０．１３ｇあった。
Example 3
(S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (L)-(-) Recrystallization of diastereomeric salts of -α-phenylethylamine
(S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid obtained in Example 1 and ( To 0.50 g of L)-(−)-α-phenylethylamine diastereomer salt, 8 mL of ethyl acetate and 6 mL of ethanol were added and heated to 50 ° C. to obtain a uniform solution. The temperature was lowered while stirring, and the precipitated crystals were stirred for 10 minutes under ice cooling and then filtered. The crystal was 0.13 g after drying.
得られたジアステレオマー塩を、キラルHPLCカラムを付けた高速液体クロマトグラフィーで分析し、ジアステレオマー塩は（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸が保持時間8.5分／13.4分＝99.1／0.9であることを確認した（分析条件は、キラルHPLCカラム：Chiralpak AD-H 4.6×250mm、溶離液：ヘキサン／0.8vol%トリフルオロ酢酸入りエタノール＝３／１、流速：0.50mL/min、オーブン温度：３０℃、検出：280nmの波長によるUV検出器）。
1H NMR (DMSO-d6, Me4Si, 300MHz) δ 7.56-7.66 (m, 3H), 7.24-7.52 (m, 7H), 4.16-4.38 (m, 3H), 2.48 (s, 3H) , 1.39 (d, J=6.9Hz, 3H)。
融点は189-192℃。
The obtained diastereomeric salt was analyzed by high performance liquid chromatography with a chiral HPLC column, and the diastereomeric salt was (S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl. -4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroiso It was confirmed that the retention time of xazozol-3-yl] -2-methylbenzoic acid was 8.5 minutes / 13.4 minutes = 99.1 / 0.9 (analysis conditions were chiral HPLC column: Chiralpak AD-H 4.6 × 250 mm, eluent : Hexane / 0.8 vol% trifluoroacetic acid-containing ethanol = 3/1, flow rate: 0.50 mL / min, oven temperature: 30 ° C., detection: UV detector with a wavelength of 280 nm).
1 H NMR (DMSO-d6, Me 4 Si, 300 MHz) δ 7.56-7.66 (m, 3H), 7.24-7.52 (m, 7H), 4.16-4.38 (m, 3H), 2.48 (s, 3H), 1.39 (d, J = 6.9Hz, 3H).
Melting point is 189-192 ° C.
また得られた結晶を、X線結晶構造解析を行うことで、４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸の絶対配置が（S）であることを確認した。測定時の絶対構造パラメーター(absolute structure parameter)の値は0.10であった、
〔実施例４〕
（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（L）−（−）−α−フェニルエチルアミンのジアステレオマー塩の分解
実施例１で得た（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（L）−（−）−α−フェニルエチルアミンのジアステレオマー塩０．５０ｇに酢酸エチル１０ｍLとトルエン１５ｍLを加え、さらに精製水３ｍLと３５％塩酸０．５３ｇを混合した希塩酸を加え、50℃に加熱した。それを分液し、有機層に、精製水３ｍLと３５％塩酸０．５３ｇを混合した希塩酸を加え、混合した後、分液した。有機層に精製水３ｍLを加え、混合した後、分液した。有機層から溶媒を減圧下に留去し、減圧乾燥後、０．４４ｇのアモルファス状物を得た。1H-NMRより４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸であった。
Further, the obtained crystal was subjected to X-ray crystal structure analysis, whereby 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]- It was confirmed that the absolute configuration of 2-methylbenzoic acid was (S). The absolute structure parameter value at the time of measurement was 0.10,
Example 4
(S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid and (L)-(-) Of diastereomeric salts of -α-phenylethylamine
(S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid obtained in Example 1 and ( L)-(-)-α-Phenylethylamine diastereomer salt 0.50 g, 10 mL of ethyl acetate and 15 mL of toluene were added, and 3 mL of purified water and dilute hydrochloric acid mixed with 0.53 g of 35% hydrochloric acid were added. Heated. The organic layer was separated, diluted hydrochloric acid mixed with 3 mL of purified water and 0.53 g of 35% hydrochloric acid was added, mixed, and then separated. After adding 3 mL of purified water to the organic layer, mixing, liquid separation was performed. The solvent was distilled off from the organic layer under reduced pressure, and after drying under reduced pressure, 0.44 g of an amorphous product was obtained. From 1 H-NMR, it was 4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-methylbenzoic acid.
得られたアモルファス状物を、キラルHPLCカラムを付けた高速液体クロマトグラフィーで分析し、アモルファス状物は（S）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸と（R）−４−[５−(３,５−ジクロロフェニル)−５−トリフルオロメチル−４,５−ジヒドロイソキサゾール−３−イル]−２−メチル安息香酸が保持時間8.3分／11.8分＝91／9であることを確認した（分析条件は、キラルHPLCカラム：Chiralpak AD-H 4.6×250mm、溶離液：ヘキサン／0.8vol%トリフルオロ酢酸入りエタノール＝３／１、流速：0.50mL/min、オーブン温度：３０℃、検出：280nmの波長によるUV検出器）。
1H NMR (CDCl3, Me4Si, 300MHz) δ 8.09 (m, 1H), 7.40-7.60 (m, 5H), 4.41 (br, 1H), 4.10 (d, J=17.4Hz, 1H), 3.71 (d, J=17.4Hz, 1H), 2.68 (s, 3H)。
The obtained amorphous product was analyzed by high performance liquid chromatography with a chiral HPLC column. The amorphous product was (S) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4. , 5-Dihydroisoxazol-3-yl] -2-methylbenzoic acid and (R) -4- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazole It was confirmed that the retention time of -3-yl] -2-methylbenzoic acid was 8.3 minutes / 11.8 minutes = 91/9 (analysis conditions were chiral HPLC column: Chiralpak AD-H 4.6 × 250 mm, eluent: hexane /0.8vol% trifluoroacetic acid-containing ethanol = 3/1, flow rate: 0.50mL / min, oven temperature: 30 ° C, detection: UV detector with a wavelength of 280nm).
1 H NMR (CDCl 3 , Me 4 Si, 300 MHz) δ 8.09 (m, 1H), 7.40-7.60 (m, 5H), 4.41 (br, 1H), 4.10 (d, J = 17.4Hz, 1H), 3.71 (d, J = 17.4Hz, 1H), 2.68 (s, 3H).
本発明のジアステレオマー塩法による４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体の製造方法及び４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物の光学活性体と光学活性な塩基性化合物とを構成成分として有するジアステレオマー塩の製造方法及びそのジアステレオマー塩は、農薬、医薬、機能材料の製造中間体として有用な化合物であるイソキサゾリン化合物及びその中間体の光学活性体の製造方法として有用である。
Process for producing optically active 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound by diastereomeric salt method of the present invention and 4- (4,5-dihydroisoxazole-3- I) A method for producing a diastereomeric salt having an optically active benzoic acid compound and an optically active basic compound as constituents, and the diastereomeric salt is useful as an intermediate for the production of agricultural chemicals, pharmaceuticals and functional materials. It is useful as a method for producing an optically active form of an isoxazoline compound and an intermediate thereof.
Claims (4)
［式中、R1は、C1〜C6ハロアルキル又はC3〜C8ハロシクロアルキルを表し、
A1、A2、A3及びA4は、それぞれ独立にN又はC-Yを表し、
A5、A6及びA7は、それぞれ独立にN又はC-Xを表し、
Xは、水素原子、ハロゲン原子、シアノ、ニトロ、-SF5、C1〜C6アルキル、C1〜C6ハロアルキル、ヒドロキシ（C1〜C6）ハロアルキル、C1〜C6アルコキシ(C1〜C6)ハロアルキル、C1〜C6ハロアルコキシ(C1〜C6)ハロアルキル、C3〜C8ハロシクロアルキル、-OR2、-OSO2R2又は-S(O)rR2を表し、各々のXは互いに同一であっても又は互いに相異なっていてもよく、
R2は、C1〜C6アルキル、C1〜C4アルコキシ(C1〜C4)アルキル、C1〜C6ハロアルキル又はC1〜C3ハロアルコキシ(C1〜C3)ハロアルキルを表し、
Yは、水素原子、ハロゲン原子、シアノ、ニトロ、C1〜C4アルキル、C1〜C4ハロアルキル、C1〜C4アルコキシ、C1〜C4ハロアルコキシ、C1〜C6アルキルチオ、C1〜C6ハロアルキルチオ、C1〜C6アルキルスルホニル、C1〜C6ハロアルキルスルホニル、-NH2、-N(R4)R3を表し、各々のYは互いに同一であっても又は互いに相異なっていてもよく、
隣接する２つのYが一緒になって、A8=A9-A10=A11を形成していても良く、
A8、A9、A10及びA11は、それぞれ独立にN又はC-Y1を表し、
Y1は、水素原子、ハロゲン原子、シアノ、ニトロ、C1〜C4アルキル、C1〜C4ハロアルキル、C1〜C4アルコキシ、C1〜C4ハロアルコキシ、C1〜C6アルキルチオ、C1〜C6ハロアルキルチオ、C1〜C6アルキルスルホニル、C1〜C6ハロアルキルスルホニル、-NH2、-N(R4)R3を表し、各々のY1は互いに同一であっても又は互いに相異なっていてもよく、
R3は、C1〜C6アルキル、-CHO、C1〜C6アルキルカルボニル、C1〜C6ハロアルキルカルボニル、C1〜C6アルコキシカルボニル、C1〜C6アルキルチオカルボニル、C1〜C6アルコキシチオカルボニル、C1〜C6アルキルジチオカルボニル、C1〜C6アルキルスルホニル又はC1〜C6ハロアルキルスルホニルを表し、
R4は、水素原子又はC1〜C6アルキルを表し、
rは、０〜２の整数を表す]で表される４−(４，５−ジヒドロイソキサゾール−３−イル)安息香酸化合物と、光学活性なα−フェニルエチルアミンと溶液中で反応させ、次に晶析により一方のジアステレオマー塩を析出させ分離する、前記溶液に対して低溶解性のジアステレオマー塩の製造方法 Formula (1):
[Wherein R 1 represents C 1 -C 6 haloalkyl or C 3 -C 8 halocycloalkyl,
A 1 , A 2 , A 3 and A 4 each independently represent N or CY,
A 5 , A 6 and A 7 each independently represent N or CX;
X is a hydrogen atom, a halogen atom, cyano, nitro, -SF 5, C 1 ~C 6 alkyl, C 1 -C 6 haloalkyl, hydroxy (C 1 -C 6) haloalkyl, C 1 -C 6 alkoxy (C 1 -C 6) haloalkyl, C 1 -C 6 haloalkoxy (C 1 ~C 6) haloalkyl, C 3 -C 8 halocycloalkyl, the -OR 2, -OSO 2 R 2, or -S (O) r R 2 Each X may be the same as or different from each other;
R 2 represents C 1 -C 6 alkyl, C 1 -C 4 alkoxy (C 1 -C 4 ) alkyl, C 1 -C 6 haloalkyl or C 1 -C 3 haloalkoxy (C 1 -C 3 ) haloalkyl. ,
Y is a hydrogen atom, a halogen atom, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 6 alkylthio, C 1 to C 6 haloalkylthio, C 1 to C 6 alkylsulfonyl, C 1 to C 6 haloalkylsulfonyl, —NH 2 , —N (R 4 ) R 3 , each Y may be the same as each other or They may be different,
Two adjacent Ys may be joined together to form A 8 = A 9 -A 10 = A 11
A 8 , A 9 , A 10 and A 11 each independently represent N or CY 1
Y 1 is a hydrogen atom, a halogen atom, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, -NH 2 , -N (R 4 ) R 3 , each Y 1 may be the same as each other Or they may be different from each other,
R 3 is, C 1 -C 6 alkyl, -CHO, C 1 ~C 6 alkyl carbonyl, C 1 -C 6 haloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylthiocarbonyl, C 1 -C 6 alkoxythiocarbonyl, C 1 -C 6 alkyl dithio carbonyl, represents C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl,
R 4 represents a hydrogen atom or C 1 -C 6 alkyl,
r represents an integer of 0 to 2], and a 4- (4,5-dihydroisoxazol-3-yl) benzoic acid compound represented by the formula (1) is reacted with optically active α-phenylethylamine in a solution; Next, a method for producing a diastereomeric salt having low solubility in the solution, wherein one diastereomeric salt is precipitated and separated by crystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2010174135A JP5679102B2 (en) | 2009-08-03 | 2010-08-03 | Optically active form and diastereomeric salt of dihydroisoxazole-substituted benzoic acid compound and method for producing the same |
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| US11530187B2 (en) | 2018-12-21 | 2022-12-20 | Intervet Inc. | Method for producing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid |
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