JP6347460B2 - (Trihalomethyl) benzene derivative and method for producing the same - Google Patents
(Trihalomethyl) benzene derivative and method for producing the same Download PDFInfo
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- JP6347460B2 JP6347460B2 JP2014043701A JP2014043701A JP6347460B2 JP 6347460 B2 JP6347460 B2 JP 6347460B2 JP 2014043701 A JP2014043701 A JP 2014043701A JP 2014043701 A JP2014043701 A JP 2014043701A JP 6347460 B2 JP6347460 B2 JP 6347460B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 22
- 125000004953 trihalomethyl group Chemical group 0.000 title claims description 18
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 60
- -1 pentafluorosulfanyl group Chemical group 0.000 claims description 38
- AZSZCFSOHXEJQE-UHFFFAOYSA-N dibromodifluoromethane Chemical compound FC(F)(Br)Br AZSZCFSOHXEJQE-UHFFFAOYSA-N 0.000 claims description 35
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 229910052749 magnesium Inorganic materials 0.000 claims description 11
- 239000011777 magnesium Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 150000002641 lithium Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Chemical group 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 41
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 30
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 28
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 25
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 24
- 150000001555 benzenes Chemical class 0.000 description 20
- 125000005336 allyloxy group Chemical group 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 12
- 150000008045 alkali metal halides Chemical class 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 8
- 229910001508 alkali metal halide Inorganic materials 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- FUJFHJAWFLGHLR-UHFFFAOYSA-N [dibromo(fluoro)methyl]benzene Chemical class FC(Br)(Br)C1=CC=CC=C1 FUJFHJAWFLGHLR-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 0 *C(*)(CC=C)c1ccc(*)cc1* Chemical compound *C(*)(CC=C)c1ccc(*)cc1* 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- IRFLMBVQZGEPRT-UHFFFAOYSA-N C[Mg]c1ccccc1 Chemical compound C[Mg]c1ccccc1 IRFLMBVQZGEPRT-UHFFFAOYSA-N 0.000 description 3
- 239000008204 material by function Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- ZZPGEOZZLFQRGZ-UHFFFAOYSA-N (bromo-chloro-fluoromethyl)benzene Chemical class FC(Cl)(Br)C1=CC=CC=C1 ZZPGEOZZLFQRGZ-UHFFFAOYSA-N 0.000 description 2
- PNADWYBJSASGIY-UHFFFAOYSA-N 1-(4-iodophenyl)sulfonyl-4-methylbenzene Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C1=CC=C(I)C=C1 PNADWYBJSASGIY-UHFFFAOYSA-N 0.000 description 2
- MMCUNAXOACRHIR-UHFFFAOYSA-N 1-fluoro-4-(4-iodophenyl)sulfonylbenzene Chemical compound C1=CC(F)=CC=C1S(=O)(=O)C1=CC=C(I)C=C1 MMCUNAXOACRHIR-UHFFFAOYSA-N 0.000 description 2
- JDDAFHUEOVUDFJ-UHFFFAOYSA-N 2-iodobenzonitrile Chemical compound IC1=CC=CC=C1C#N JDDAFHUEOVUDFJ-UHFFFAOYSA-N 0.000 description 2
- UJXAVMZSVIODSH-UHFFFAOYSA-N 2-methylbenzene-1,4-dicarbonitrile Chemical compound CC1=CC(C#N)=CC=C1C#N UJXAVMZSVIODSH-UHFFFAOYSA-N 0.000 description 2
- BGARPMGQRREXLN-UHFFFAOYSA-N 3-iodobenzonitrile Chemical compound IC1=CC=CC(C#N)=C1 BGARPMGQRREXLN-UHFFFAOYSA-N 0.000 description 2
- XOKDXPVXJWTSRM-UHFFFAOYSA-N 4-iodobenzonitrile Chemical compound IC1=CC=C(C#N)C=C1 XOKDXPVXJWTSRM-UHFFFAOYSA-N 0.000 description 2
- MDXGRFMFORMPGT-UHFFFAOYSA-N 4-methylbenzene-1,2-dicarbonitrile Chemical compound CC1=CC=C(C#N)C(C#N)=C1 MDXGRFMFORMPGT-UHFFFAOYSA-N 0.000 description 2
- IUNABFKKIMSGTM-UHFFFAOYSA-M Br[Mg]C1=CC=CC=C1C#N Chemical compound Br[Mg]C1=CC=CC=C1C#N IUNABFKKIMSGTM-UHFFFAOYSA-M 0.000 description 2
- LVMQBRXZZRHWDD-UHFFFAOYSA-M C(#N)C1=C(C=CC=C1)[Mg]Cl Chemical compound C(#N)C1=C(C=CC=C1)[Mg]Cl LVMQBRXZZRHWDD-UHFFFAOYSA-M 0.000 description 2
- RAAQQIJKXIMEHL-UHFFFAOYSA-N C(#N)[Mg]C1=CC=CC=C1 Chemical compound C(#N)[Mg]C1=CC=CC=C1 RAAQQIJKXIMEHL-UHFFFAOYSA-N 0.000 description 2
- MZOOSOLOZXEZPR-UHFFFAOYSA-M CC(C=C1)=CC=C1S(C(C=C1)=CC=C1[Mg+])(=O)=O.[Br-] Chemical compound CC(C=C1)=CC=C1S(C(C=C1)=CC=C1[Mg+])(=O)=O.[Br-] MZOOSOLOZXEZPR-UHFFFAOYSA-M 0.000 description 2
- YOMFTVZVWRSNIO-UHFFFAOYSA-M Cl[Mg]c1cccc(c1)C#N Chemical compound Cl[Mg]c1cccc(c1)C#N YOMFTVZVWRSNIO-UHFFFAOYSA-M 0.000 description 2
- WGNPBYWKLLUNMJ-UHFFFAOYSA-M FC1=CC=C(C=C1)S(=O)(=O)C1=CC=C(C=C1)[Mg]Cl Chemical compound FC1=CC=C(C=C1)S(=O)(=O)C1=CC=C(C=C1)[Mg]Cl WGNPBYWKLLUNMJ-UHFFFAOYSA-M 0.000 description 2
- NRUZBZJKRBOWRA-UHFFFAOYSA-M O=S(C(C=C1)=CC=C1F)(C(C=C1)=CC=C1[Mg+])=O.[Br-] Chemical compound O=S(C(C=C1)=CC=C1F)(C(C=C1)=CC=C1[Mg+])=O.[Br-] NRUZBZJKRBOWRA-UHFFFAOYSA-M 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- HZWSACODLNHFPJ-UHFFFAOYSA-M [Br-].C(#N)C=1C=C(C=CC1)[Mg+] Chemical compound [Br-].C(#N)C=1C=C(C=CC1)[Mg+] HZWSACODLNHFPJ-UHFFFAOYSA-M 0.000 description 2
- GNWHVUYSAAZKTQ-UHFFFAOYSA-M [Br-].[Mg+]C1=CC=C(C#N)C=C1 Chemical compound [Br-].[Mg+]C1=CC=C(C#N)C=C1 GNWHVUYSAAZKTQ-UHFFFAOYSA-M 0.000 description 2
- CRMLIRSLRJQNGW-UHFFFAOYSA-M [Cl-].COC(=O)C1=CC=C([Mg+])C=C1 Chemical compound [Cl-].COC(=O)C1=CC=C([Mg+])C=C1 CRMLIRSLRJQNGW-UHFFFAOYSA-M 0.000 description 2
- DXOUZUAACVADOH-UHFFFAOYSA-M [Cl-].[Mg+]C1=CC=C(C#N)C=C1 Chemical compound [Cl-].[Mg+]C1=CC=C(C#N)C=C1 DXOUZUAACVADOH-UHFFFAOYSA-M 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- AMTCFHNIEBPFLM-UHFFFAOYSA-N methyl 4-iodo-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1C AMTCFHNIEBPFLM-UHFFFAOYSA-N 0.000 description 2
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 1
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- IQVCEQDNKGWJDB-UHFFFAOYSA-N 1-[4-[dibromo(fluoro)methyl]phenyl]sulfonyl-4-methylbenzene Chemical compound CC1=CC=C(C=C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(Br)Br IQVCEQDNKGWJDB-UHFFFAOYSA-N 0.000 description 1
- LLCGWFDJOADZAA-UHFFFAOYSA-N 1-[dibromo(fluoro)methyl]-4-(4-fluorophenyl)sulfonylbenzene Chemical compound FC1=CC=C(C=C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(Br)Br LLCGWFDJOADZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- QLZDTHTXOUOSCV-UHFFFAOYSA-N 2,4-dimethylbenzonitrile Chemical compound CC1=CC=C(C#N)C(C)=C1 QLZDTHTXOUOSCV-UHFFFAOYSA-N 0.000 description 1
- KJUCPVIVNLPLEE-UHFFFAOYSA-N 2,6-difluoro-n-[2-fluoro-5-[5-[2-[(6-morpholin-4-ylpyridin-3-yl)amino]pyrimidin-4-yl]-2-propan-2-yl-1,3-thiazol-4-yl]phenyl]benzenesulfonamide Chemical compound S1C(C(C)C)=NC(C=2C=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C(F)=CC=2)=C1C(N=1)=CC=NC=1NC(C=N1)=CC=C1N1CCOCC1 KJUCPVIVNLPLEE-UHFFFAOYSA-N 0.000 description 1
- ZSDGHWLLLGYAJV-AHEHSYJASA-N 2-[(E)-[(E)-3-[1-(2-nitrophenyl)pyrrol-2-yl]prop-2-enylidene]amino]guanidine Chemical compound NC(N)=N\N=C\C=C\C1=CC=CN1C1=CC=CC=C1[N+]([O-])=O ZSDGHWLLLGYAJV-AHEHSYJASA-N 0.000 description 1
- SSORSZACHCNXSJ-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NCC(C)O SSORSZACHCNXSJ-UHFFFAOYSA-N 0.000 description 1
- DILISPNYIVRDBP-UHFFFAOYSA-N 2-[3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile Chemical compound OC(CNC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=CC2=CC=CC=C2C=C1)C DILISPNYIVRDBP-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- VHDLWGQRFLPNMI-UHFFFAOYSA-N 2-methoxybenzene-1,4-dicarbonitrile Chemical compound COC1=CC(C#N)=CC=C1C#N VHDLWGQRFLPNMI-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- DMHDHMQVXJEDBW-UHFFFAOYSA-N 4-(bromo-chloro-fluoromethyl)benzonitrile Chemical compound FC(Cl)(Br)C1=CC=C(C#N)C=C1 DMHDHMQVXJEDBW-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- LTLYQTBXAKQSAK-UHFFFAOYSA-N 4-[dibromo(fluoro)methyl]benzonitrile Chemical compound BrC(C1=CC=C(C#N)C=C1)(F)Br LTLYQTBXAKQSAK-UHFFFAOYSA-N 0.000 description 1
- SKXUZFJOLNNWIG-UHFFFAOYSA-N 4-bromo-3-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC=C1Br SKXUZFJOLNNWIG-UHFFFAOYSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、医農薬、機能性材料及びそれらの製造中間体として有用な（トリハロメチル）ベンゼン誘導体及びその製造方法に関する。 The present invention relates to (trihalomethyl) benzene derivatives useful as medicines and agricultural chemicals, functional materials, and production intermediates thereof, and a method for producing the same.
（トリハロメチル）ベンゼン誘導体は医農薬、機能性材料及びそれらの製造中間体として有用である。しかしながら、（トリハロメチル）ベンゼン誘導体の中で、（ジブロモフルオロメチル）ベンゼン誘導体はほとんど知られていない。従来、（ジブロモフルオロメチル）ベンゼン誘導体は、対応する（トリブロモメチル）ベンゼン誘導体をフッ化水素により臭素原子をフッ素原子で置換する方法（特許文献１）及び（トリフルオロメチル）ベンゼン誘導体を三臭化ホウ素によりフッ素原子を臭素原子で置換する方法（非特許文献１）で製造されている。また、（ブロモフルオロメチル）ベンゼン誘導体の臭素化反応により（ジブロモフルオロメチル）ベンゼン誘導体を製造する方法が開示されている（非特許文献２）。しかしながら、何れの方法も過酷な反応条件が必要であり、基質一般性の低い方法である。また、（トリハロメチル）ベンゼン誘導体である（ブロモクロロフルオロメチル）ベンゼン誘導体及びその製造方法もこれまでほとんど報告されていない。
これまでに、アリールマグネシウム試薬とジブロモジフルオロメタンをハロゲン化アルカリ金属塩又はハロゲン化マグネシウム存在下反応させて、（ブロモクロロフルオロメチル）ベンゼン誘導体及び（ジブロモフルオロメチル）ベンゼン誘導体を得る製造法は全く報告されていない。
(Trihalomethyl) benzene derivatives are useful as medical pesticides, functional materials and production intermediates thereof. However, among (trihalomethyl) benzene derivatives, (dibromofluoromethyl) benzene derivatives are hardly known. Conventionally, (dibromofluoromethyl) benzene derivatives are obtained by replacing the corresponding (tribromomethyl) benzene derivative with hydrogen fluoride to replace bromine atoms with fluorine atoms (Patent Document 1) and (trifluoromethyl) benzene derivatives with three odors. It is manufactured by a method (Non-patent Document 1) in which a fluorine atom is substituted with a bromine atom by boron bromide. In addition, a method for producing a (dibromofluoromethyl) benzene derivative by bromination reaction of a (bromofluoromethyl) benzene derivative is disclosed (Non-Patent Document 2). However, each method requires harsh reaction conditions and is a method with low substrate generality. Also, there have been few reports on (bromochlorofluoromethyl) benzene derivatives which are (trihalomethyl) benzene derivatives and methods for producing the same.
So far, there has been no report on a process for producing (bromochlorofluoromethyl) benzene derivatives and (dibromofluoromethyl) benzene derivatives by reacting arylmagnesium reagents with dibromodifluoromethane in the presence of alkali metal halides or magnesium halides. It has not been.
従来の（トリハロメチル）ベンゼン誘導体の製造方法は、過酷な反応条件や基質寛容性の低い試薬を用いるため、基質一般性の高い製造法ではなかった。本発明の課題は、医農薬、機能性材料及びそれらの製造中間体として有用な（トリハロメチル）ベンゼン誘導体及び基質一般性の高い（トリハロメチル）ベンゼン誘導体の製造方法を提供することにある。 The conventional method for producing a (trihalomethyl) benzene derivative was not a production method with high substrate generality because it uses harsh reaction conditions and a reagent with low substrate tolerance. An object of the present invention is to provide a method for producing a (trihalomethyl) benzene derivative useful as a medical pesticide, a functional material, and a production intermediate thereof, and a (trihalomethyl) benzene derivative having a high generality of substrate.
本発明者らは、上記課題を鑑み鋭意検討を重ねた結果、アリールマグネシウム試薬をハロゲン化アルカリ金属塩又はハロゲン化マグネシウム存在下、ジブロモジフルオロメタンと反応させることにより、（トリハロメチル）ベンゼン誘導体を簡便に製造できることを見出し、本発明を完成するに至った。
すなわち本発明は、一般式（２）
As a result of intensive studies in view of the above-mentioned problems, the present inventors have made it easy to convert a (trihalomethyl) benzene derivative by reacting an arylmagnesium reagent with dibromodifluoromethane in the presence of an alkali metal halide or magnesium halide. As a result, the present invention was completed.
That is, the present invention relates to the general formula (2)
（式中、Ｒ１は炭素数１から６のフルオロアルキル基；（炭素数１から６のアルコキシ）カルボニル基；シアノ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基；フッ素原子；又はペンタフルオロスルファニル基を表し、Ｒ２は炭素数１から６のフルオロアルキル基；（炭素数１から６のアルコキシ）カルボニル基；シアノ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基；フッ素原子；ペンタフルオロスルファニル基；炭素数１から６のアルキル基；炭素数１から６のアルコキシ基；炭素数３から６のアルケニルオキシ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよい炭素数６から１２の芳香族炭化水素基；又は塩素原子を表す。ｎは０から３の整数を表し、ｎが２又は３の整数の場合、複数のＲ２は同一又は相異なっていてもよい。Ｑは塩素原子又は臭素原子を表す。）で表される（トリハロメチル）ベンゼン誘導体に関する。
また、本発明は、一般式（１）
(Wherein R 1 is a fluoroalkyl group having 1 to 6 carbon atoms; (alkoxy having 1 to 6 carbon atoms) carbonyl group; cyano group; an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms) Or a phenylsulfonyl group optionally substituted with a fluorine atom; a fluorine atom; or a pentafluorosulfanyl group, wherein R 2 is a fluoroalkyl group having 1 to 6 carbon atoms; (an alkoxy having 1 to 6 carbon atoms) carbonyl group; A cyano group; an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, or a phenylsulfonyl group optionally substituted with a fluorine atom; a fluorine atom; a pentafluorosulfanyl group; an alkyl having 1 to 6 carbon atoms Group: an alkoxy group having 1 to 6 carbon atoms; an alkenyloxy group having 3 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; 6 represents an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with a fluoroalkyl group or a fluorine atom; or represents a chlorine atom, n represents an integer of 0 to 3, and n represents 2 or 3 In the case of an integer, a plurality of R 2 may be the same or different. Q represents a chlorine atom or a bromine atom.) (Trihalomethyl) benzene derivative
In addition, the present invention provides a general formula (1)
（式中、Ｒ１は炭素数１から６のフルオロアルキル基；（炭素数１から６のアルコキシ）カルボニル基；シアノ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基；フッ素原子；又はペンタフルオロスルファニル基を表し、Ｒ２は炭素数１から６のフルオロアルキル基；（炭素数１から６のアルコキシ）カルボニル基；シアノ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基；フッ素原子；ペンタフルオロスルファニル基；炭素数１から６のアルキル基；炭素数１から６のアルコキシ基；炭素数３から６のアルケニルオキシ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよい炭素数６から１２の芳香族炭化水素基；又は塩素原子を表す。ｎは０から３の整数を表し、ｎが２又は３の整数の場合、複数のＲ２は同一又は相異なっていてもよい。Ｘはハロゲン原子を表す。）で表されるアリールマグネシウム試薬を、一般式（５）［ＭＱ（５）］（式中、Ｍはアルカリ金属、Ｑは塩素原子又は臭素原子を表す。）で表されるハロゲン化アルカリ金属塩又は一般式（６）［ＭｇＱ２（６）］（式中、Ｑは塩素原子又は臭素原子を表す。）で表されるハロゲン化マグネシウム存在下、ジブロモジフルオロメタンと反応させることを特徴とする、一般式（２） (Wherein R 1 is a fluoroalkyl group having 1 to 6 carbon atoms; (alkoxy having 1 to 6 carbon atoms) carbonyl group; cyano group; an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms) Or a phenylsulfonyl group optionally substituted with a fluorine atom; a fluorine atom; or a pentafluorosulfanyl group, wherein R 2 is a fluoroalkyl group having 1 to 6 carbon atoms; (an alkoxy having 1 to 6 carbon atoms) carbonyl group; A cyano group; an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, or a phenylsulfonyl group optionally substituted with a fluorine atom; a fluorine atom; a pentafluorosulfanyl group; an alkyl having 1 to 6 carbon atoms Group: an alkoxy group having 1 to 6 carbon atoms; an alkenyloxy group having 3 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; 6 represents an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with a fluoroalkyl group or a fluorine atom; or represents a chlorine atom, n represents an integer of 0 to 3, and n represents 2 or 3 In the case of an integer, a plurality of R 2 may be the same or different. X represents a halogen atom.) An arylmagnesium reagent represented by the general formula (5) [MQ (5)] (wherein M represents an alkali metal, Q represents a chlorine atom or a bromine atom) or a halogenated alkali metal salt represented by the general formula (6) [MgQ 2 (6)] (wherein Q represents a chlorine atom or a bromine atom) And represented by the general formula (2), characterized by reacting with dibromodifluoromethane in the presence of magnesium halide represented by formula (2)
（式中、Ｒ１、Ｒ２、Ｑ及びｎは前記と同じ意味を表す。）で表される（トリハロメチル）ベンゼン誘導体の製造方法に関するものである。 (Wherein R 1 , R 2 , Q and n represent the same meanings as described above). This relates to a method for producing a (trihalomethyl) benzene derivative represented by:
本発明により、医農薬、機能性材料及びそれらの製造中間体として有用な（トリハロメチル）ベンゼン誘導体を簡便に製造することができる。 According to the present invention, (trihalomethyl) benzene derivatives useful as medicines and agricultural chemicals, functional materials, and production intermediates thereof can be easily produced.
以下に、本発明をさらに詳細に説明する。 The present invention is described in further detail below.
本明細書におけるＲ１、Ｒ２、Ｍ、Ｘ、Ｙ及びＺの定義について説明する。 The definitions of R 1 , R 2 , M, X, Y, and Z in this specification will be described.
Ｒ１で表される炭素数１から６のフルオロアルキル基としては、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、ペルフルオロエチル基、ペルフルオロプロピル基、ペルフルオロブチル基、ペルフルオロペンチル基、ペルフルオロヘキシル基等を例示することができる。 Examples of the fluoroalkyl group having 1 to 6 carbon atoms represented by R 1 include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a perfluoroethyl group, a perfluoropropyl group, a perfluorobutyl group, a perfluoropentyl group, and a perfluorohexyl group. Etc. can be illustrated.
Ｒ１で表される（炭素数１から６のアルコキシ）カルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、ｔｅｒｔ−ブトキシカルボニル、ヘキシルオキシカルボニル基等を例示することができる。
Ｒ１で表される炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基としては、フェニルスルホニル基、（４−メチルフェニル）スルホニル基、メシチルスルホニル基、［（４−トリフルオロメチル）フェニル］スルホニル基、（４−フルオロフェニル）スルホニル基等を例示することができる。
Examples of the (carbonyl group having 1 to 6 carbon atoms) carbonyl represented by R 1 include methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl, hexyloxycarbonyl group and the like.
Examples of the phenylsulfonyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms or a fluorine atom represented by R 1 include a phenylsulfonyl group, (4-methylphenyl) Examples include a sulfonyl group, a mesitylsulfonyl group, a [(4-trifluoromethyl) phenyl] sulfonyl group, a (4-fluorophenyl) sulfonyl group, and the like.
Ｒ２で表される炭素数１から６のアルキル基としては、直鎖状、環状又は分岐状のいずれであってもよく、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、シクロプロピル基、シクロプロピルメチル基、ペンチル基、ヘキシル基等を例示することができる。
Ｒ２で表される炭素数１から６のアルコキシ基としては、直鎖状、環状又は分岐状のいずれであってもよく、メトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、シクロプロピルオキシ基、ブトキシ基、イソブチルオキシ基、ｓｅｃ−ブチルオキシ基、ｔｅｒｔ−ブチルオキシ基、ヘキシルオキシ基、シクロブチルオキシ基、シクロプロピルメチルオキシ基等を例示することができる。
The alkyl group having 1 to 6 carbon atoms represented by R 2 may be linear, cyclic or branched, and may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or an isobutyl group. , Sec-butyl group, tert-butyl group, cyclopropyl group, cyclopropylmethyl group, pentyl group, hexyl group and the like.
The alkoxy group having 1 to 6 carbon atoms represented by R 2 may be linear, cyclic or branched, and is a methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropyloxy Group, butoxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group, hexyloxy group, cyclobutyloxy group, cyclopropylmethyloxy group and the like can be exemplified.
Ｒ２で表される炭素数３から６のアルケニルオキシ基としては、アリルオキシ基、２−ブテニルオキシ基、３−ブテニルオキシ基、４−ペンテニルオキシ基、５−ヘキセニルオキシ基等を例示することができる。 Examples of the alkenyloxy group having 3 to 6 carbon atoms represented by R 2 include an allyloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a 4-pentenyloxy group, and a 5-hexenyloxy group.
Ｒ２で表される炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよい炭素数６から１２の芳香族炭化水素基としては、フェニル基、１−ナフチル基、２−ナフチル基、４−ビフェニリル基、ｐ−トリル基、ｍ−トリル基、ｏ−トリル基、メシチル基、４−（トリフルオロメチル）フェニル基、３−（トリフルオロメチル）フェニル基、２−（トリフルオロメチル）フェニル基、４’−（トリフルオロメチル）−４−ビフェニリル基、４−フルオロフェニル基、２，３−ジフルオロフェニル基、２，４−ジフルオロフェニル基、３，４−ジフルオロフェニル基、３，５−ジフルオロフェニル基等を例示することができる。
Ｍで表されるアルカリ金属としては、リチウム原子、ナトリウム原子、カリウム原子、セシウム原子を例示することができる。Ｍは収率が良い点で、リチウム原子を用いることが好ましい。
Examples of the alkyl group having 1 to 6 carbon atoms represented by R 2 , a fluoroalkyl group having 1 to 6 carbon atoms, or an aromatic hydrocarbon group having 6 to 12 carbon atoms that may be substituted with a fluorine atom include a phenyl group 1-naphthyl group, 2-naphthyl group, 4-biphenylyl group, p-tolyl group, m-tolyl group, o-tolyl group, mesityl group, 4- (trifluoromethyl) phenyl group, 3- (trifluoromethyl) ) Phenyl group, 2- (trifluoromethyl) phenyl group, 4 ′-(trifluoromethyl) -4-biphenylyl group, 4-fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, Examples thereof include 3,4-difluorophenyl group and 3,5-difluorophenyl group.
Examples of the alkali metal represented by M include a lithium atom, a sodium atom, a potassium atom, and a cesium atom. M is preferably a lithium atom because of its good yield.
Ｘで表されるハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子を例示することができる。 Examples of the halogen atom represented by X include a chlorine atom, a bromine atom, and an iodine atom.
Ｙで表されるハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子を例示することができる。 Examples of the halogen atom represented by Y include a chlorine atom, a bromine atom, and an iodine atom.
Ｚで表されるハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子を例示することができる。Ｚは収率が良い点で、Ｑと同一のハロゲン原子を用いることが好ましい。
次に、本発明の製造方法について詳しく述べる。本発明の（トリハロメチル）ベンゼン誘導体（２）の製造方法は、下記スキームに示す通りである。
Examples of the halogen atom represented by Z include a chlorine atom, a bromine atom, and an iodine atom. Z is preferably the same halogen atom as Q in terms of good yield.
Next, the production method of the present invention is described in detail. The production method of the (trihalomethyl) benzene derivative (2) of the present invention is as shown in the following scheme.
すなわち、アリールマグネシウム試薬（１）をハロゲン化アルカリ金属塩（５）又はハロゲン化マグネシウム（６）存在下、ジブロモジフルオロメタンと反応させることにより、本発明の（トリハロメチル）ベンゼン誘導体（２）を製造することができる。 That is, the (trihalomethyl) benzene derivative (2) of the present invention is produced by reacting the arylmagnesium reagent (1) with dibromodifluoromethane in the presence of the alkali metal halide (5) or magnesium halide (6). can do.
（式中、Ｒ１、Ｒ２、Ｍ、Ｑ、Ｘ及びｎは前記と同じ意味を表す。Ｙはハロゲン原子を表し、Ｚはハロゲン原子を表す。）
本発明の製造方法の原料であるアリールマグネシウム試薬（１）は、対応するハロゲン化ベンゼン誘導体（３）から調製することができる。市販されているハロゲン化ベンゼン誘導体、あるいは市販の原料から容易に調製可能なハロゲン化ベンゼン誘導体を用いることができる。
アリールマグネシウム試薬（１）の調製方法に特に制限はなく、一般的なグリニヤール試薬の調製方法に準じて調製することができる。例えば、金属マグネシウムに有機溶媒を加え、次いでハロゲン化ベンゼン誘導体（３）を加えることにより容易に調製することができる。アリールマグネシウム試薬（１）の調製に用いることのできる溶媒は、反応を阻害しない溶媒であれば良く、具体的には、テトラヒドロフラン（以下、ＴＨＦと略す。）、ジエチルエーテル、１，４−ジオキサン、１，２−ジメトキシエタン等を挙げることができ、適宜これらを組み合わせて用いても良い。反応を促進するために、ヨウ素又は１，２−ジブロモメタンを添加してもよい。
(In the formula, R 1 , R 2 , M, Q, X and n represent the same meaning as described above. Y represents a halogen atom, and Z represents a halogen atom.)
The arylmagnesium reagent (1) which is a raw material for the production method of the present invention can be prepared from the corresponding halogenated benzene derivative (3). Commercially available halogenated benzene derivatives or halogenated benzene derivatives that can be easily prepared from commercially available raw materials can be used.
There is no restriction | limiting in particular in the preparation method of an aryl magnesium reagent (1), It can prepare according to the preparation method of a general Grignard reagent. For example, it can be easily prepared by adding an organic solvent to metallic magnesium and then adding the halogenated benzene derivative (3). The solvent that can be used for the preparation of the arylmagnesium reagent (1) may be any solvent that does not inhibit the reaction. Specifically, tetrahydrofuran (hereinafter abbreviated as THF), diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and the like can be mentioned, and these may be used in combination as appropriate. To accelerate the reaction, iodine or 1,2-dibromomethane may be added.
また、アリールマグネシウム試薬（１）は、一般的な化学的手法であるグリニヤール交換反応によっても調製することができ、例えば、ハロゲン化ベンゼン誘導体（３）とイソプロピルマグネシウムハライド（４）とを反応させることにより、アリールマグネシウム試薬（１）を調製することができる。グリニヤール交換反応によるアリールマグネシウム試薬（１）の調製に用いることのできる溶媒は、反応を阻害しない溶媒であれば良く、具体的には、ＴＨＦ、ジエチルエーテル、１，４−ジオキサン、１，２−ジメトキシエタン等を挙げることができ、適宜これらを組み合わせて用いても良い。 The arylmagnesium reagent (1) can also be prepared by a general chemical method Grignard exchange reaction, for example, reacting a halogenated benzene derivative (3) with isopropylmagnesium halide (4). Thus, the arylmagnesium reagent (1) can be prepared. The solvent that can be used for the preparation of the arylmagnesium reagent (1) by the Grignard exchange reaction may be any solvent that does not inhibit the reaction. Specifically, THF, diethyl ether, 1,4-dioxane, 1,2- Dimethoxyethane and the like can be mentioned, and these may be used in combination as appropriate.
調製したアリールマグネシウム試薬（１）は、調製後に単離して用いても良いが、溶液のまま本発明の製造方法に供することができる。 The prepared arylmagnesium reagent (1) may be isolated and used after preparation, but can be used in the production method of the present invention as a solution.
本発明の製造方法の原料であるジブロモジフルオロメタンは市販されている。
本発明の製造方法はハロゲン化アルカリ金属塩（５）又はハロゲン化マグネシウム（６）存在下反応を行うことが必須である。ハロゲン化アルカリ金属塩（５）としては、塩化リチウム、塩化ナトリウム、塩化カリウム、塩化セシウム、臭化リチウム、臭化ナトリウム、臭化カリウム、臭化セシウム等を例示することができる。ハロゲン化マグネシウムとしては、塩化マグネシウム、臭化マグネシウムを例示することができる。収率が良い点で、ハロゲン化アルカリ金属塩（５）を用いることが好ましく、さらに塩化リチウム又は臭化リチウムを用いることが好ましい。ハロゲン化アルカリ金属塩（５）又はハロゲン化マグネシウム（６）は、ハロゲン化ベンゼン誘導体（３）からアリールマグネシウム試薬（１）を調製する時に添加してもよく、又は、アリールマグネシウム試薬（１）とジブロモジフルオロメタンとの反応時に添加してもよい。
Dibromodifluoromethane, which is a raw material for the production method of the present invention, is commercially available.
In the production method of the present invention, it is essential to carry out the reaction in the presence of an alkali metal halide (5) or magnesium (6) halide. Examples of the alkali metal halide (5) include lithium chloride, sodium chloride, potassium chloride, cesium chloride, lithium bromide, sodium bromide, potassium bromide, cesium bromide and the like. Examples of the magnesium halide include magnesium chloride and magnesium bromide. From the viewpoint of good yield, it is preferable to use the alkali metal halide (5), and it is more preferable to use lithium chloride or lithium bromide. Alkali metal halide (5) or magnesium halide (6) may be added when preparing arylmagnesium reagent (1) from halogenated benzene derivative (3), or arylmagnesium reagent (1) and It may be added during the reaction with dibromodifluoromethane.
本発明の製造法に用いることのできる溶媒は、反応を阻害しない溶媒であれば良く、具体的には、ＴＨＦ、ジエチルエーテル、１，４−ジオキサン、１，２−ジメトキシエタン等を挙げることができ、適宜これらを組み合わせて用いても良い。アリールマグネシウム試薬（１）とジブロモジフルオロメタンとのモル比は、１：１から１：５が好ましく、収率が良い点で１：１から１：３がさらに好ましい。 The solvent that can be used in the production method of the present invention may be any solvent that does not inhibit the reaction. Specific examples include THF, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, and the like. These may be used in combination as appropriate. The molar ratio of the arylmagnesium reagent (1) and dibromodifluoromethane is preferably 1: 1 to 1: 5, and more preferably 1: 1 to 1: 3 in terms of good yield.
反応温度は、−１１０℃から５０℃までの範囲で適宜選ばれた温度で行うことができる。収率が良い点で０℃から３０℃の範囲が好ましい。
反応後の溶液から（トリハロメチル）ベンゼン誘導体（２）を単離する方法に特に限定はないが、溶媒抽出、カラムクロマトグラフィー、分取薄層クロマトグラフィー、分取液体クロマトグラフィー、再結晶または昇華等の汎用的な方法で目的物を得ることができる。
The reaction temperature can be appropriately selected from the range of -110 ° C to 50 ° C. A range of 0 ° C. to 30 ° C. is preferable in terms of good yield.
The method for isolating the (trihalomethyl) benzene derivative (2) from the solution after the reaction is not particularly limited, but solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained by a general-purpose method such as
次に本発明を実施例によってさらに詳細に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Next, although an Example demonstrates this invention still in detail, this invention is not limited to these.
実施例−１ Example-1
アルゴン雰囲気下、４−ヨードベンゾニトリル（２２９．０ｍｇ，１．０ｍｍｏｌ）と塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）をＴＨＦ（４．５ｍｌ）に加え、−４０℃に冷却した。得られた混合溶液にイソプロピルマグネシウムクロリドのジエチルエーテル溶液（２．０Ｍ、５２５μｌ，１．０５ｍｍｏｌ）を加え、２０分間攪拌した。その後、反応溶液を−４０℃で三時間攪拌を行い、４−シアノフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−シアノフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を、２０℃でジブロモジフルオロメタンのＴＨＦ溶液（２．４６Ｍ、９８０μｌ，２．４ｍｍｏｌ）に滴下し、２０℃で３０分間攪拌を行った。反応液に飽和塩化アンモニウム水溶液（２．０ｍｌ）を加えて、酢酸エチルにて抽出した。有機層を合わせて、水と飽和塩化ナトリウム水溶液で洗浄し、乾燥後、ろ液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル−ヘキサン）とリサイクルＧＰＣ（クロロホルム）により精製することで、４−（ブロモクロロフルオロメチル）ベンゾニトリル（１０１．９ｍｇ、４１％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ７．７５（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．７９（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．９（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ１０２．５（ｄ，Ｊ＝３０５Ｈｚ），１１４．７，１１７．６，１２５．０（ｄ，Ｊ＝６．６Ｈｚ，２Ｃ），１３２．５（ｓ，２Ｃ），１４６．８（ｄ，Ｊ＝２２．８Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）５０（７．４），５７（５．９），８１（６．６），８４（５．４），１０６（９．４），１１４（２．６），１３３（１３．４），１４１（４．６），１６８（１００），１７０（３６．３），２１２（６．３），２１４（６．３）．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ８Ｈ５ＢｒＣｌＦＮ：２４６．９２００；Ｆｏｕｎｄ：２４６．９１９６． Under an argon atmosphere, 4-iodobenzonitrile (229.0 mg, 1.0 mmol) and lithium chloride (101.7 mg, 2.4 mmol) were added to THF (4.5 ml) and cooled to −40 ° C. To the resulting mixed solution was added a solution of isopropyl magnesium chloride in diethyl ether (2.0 M, 525 μl, 1.05 mmol), and the mixture was stirred for 20 minutes. Thereafter, the reaction solution was stirred at −40 ° C. for 3 hours to prepare a THF-diethyl ether solution of 4-cyanophenylmagnesium chloride. The prepared THF-diethyl ether solution of 4-cyanophenyl magnesium chloride was added dropwise at 20 ° C. to a THF solution of dibromodifluoromethane (2.46 M, 980 μl, 2.4 mmol), and the mixture was stirred at 20 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution (2.0 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, dried, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-hexane) and recycled GPC (chloroform) to give 4- (bromochlorofluoromethyl) benzonitrile (101.9 mg, 41%) as a yellow oil. Obtained as material. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.9 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 102.5 (d, J = 305 Hz), 114.7, 117.6, 125.0 (d, J = 6.6 Hz, 2C), 132.5 (s, 2C), 146.8 (d, J = 22.8 Hz). GC-MS (m / z) 50 (7.4), 57 (5.9), 81 (6.6), 84 (5.4), 106 (9.4), 114 (2.6), 133 (13.4), 141 (4.6), 168 (100), 170 (36.3), 212 (6.3), 214 (6.3). HRMS (FAB, m / z) Calcd for C 8 H 5 BrClFN: 246.9200; Found: 246.9196.
実施例−２ Example-2
実施例―１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、３−ヨードベンゾニトリル（２２９．０ｍｇ，１．０ｍｍｏｌ）を用いて３−シアノフェニルマグネシウムクロリドのテトラヒドロフラン−ジエチルエーテル溶液を調製した。調製した３−シアノフェニルマグネシウムクロリドのテトラヒドロフラン−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、３−（ブロモクロロフルオロメチル）ベンゾニトリル（５２．４ｍｇ，２１％）を無色油状物質として得た。１Ｈ−ＮＭＲ．δ７．５８（ｄｄ，Ｊ＝７．７，８．２Ｈｚ，１Ｈ），７．７０（ｄｄｄ，Ｊ＝１．２，１．２，７．７Ｈｚ，１Ｈ），７．９１（ｄｄｄ，Ｊ＝１．２，１．２，８．２Ｈｚ，１Ｈ），７．９７（ｄｄ，Ｊ＝１．２，１．２Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ１０２．５（ｄ，Ｊ＝３０４．５Ｈｚ），１１２．９，１１７．５，１２７．８（ｄ，Ｊ＝６．８Ｈｚ），１２８．４（ｄ，Ｊ＝６．２Ｈｚ），１２９．７，１３４．０，１４４．２（ｄ，Ｊ＝２２．９Ｈｚ）．ＧＣ−ＭＳ（７０ｅＶ，ｍ／ｚ）４０（０．３），５０（１１．０），５７（９．０），８１（１０．３），８４（８．３），１０６（１１．８），１１４（３．２），１３２（１３．８），１３３（１６．２），１６８（１００），１７０（３３．０），２１２（５．７），２１４（５．５）． In the same manner as in Example 1, 3-cyanophenylmagnesium chloride tetrahydrofuran-diethyl using 3-iodobenzonitrile (229.0 mg, 1.0 mmol) in the presence of lithium chloride (101.7 mg, 2.4 mmol). An ether solution was prepared. The prepared 3-cyanophenyl magnesium chloride solution in tetrahydrofuran-diethyl ether was reacted with dibromodifluoromethane to obtain 3- (bromochlorofluoromethyl) benzonitrile (52.4 mg, 21%) as a colorless oily substance. 1 H-NMR. δ 7.58 (dd, J = 7.7, 8.2 Hz, 1H), 7.70 (ddd, J = 1.2, 1.2, 7.7 Hz, 1H), 7.91 (ddd, J = 1.2, 1.2, 8.2 Hz, 1H), 7.97 (dd, J = 1.2, 1.2 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.4 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 102.5 (d, J = 304.5 Hz), 112.9, 117.5, 127.8 (d, J = 6.8 Hz), 128.4 (d, J = 6.2 Hz), 129.7, 134.0, 144.2 (d, J = 22.9 Hz). GC-MS (70 eV, m / z) 40 (0.3), 50 (11.0), 57 (9.0), 81 (10.3), 84 (8.3), 106 (11.8) ), 114 (3.2), 132 (13.8), 133 (16.2), 168 (100), 170 (33.0), 212 (5.7), 214 (5.5).
実施例−３ Example-3
実施例１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、２−ヨードベンゾニトリル（２２９．０ｍｇ，１．０ｍｍｏｌ）を用いて２−シアノフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した２−シアノフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、２−（ブロモクロロフルオロメチル）ベンゾニトリル（１０１．９ｍｇ、４１％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ７．５６（ｔｄ，Ｊ＝１．２，７．６Ｈｚ，１Ｈ），７．６７（ｔｄ，Ｊ＝１．２，７．６Ｈｚ，１Ｈ），７．８０−７．８５（ｍ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５５．０２（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ１０１．５（ｄ，Ｊ＝３０４Ｈｚ），１０９．４（ｄ，Ｊ＝３．２Ｈｚ），１１６．０，１２４．３（ｔ，Ｊ＝１０．０Ｈｚ），１３０．９，１３２．６，１３５．５，１４４．５（ｔ，Ｊ＝２１．６Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）５０（９．７），５７（７．４），７５（８．１），８１（８．３），１０６（１１．５），１３２（１２．９），１３３（１６．２），１４２（６．２），１６８（１００），１７０（３２．４），２１２（７．９），２１４（７．９）．ｍｐ６６．１−６８．５℃．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ８Ｈ４ＢｒＣｌＦＮ：２４７．９２７８（ＭＨ＋）；Ｆｏｕｎｄ：２４７．９２８１． In the same manner as in Example 1, 2-cyanophenylmagnesium chloride in THF-diethyl ether using 2-iodobenzonitrile (229.0 mg, 1.0 mmol) in the presence of lithium chloride (101.7 mg, 2.4 mmol). A solution was prepared. The prepared 2-cyanophenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 2- (bromochlorofluoromethyl) benzonitrile (101.9 mg, 41%) as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.56 (td, J = 1.2, 7.6 Hz, 1H), 7.67 (td, J = 1.2, 7.6 Hz, 1H), 7. 80-7.85 (m, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-55.02 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 101.5 (d, J = 304 Hz), 109.4 (d, J = 3.2 Hz), 116.0, 124.3 (t, J = 10.0 Hz) 130.9, 132.6, 135.5, 144.5 (t, J = 21.6 Hz). GC-MS (m / z) 50 (9.7), 57 (7.4), 75 (8.1), 81 (8.3), 106 (11.5), 132 (12.9), 133 (16.2), 142 (6.2), 168 (100), 170 (32.4), 212 (7.9), 214 (7.9). mp 66.1-68.5 ° C. HRMS (FAB, m / z) Calcd for C 8 H 4 BrClFN: 247.9278 (MH +); Found: 247.9281.
実施例−４ Example-4
実施例１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、２−ブロモ―４−メチルベンゾニトリル（１９６．０ｍｇ，１．０ｍｍｏｌ）を用いて２−シアノ−５−メチルフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した２−シアノ−５−メチルフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、２−（ブロモクロロフルオロメチル）−４−メチルベンゾニトリル（７８．８ｍｇ、３０％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．４９（ｓ，３Ｈ），７．３４（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．６０（ｓ，１Ｈ），７．７１（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５４．９（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２１．９，１０１．５（ｄ，Ｊ＝３０４．６Ｈｚ），１０６．３，１１６．３，１２５．１（ｄ，Ｊ＝１０．１Ｈｚ），１３１．４，１３５．４，１４３．９，１４４．３（ｄ，Ｊ＝２０．９Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（１．１），５１（７．６），６３（８．０），７５（７．７），９１（５．４），９９（６．０），１２０（１１．０），１２６（１３．２），１４８（８．０），１５５（０．５），１８２（１００），１８４（３３．０），２２６（５．９），２２８（５．９）．ｍｐ１０３．７−１０５．８℃．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ９Ｈ７ＢｒＣｌＦＮ：２６１．９４３４（ＭＨ＋）；Ｆｏｕｎｄ：２６１．９４３０． In the same manner as in Example 1, 2-cyano-4-methylbenzonitrile (196.0 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol) and 2-cyano-5-methyl. A solution of phenylmagnesium chloride in THF-diethyl ether was prepared. The prepared 2-cyano-5-methylphenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 2- (bromochlorofluoromethyl) -4-methylbenzonitrile (78.8 mg, 30%). Obtained as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.49 (s, 3H), 7.34 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.71 (d, J = 7.8 Hz, 1 H). 19 F-NMR (376 MHz, CDCl 3 ) δ-54.9 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 21.9, 101.5 (d, J = 304.6 Hz), 106.3, 116.3, 125.1 (d, J = 10.1 Hz), 131. 4, 135.4, 143.9, 144.3 (d, J = 20.9 Hz). GC-MS (m / z) 40 (1.1), 51 (7.6), 63 (8.0), 75 (7.7), 91 (5.4), 99 (6.0), 120 (11.0), 126 (13.2), 148 (8.0), 155 (0.5), 182 (100), 184 (33.0), 226 (5.9), 228 (5 .9). mp 103.7-105.8 ° C. HRMS (FAB, m / z) Calcd for C 9 H 7 BrClFN: 261.9434 (MH +); Found: 261.9430.
実施例−５ Example-5
実施例１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、２−（アリルオキシ）−４−ブロモベンゾニトリル（２３８．１ｍｇ，１．０ｍｍｏｌ）を用いて３−（アリルオキシ）−４−シアノフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した３−アリルオキシ−４−シアノフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、２−（アリルオキシ）−４−（ブロモクロロフルオロメチル）ベンゾニトリル（１５４．２ｍｇ、５４％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ４．７４（ｄｄｄ，Ｊ＝１．５，１．５，５．１Ｈｚ，２Ｈ），５．３９（ｔｄｄ，Ｊ＝１．５，１．５，１０．５Ｈｚ，１Ｈ），５．５１（ｔｄｄ，Ｊ＝１．５，１．５，１７．２Ｈｚ，１Ｈ），６．０６（ｍ，１Ｈ），７．２２（ｄ，Ｊ＝１．７Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝１．７，８．１Ｈｚ，１Ｈ），７．６４（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．５４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ７０．０，１０２．５（ｄ，Ｊ＝３０５．０Ｈｚ），１０４．５，１０８．６（ｄ，Ｊ＝７．０Ｈｚ），１１５．２，１１６．６（ｄ，Ｊ＝７．０Ｈｚ），１１９．１，１３１．１，１３４．０，１４８．１（ｄ，Ｊ＝２２．５Ｈｚ），１６０．０．ＧＣ−ＭＳ（ｍ／ｚ）４１（１００），６９（１．７），７５（１．４），９４（１．８），１００（２．４），１２０（３．３），１３２（２．０），１５５（２．４），１８４（１．５），１９６（１．５），２２４（２０．６），３０２（３．０），３０４（３．９），３０７（１．０）．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ１１Ｈ９ＢｒＣｌＦＮ：３０３．９５４０（ＭＨ＋）；Ｆｏｕｎｄ：３０３．９５３８． In the same manner as in Example 1, 2- (allyloxy) -4-bromobenzonitrile (238.1 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol) to give 3- (allyloxy). A THF-diethyl ether solution of -4-cyanophenylmagnesium chloride was prepared. The prepared 3-allyloxy-4-cyanophenyl magnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 2- (allyloxy) -4- (bromochlorofluoromethyl) benzonitrile (154.2 mg, 54% ) Was obtained as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 4.74 (ddd, J = 1.5, 1.5, 5.1 Hz, 2H), 5.39 (tdd, J = 1.5, 1.5, 10 .5 Hz, 1 H), 5.51 (tdd, J = 1.5, 1.5, 17.2 Hz, 1 H), 6.06 (m, 1 H), 7.22 (d, J = 1.7 Hz, 1H), 7.30 (dd, J = 1.7, 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.54 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 70.0, 102.5 (d, J = 305.0 Hz), 104.5, 108.6 (d, J = 7.0 Hz), 115.2, 116. 6 (d, J = 7.0 Hz), 119.1, 131.1, 134.0, 148.1 (d, J = 22.5 Hz), 160.0. GC-MS (m / z) 41 (100), 69 (1.7), 75 (1.4), 94 (1.8), 100 (2.4), 120 (3.3), 132 ( 2.0), 155 (2.4), 184 (1.5), 196 (1.5), 224 (20.6), 302 (3.0), 304 (3.9), 307 (1 .0). HRMS (FAB, m / z) Calcd for C 11 H 9 BrClFN: 303.9540 (MH +); Found: 303.9538.
実施例−６ Example-6
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、４−ブロモ―２―メトキシベンゾニトリル（２１２．０ｍｇ，１．０ｍｍｏｌ）を用いて４−シアノ−３−メトキシフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−シアノ−３−メトキシフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、４−（ブロモクロロフルオロメチル）−２−メトキシベンゾニトリル（１０８．２ｍｇ、３９％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ４．０１（ｓ，３Ｈ），７．２２（ｄ，Ｊ＝１．６Ｈｚ，１Ｈ），７．３３（ｄｄ，Ｊ＝１．６，８．１Ｈｚ，１Ｈ），７．６４（ｄ，Ｊ＝８．１Ｈｚ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．５５（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ５６．４３，１０２．５（ｄ，Ｊ＝３０４．９Ｈｚ），１０４．１，１０７．１（ｄ，Ｊ＝６．６Ｈｚ），１１５．２，１１６．６（ｄ，Ｊ＝６．６Ｈｚ），１３４．０，１４８．３（ｄ，Ｊ＝２２．４Ｈｚ），１６１．０．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ９Ｈ６ＢｒＣｌＦＮ：２７７．９３８４；Ｆｏｕｎｄ：２７７．９３８６． In the same manner as in Example 1, 4-cyano-3-methoxybenzonitrile (212.0 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol) in the presence of 4-cyano-3- A solution of methoxyphenyl magnesium chloride in THF-diethyl ether was prepared. The prepared 4-cyano-3-methoxyphenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 4- (bromochlorofluoromethyl) -2-methoxybenzonitrile (108.2 mg, 39%). Obtained as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 4.01 (s, 3H), 7.22 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 1.6, 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.55 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 56.43, 102.5 (d, J = 304.9 Hz), 104.1, 107.1 (d, J = 6.6 Hz), 115.2, 116. 6 (d, J = 6.6 Hz), 134.0, 148.3 (d, J = 22.4 Hz), 161.0. HRMS (FAB, m / z) Calcd for C 9 H 6 BrClFN: 277.9384; Found: 277.9386.
実施例−７ Example-7
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、４−ブロモ―２―メチルベンゾニトリル（１９６．０ｍｇ，１．０ｍｍｏｌ）を用いて４−シアノ−３−メチルフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−シアノ−３−メチルフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、４−（ブロモクロロフルオロメチル）−２−メチルベンゾニトリル（７２．５ｍｇ、３９％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．６２（ｓ，３Ｈ），７．５８（ｄｄ，Ｊ＝１．９，８．７Ｈｚ，１Ｈ），７．６３（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．６８（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．５８（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２０．７，１０３．５（ｄ，Ｊ＝３０４．９Ｈｚ），１１５．０，１１６．９，１２２．１（ｄ，Ｊ＝６．７Ｈｚ），１２５．８（ｄ，Ｊ＝６．７Ｈｚ），１３２．８，１４２．７，１４６．５（ｄ，Ｊ＝２２．５Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（０．９），５０（６．９），５１（５．９），６３（７．９），７５（６．５），９１（５．３），９９（６．０），１２０（１３．５），１２６（１０．５），１４７（６．９），１５５（０．８），１８２（１００），１８４（３３．６），２２６（４．３），２２８（４．４）． In the same manner as in Example 1, 4-cyano-3-methylbenzonitrile (196.0 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol) in the presence of 4-cyano-3- A THF-diethyl ether solution of methylphenylmagnesium chloride was prepared. The prepared 4-cyano-3-methylphenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 4- (bromochlorofluoromethyl) -2-methylbenzonitrile (72.5 mg, 39%). Obtained as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.62 (s, 3H), 7.58 (dd, J = 1.9, 8.7 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.58 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 20.7, 103.5 (d, J = 304.9 Hz), 115.0, 116.9, 122.1 (d, J = 6.7 Hz), 125. 8 (d, J = 6.7 Hz), 132.8, 142.7, 146.5 (d, J = 22.5 Hz). GC-MS (m / z) 40 (0.9), 50 (6.9), 51 (5.9), 63 (7.9), 75 (6.5), 91 (5.3), 99 (6.0), 120 (13.5), 126 (10.5), 147 (6.9), 155 (0.8), 182 (100), 184 (33.6), 226 (4 .3), 228 (4.4).
実施例−８ Example-8
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、４−ブロモ−３−メチルベンゾニトリル（１９６．０ｍｇ，１．０ｍｍｏｌ）を用いて４−シアノ−２−メチルフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−シアノ−２−メチルフェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、４−（ブロモクロロフルオロメチル）−３−メチルベンゾニトリル（４１．２ｍｇ、１６％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．６２（ｓ，３Ｈ），７．５６−７．５８（ｍ，２Ｈ），７．７７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５１．００（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２０．８，１０３．７（ｄ，Ｊ＝３０４．６Ｈｚ），１１４．６，１１７．６，１２５．０（ｄ，Ｊ＝１１．９Ｈｚ），１２９．６，１３６．２，１３６．７，１４４．０（ｄ，Ｊ＝２０．１Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（０．６），５０（１０．６），６３（８．７），７５（９．６），９１（４．８），９９（７．８），１２０（１０．０），１２６（１８．３），１４７（２２．３），１６２（３．９），１８２（１００），２２６（３．７），２２８（３．６）． In the same manner as in Example 1, 4-cyano-2-methylbenzonitrile (196.0 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol) in the presence of 4-cyano-2- A THF-diethyl ether solution of methylphenylmagnesium chloride was prepared. The prepared 4-cyano-2-methylphenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 4- (bromochlorofluoromethyl) -3-methylbenzonitrile (41.2 mg, 16%). Obtained as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.62 (s, 3H), 7.56-7.58 (m, 2H), 7.77 (d, J = 8.7 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-51.00 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 20.8, 103.7 (d, J = 304.6 Hz), 114.6, 117.6, 125.0 (d, J = 11.9 Hz), 129. 6, 136.2, 136.7, 144.0 (d, J = 20.1 Hz). GC-MS (m / z) 40 (0.6), 50 (10.6), 63 (8.7), 75 (9.6), 91 (4.8), 99 (7.8), 120 (10.0), 126 (18.3), 147 (22.3), 162 (3.9), 182 (100), 226 (3.7), 228 (3.6).
実施例−９ Example-9
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、４−ヨード安息香酸メチル（２６２．０ｍｇ，１．０ｍｍｏｌ）を用いて４−（メトキシカルボニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−（メトキシカルボニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、４−（ブロモクロロフルオロメチル）安息香酸メチル（９８．２ｍｇ，３５％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ３．９５（ｓ，３Ｈ），７．７５（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），８．１０（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５５．３７（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ５２．５，１０３．５（ｄ，Ｊ＝３０５Ｈｚ），１２４．２（ｄ，Ｊ＝６．６Ｈｚ，２Ｃ），１３０．０（ｓ，２Ｃ），１３２．１，１４６．７（ｄ，Ｊ＝２２．０Ｈｚ），１６５．９．ＧＣ−ＭＳ（ｍ／ｚ）５０（５．５），５７（１０．０），８１（８．０），１０７（３９．０），１２３（１．９），１３０（１．０），１４２（１９．９），１７０（１４．０），１７３（１８．２），２０１（１００），２１６（１．３），２１８（１．２），２４７（２．４），２４９（３．５），２５１（４．５），２５３（１．１）．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ９Ｈ８ＢｒＣｌＦＯ２：２８０．９３８０（ＭＨ＋）；Ｆｏｕｎｄ：２８０．９３８１． In the same manner as in Example 1, 4- (methoxycarbonyl) phenylmagnesium chloride using methyl 4-iodobenzoate (262.0 mg, 1.0 mmol) in the presence of lithium chloride (101.7 mg, 2.4 mmol). Of THF-diethyl ether was prepared. Reaction of the prepared 4- (methoxycarbonyl) phenylmagnesium chloride in THF-diethyl ether and dibromodifluoromethane gave methyl 4- (bromochlorofluoromethyl) benzoate (98.2 mg, 35%) as a white solid. It was. 1 H-NMR (400 MHz, CDCl 3 ) δ 3.95 (s, 3H), 7.75 (d, J = 8.7 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-55.37 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 52.5, 103.5 (d, J = 305 Hz), 124.2 (d, J = 6.6 Hz, 2C), 130.0 (s, 2C), 132 1,146.7 (d, J = 22.0 Hz), 165.9. GC-MS (m / z) 50 (5.5), 57 (10.0), 81 (8.0), 107 (39.0), 123 (1.9), 130 (1.0), 142 (19.9), 170 (14.0), 173 (18.2), 201 (100), 216 (1.3), 218 (1.2), 247 (2.4), 249 (3 .5), 251 (4.5), 253 (1.1). HRMS (FAB, m / z) Calcd for C 9 H 8 BrClFO 2: 280.9380 (MH +); Found: 280.9381.
実施例−１０ Example-10
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、２−（アリルオキシ）−４−ヨード安息香酸メチル（３１８．１ｍｇ，１．０ｍｍｏｌ）を用いて３−（アリルオキシ）−４−（メトキシカルボニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した３−（アリルオキシ）−４−（メトキシカルボニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、２−（アリルオキシ）−４−（ブロモクロロフルオロメチル）安息香酸メチル（８０．４ｍｇ，２４％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ３．９２（ｓ，３Ｈ），４．６８（ｄｄｄ，Ｊ＝１．５，１．５，４．９Ｈｚ，２Ｈ），５．３４（ｔｄｄ，Ｊ＝１．５，１．５，１０．６Ｈｚ，１Ｈ），５．５３（ｔｄｄ，Ｊ＝１．５，１．５，１７．２Ｈｚ，１Ｈ），６．０７（ｍ，１Ｈ），７．２２（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝１．８，８．２Ｈｚ，１Ｈ），７．８３（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５５．３２（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ５２．３，６９．８，１０３．５（ｄ，Ｊ＝３０４．８Ｈｚ），１０９．６（ｄ，Ｊ＝６．８Ｈｚ），１１６．０（ｄ，Ｊ＝６．８Ｈｚ），１１８．１，１２２．７，１３１．９，１３２．１，１４７．１（ｄ，Ｊ＝２２．０Ｈｚ），１５７．７，１６５．７．ＧＣ−ＭＳ（ｍ／ｚ）４１（１００），５９（１２．６），７２（１３．０），９４（１１．０），１０７（５．５），１０９（７．０），１２９（７．６），１５７（１９．３），１８６（４．６），１９７（２１．８），２２９（１０．９），２５７（３２．８），２５９（１０．８），２６７（２．７），３０５（４．３），３０９（１．９），３３６（１．７），３３８（２．１），３４０（０．６）． In the same manner as in Example 1, 3- (allyloxy) -4-iodobenzoate methyl (318.1 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol) to give 3- ( A THF-diethyl ether solution of allyloxy) -4- (methoxycarbonyl) phenylmagnesium chloride was prepared. The prepared 3- (allyloxy) -4- (methoxycarbonyl) phenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give methyl 2- (allyloxy) -4- (bromochlorofluoromethyl) benzoate ( 80.4 mg, 24%) was obtained as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 3.92 (s, 3H), 4.68 (ddd, J = 1.5, 1.5, 4.9 Hz, 2H), 5.34 (tdd, J = 1.5, 1.5, 10.6 Hz, 1H), 5.53 (tdd, J = 1.5, 1.5, 17.2 Hz, 1H), 6.07 (m, 1H), 7.22 (D, J = 1.8 Hz, 1H), 7.28 (dd, J = 1.8, 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-55.32 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 52.3, 69.8, 103.5 (d, J = 304.8 Hz), 109.6 (d, J = 6.8 Hz), 116.0 (d, J = 6.8 Hz), 118.1, 122.7, 131.9, 132.1, 147.1 (d, J = 22.0 Hz), 157.7, 165.7. GC-MS (m / z) 41 (100), 59 (12.6), 72 (13.0), 94 (11.0), 107 (5.5), 109 (7.0), 129 ( 7.6), 157 (19.3), 186 (4.6), 197 (21.8), 229 (10.9), 257 (32.8), 259 (10.8), 267 (2 .7), 305 (4.3), 309 (1.9), 336 (1.7), 338 (2.1), 340 (0.6).
実施例−１１ Example-11
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、４−ヨード−２−メチル安息香酸メチル（３１８．１ｍｇ，１．０ｍｍｏｌ）を用いて４−（メトキシカルボニル）−３−メチルフェニルマグネシウムクロリドのテトラヒドロフラン−ジエチルエーテル溶液を調製した。調製した４−（メトキシカルボニル）−３−メチルフェニルマグネシウムクロリドのテトラヒドロフラン−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、４−（ブロモクロロフルオロメチル）−２−メチル安息香酸メチル（１９．７ｍｇ，６％）を無色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．６４（ｓ，３Ｈ），３．９２（ｓ，３Ｈ），７．５４（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．５４（ｓ，１Ｈ），７．９５（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５５．２（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２１．８，５２．２，１０３．５（ｄ，Ｊ＝３０４．７Ｈｚ），１２１．５（ｄ，Ｊ＝６．５Ｈｚ），１２７．１（ｄ，Ｊ＝６．５Ｈｚ），１３０．８，１３１．７，１４０．７，１４５．６（ｄ，Ｊ＝２１．９Ｈｚ），１６７．０．ＧＣ−ＭＳ（７０ｅＶ，ｍ／ｚ） ５１（６．５），６０（６．３），７５（８．３），９２（４．９），１０１（１９．１），１２１（１０．０），１５６（８．４），１８７（１５．９），２１５（１００），２１７（３３．６），２３１（１．２），２５９（２．３），２６１（２．１），２６３（３．５），２６５（４．５），２６７（１．１）． In the same manner as in Example-1, 4- (methoxycarbonyl) was obtained using methyl 4-iodo-2-methylbenzoate (318.1 mg, 1.0 mmol) in the presence of lithium chloride (101.7 mg, 2.4 mmol). A tetrahydrofuran-diethyl ether solution of) -3-methylphenylmagnesium chloride was prepared. The prepared 4- (methoxycarbonyl) -3-methylphenylmagnesium chloride in tetrahydrofuran-diethyl ether was reacted with dibromodifluoromethane to give methyl 4- (bromochlorofluoromethyl) -2-methylbenzoate (19.7 mg, 6%) was obtained as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.64 (s, 3H), 3.92 (s, 3H), 7.54 (d, J = 9.0 Hz, 1H), 7.54 (s, 1H ), 7.95 (d, J = 9.0 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-55.2 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 21.8, 52.2, 103.5 (d, J = 304.7 Hz), 121.5 (d, J = 6.5 Hz), 127.1 (d, J = 6.5 Hz), 130.8, 131.7, 140.7, 145.6 (d, J = 21.9 Hz), 167.0. GC-MS (70 eV, m / z) 51 (6.5), 60 (6.3), 75 (8.3), 92 (4.9), 101 (19.1), 121 (10.0 ), 156 (8.4), 187 (15.9), 215 (100), 217 (33.6), 231 (1.2), 259 (2.3), 261 (2.1), 263 (3.5), 265 (4.5), 267 (1.1).
実施例−１２ Example-12
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、１−ヨード−４−（４−メチルフェニルスルホニル）ベンゼン（３５８．１９ｍｇ，１．０ｍｍｏｌ）を用いて４−（４−メチルフェニルスルホニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−（４−メチルフェニルスルホニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、１−（ブロモクロロフルオロメチル）−４−（４−メチルフェニルスルホニル）ベンゼン（１８８．９ｍｇ，５０％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．４２（ｓ，３Ｈ），７．３３（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．７８（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．８４（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），８．０１（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．３（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２１．６，１０３．５（ｄ，Ｊ＝３０４．６Ｈｚ），１２５．１（ｄ，Ｊ＝６．６Ｈｚ，２Ｃ），１２７．７（ｓ，２Ｃ），１２７．９（ｓ，２Ｃ），１３０．２（ｓ，２Ｃ），１３７．８，１４２．２，１４４．８，１４６．９（ｄ，Ｊ＝２２．７Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４１（３．３），５１（４．９），６５（２３．９），７７（１０．６），９１（２１．７），１０７（３９．４），１２３（１．６），１３９（１００），１５９（０．６），１９０（２．５），２９７（５０．４），２９９（１９．３），３０１（１．０）．ｍｐ１５２．１−１５５．１℃．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ１４Ｈ１２ＢｒＣｌＦＯ２Ｓ：３７６．９４１４（ＭＨ＋）；Ｆｏｕｎｄ：３７６．９４１０． In the same manner as in Example 1, 1-iodo-4- (4-methylphenylsulfonyl) benzene (358.19 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol). A THF-diethyl ether solution of-(4-methylphenylsulfonyl) phenylmagnesium chloride was prepared. The prepared 4- (4-methylphenylsulfonyl) phenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 1- (bromochlorofluoromethyl) -4- (4-methylphenylsulfonyl) benzene (188). 0.9 mg, 50%) as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.42 (s, 3H), 7.33 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7 .84 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.3 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 21.6, 103.5 (d, J = 304.6 Hz), 125.1 (d, J = 6.6 Hz, 2C), 127.7 (s, 2C) , 127.9 (s, 2C), 130.2 (s, 2C), 137.8, 142.2, 144.8, 146.9 (d, J = 22.7 Hz). GC-MS (m / z) 41 (3.3), 51 (4.9), 65 (23.9), 77 (10.6), 91 (21.7), 107 (39.4), 123 (1.6), 139 (100), 159 (0.6), 190 (2.5), 297 (50.4), 299 (19.3), 301 (1.0). mp 152.1-155.1 ° C. HRMS (FAB, m / z) Calcd for C 14 H 12 BrClFO 2 S: 376.9414 (MH +); Found: 376.9410.
実施例−１３ Example-13
実施例−１と同様にして、塩化リチウム（１０１．７ｍｇ，２．４ｍｍｏｌ）存在下、１−ヨード−４−（４−フルオロフェニルスルホニル）ベンゼン（３６２．１６ｍｇ，１．０ｍｍｏｌ）を用いて、４−（４−フルオロフェニルスルホニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液を調製した。調製した４−（４−フルオロフェニルスルホニル）フェニルマグネシウムクロリドのＴＨＦ−ジエチルエーテル溶液とジブロモジフルオロメタンを反応させて、１−（ブロモクロロフルオロメチル）−４−（４−フルオロフェニルスルホニル）ベンゼン（１７２．１ｍｇ、４５％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ．７．２２（ｄｄ，Ｊ＝８．４３，８．６Ｈｚ，２Ｈ），７．８０（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．９７−８．００（ｍ，４Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．５（ｓ，１Ｆ），−１０４．４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ１０３．４（ｄ，Ｊ＝３０５．０Ｈｚ），１１６．９（ｄ，Ｊ＝２２．６Ｈｚ，２Ｃ），１２５．３（ｄ，Ｊ＝６．６Ｈｚ，２Ｃ），１２７．９（ｓ，２Ｃ），１３０．７（ｄ，Ｊ＝９．６Ｈｚ，２Ｃ），１３６．７（ｄ，Ｊ＝３．４Ｈｚ），１４３．７，１６７．２（ｄ，Ｊ＝２１．６Ｈｚ），１６５．８（ｄ，Ｊ＝２２５Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）５０（７．３），５７（１４．３），７５（２０．７），９５（２６．３），１０７（５６．８），１１５（１９．０），１４３（１００），１４６（１．１），１９１（２．９），２０１（２．４），２３７（０．９），２６７（５．６），３０１（６５．０），３０３（２４．６），３４７（０．６）．ｍｐ９８．２−９９．８℃．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ１３Ｈ９ＢｒＣｌＦＯ２Ｓ：３８０．９１６３（ＭＨ＋）；Ｆｏｕｎｄ：３８０．９１５４． In the same manner as in Example 1, 1-iodo-4- (4-fluorophenylsulfonyl) benzene (362.16 mg, 1.0 mmol) was used in the presence of lithium chloride (101.7 mg, 2.4 mmol). A THF-diethyl ether solution of 4- (4-fluorophenylsulfonyl) phenylmagnesium chloride was prepared. The prepared 4- (4-fluorophenylsulfonyl) phenylmagnesium chloride in THF-diethyl ether was reacted with dibromodifluoromethane to give 1- (bromochlorofluoromethyl) -4- (4-fluorophenylsulfonyl) benzene (172). 0.1 mg, 45%) as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ. 7.22 (dd, J = 8.43, 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.97-8.00 (m, 4H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.5 (s, 1F), -104.4 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 103.4 (d, J = 305.0 Hz), 116.9 (d, J = 22.6 Hz, 2C), 125.3 (d, J = 6.6 Hz, 2C), 127.9 (s, 2C), 130.7 (d, J = 9.6 Hz, 2C), 136.7 (d, J = 3.4 Hz), 143.7, 167.2 (d, J = 21.6 Hz), 165.8 (d, J = 225 Hz). GC-MS (m / z) 50 (7.3), 57 (14.3), 75 (20.7), 95 (26.3), 107 (56.8), 115 (19.0), 143 (100), 146 (1.1), 191 (2.9), 201 (2.4), 237 (0.9), 267 (5.6), 301 (65.0), 303 (24 .6), 347 (0.6). mp 98.2-99.8 ° C. HRMS (FAB, m / z) Calcd for C 13 H 9 BrClFO 2 S: 380.9163 (MH +); Found: 380.9154.
実施例−１４ Example-14
アルゴン雰囲気下、４−ヨードベンゾニトリル（２２９．０ｍｇ，１．０ｍｍｏｌ）と臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）をＴＨＦ（３．５ｍｌ）に加え、−４０℃に冷却した。得られた混合溶液にイソプロピルマグネシウムブロミドのＴＨＦ溶液（０．７Ｍ、１．５ｍｌ，１．０５ｍｍｏｌ）を加え、２０分間攪拌した。その後、反応溶液を−４０℃で三時間攪拌を行い、４−シアノフェニルマグネシウムブロミドのＴＨＦ溶液を調製した。調製した４−シアノフェニルマグネシウムブロミドのＴＨＦ溶液を、２０℃でジブロモジフルオロメタンのＴＨＦ溶液（２．４６Ｍ、９８０μｌ，２．４ｍｍｏｌ）に滴下し、２０℃で３０分間攪拌を行った。反応液に飽和塩化アンモニウム水溶液（２．０ｍｌ）を加えて、酢酸エチルにて抽出した。有機層を合わせて、水と飽和塩化ナトリウム水溶液で洗浄し、乾燥後、ろ液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル−ヘキサン）とリサイクルＧＰＣ（クロロホルム）により精製することで、４−（ジブロモフルオロメチル）ベンゾニトリル（１０１．９ｍｇ、４１％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ７．７３（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．７７（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５７．９（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ８８．４（ｄ，Ｊ＝３１５Ｈｚ），１１４．５，１１７．６，１２４．９（ｄ，Ｊ＝７．１Ｈｚ，２Ｃ），１３２．３（ｓ，２Ｃ），１４８．３（ｄ，Ｊ＝２１．０Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）５０（８．８），５７（８．９），８１（１０．３），８７（６．６），１０６（２０．３），１１４（４．１）１３３（３９．１），２１２（１００），２１４（９７．３）．ＨＲＭＳ（ＥＩ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ８Ｈ４Ｂｒ２ＦＮ：２９０．８６９４；Ｆｏｕｎｄ：２９０．８６９５． Under an argon atmosphere, 4-iodobenzonitrile (229.0 mg, 1.0 mmol) and lithium bromide (208.4 mg, 2.4 mmol) were added to THF (3.5 ml) and cooled to −40 ° C. To the obtained mixed solution was added a solution of isopropylmagnesium bromide in THF (0.7 M, 1.5 ml, 1.05 mmol), and the mixture was stirred for 20 minutes. Thereafter, the reaction solution was stirred at −40 ° C. for 3 hours to prepare a THF solution of 4-cyanophenylmagnesium bromide. The prepared THF solution of 4-cyanophenylmagnesium bromide was added dropwise to a THF solution of dibromodifluoromethane (2.46M, 980 μl, 2.4 mmol) at 20 ° C., and the mixture was stirred at 20 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution (2.0 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, dried, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate-hexane) and recycled GPC (chloroform) to give 4- (dibromofluoromethyl) benzonitrile (101.9 mg, 41%) as a white solid. Obtained. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-57.9 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 88.4 (d, J = 315 Hz), 114.5, 117.6, 124.9 (d, J = 7.1 Hz, 2C), 132.3 (s, 2C), 148.3 (d, J = 21.0 Hz). GC-MS (m / z) 50 (8.8), 57 (8.9), 81 (10.3), 87 (6.6), 106 (20.3), 114 (4.1) 133 (39.1), 212 (100), 214 (97.3). HRMS (EI, m / z) Calcd for C 8 H 4 Br 2 FN: 290.8694; Found: 290.8695.
実施例−１５ Example-15
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、３−ヨードベンゾニトリル（２２９．０ｍｇ，１．０ｍｍｏｌ）を用いて３−シアノフェニルマグネシウムブロミドのテトラヒドロフラン溶液を調製した。調製した３−シアノフェニルマグネシウムブロミドのテトラヒドロフラン溶液とジブロモジフルオロメタンを反応させて、３−（ジブロモフルオロメチル）ベンゾニトリル（２０．２ｍｇ、７％）を白色固体として得た。１Ｈ−ＮＭＲ．δ７．５８（ｄｄ，Ｊ＝７．８，８．０Ｈｚ，１Ｈ），７．６９（ｄｄｄ，Ｊ＝１．３，１．３，７．８Ｈｚ，１Ｈ），７．９０（ｄｄｄ，Ｊ＝１．１，１．３，８．０Ｈｚ，１Ｈ），７．９５（ｄｄ，Ｊ＝１．１，１．３Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５７．７（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ８８．０（ｄ，Ｊ＝３１４．３Ｈｚ），１１３．０，１１７．５，１２７．６（ｄ，Ｊ＝６．６Ｈｚ），１２８．４（ｄ，Ｊ＝６．６Ｈｚ），１２９．６，１３３．９，１４５．７（ｄ，Ｊ＝２１．３Ｈｚ）． ＧＣ−ＭＳ（７０ｅＶ，ｍ／ｚ）５０（１０．０），５７（１０．０），８１（１２．２），８７（６．７），１０６（２１．９），１１４（４．４），１３３（４２．６），１４６（０．３），１８５（０．２），２１２（１００），２１４（９８．４）． In the same manner as in Example-14, a solution of 3-cyanophenylmagnesium bromide in tetrahydrofuran using 3-iodobenzonitrile (229.0 mg, 1.0 mmol) in the presence of lithium bromide (208.4 mg, 2.4 mmol). Was prepared. The prepared tetrahydrofuran solution of 3-cyanophenylmagnesium bromide was reacted with dibromodifluoromethane to obtain 3- (dibromofluoromethyl) benzonitrile (20.2 mg, 7%) as a white solid. 1 H-NMR. δ 7.58 (dd, J = 7.8, 8.0 Hz, 1H), 7.69 (ddd, J = 1.3, 1.3, 7.8 Hz, 1H), 7.90 (ddd, J = 1.1, 1.3, 8.0 Hz, 1H), 7.95 (dd, J = 1.1, 1.3 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-57.7 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 88.0 (d, J = 314.3 Hz), 113.0, 117.5, 127.6 (d, J = 6.6 Hz), 128.4 (d, J = 6.6 Hz), 129.6, 133.9, 145.7 (d, J = 21.3 Hz). GC-MS (70 eV, m / z) 50 (10.0), 57 (10.0), 81 (12.2), 87 (6.7), 106 (21.9), 114 (4.4) ), 133 (42.6), 146 (0.3), 185 (0.2), 212 (100), 214 (98.4).
実施例−１６ Example-16
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、２−ヨードベンゾニトリル（２２９．０ｍｇ，１．０ｍｍｏｌ）を用いて２−シアノフェニルマグネシウムブロミドのＴＨＦ溶液を調製した。調製した２−シアノフェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、２−（ジブロモフルオロメチル）ベンゾニトリル（１０７．７ｍｇ、３７％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ７．５２（ｔｄ，Ｊ＝１．１，７．６Ｈｚ，１Ｈ），７．６５（ｔｄ，Ｊ＝１．１，８．１Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），７．８２（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５５．４５（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ８６．０（ｄ，Ｊ＝３１４Ｈｚ），１０９．３（ｄ，Ｊ＝３．１Ｈｚ），１１６．０，１２４．１（ｄ，Ｊ＝１１．０Ｈｚ），１３０．７，１３２．５（ｄ，Ｊ＝１．６Ｈｚ），１３５．５，１４５．８（ｄ，Ｊ＝２０．７Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）５０（８．８），５７（８．９），８１（１０．３），８７（６．６），１０６（２０．３），１１４（４．１），１３３（３９．１），２１２（１００），２１４（９７．３）．ｍｐ８７．１−８９．９℃．ＨＲＭＳ（ＥＩ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ８Ｈ４Ｂｒ２ＦＮ：２９０．８６９４；Ｆｏｕｎｄ：２９０．８６９５． In the same manner as in Example-14, 2-cyanophenylmagnesium bromide in THF using 2-iodobenzonitrile (229.0 mg, 1.0 mmol) in the presence of lithium bromide (208.4 mg, 2.4 mmol). Was prepared. The prepared 2-cyanophenylmagnesium bromide in THF and dibromodifluoromethane were reacted to obtain 2- (dibromofluoromethyl) benzonitrile (107.7 mg, 37%) as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 7.52 (td, J = 1.1, 7.6 Hz, 1H), 7.65 (td, J = 1.1, 8.1 Hz, 1H), 7. 80 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-55.45 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 86.0 (d, J = 314 Hz), 109.3 (d, J = 3.1 Hz), 116.0, 124.1 (d, J = 11.0 Hz) 130.7, 132.5 (d, J = 1.6 Hz), 135.5, 145.8 (d, J = 20.7 Hz). GC-MS (m / z) 50 (8.8), 57 (8.9), 81 (10.3), 87 (6.6), 106 (20.3), 114 (4.1), 133 (39.1), 212 (100), 214 (97.3). mp 87.1-89.9 ° C. HRMS (EI, m / z) Calcd for C 8 H 4 Br 2 FN: 290.8694; Found: 290.8695.
実施例−１７ Example-17
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、２−ブロモ―４−メチルベンゾニトリル（１９６．０ｍｇ，１．０ｍｍｏｌ）を用いて２−シアノ−５−メチルフェニルマグネシウムブロミドのＴＨＦ溶液を調製した。調製した２−シアノ−５−メチルフェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、２−（ジブロモフルオロメチル）−４−メチルベンゾニトリル（４７．４ｍｇ，１５％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．４８（ｓ，３Ｈ），７．３１（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．５７（ｓ，１Ｈ），７．６９（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５５．３（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２１．９，８６．３（ｄ，Ｊ＝３１４．０Ｈｚ），１０６．２（ｄ，Ｊ＝３．２Ｈｚ），１１６．３，１２４．９（ｄ，Ｊ＝１０．９Ｈｚ），１３１．３，１３５．４，１４３．８，１４５．５（ｄ，Ｊ＝２０．３Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（０．９），５０（９．８），５１（９．８），６３（１３．４），７５（１５．５），９４（８．１），９９（１１．７），１００（１１．４），１２０（１８．５），１２１（１２．２），１２６（１２．２），１４７（８６．３），２２６（１００），２２８（９５．１）． In the same manner as in Example-14, 2-cyano-5-methylbenzonitrile (196.0 mg, 1.0 mmol) was used in the presence of lithium bromide (208.4 mg, 2.4 mmol) in the presence of 2-cyano-5. -A THF solution of methylphenylmagnesium bromide was prepared. The prepared 2-cyano-5-methylphenylmagnesium bromide in THF was reacted with dibromodifluoromethane to give 2- (dibromofluoromethyl) -4-methylbenzonitrile (47.4 mg, 15%) as a white solid. It was. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.48 (s, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.69 (d, J = 7.8 Hz, 1 H). 19 F-NMR (376 MHz, CDCl 3 ) δ-55.3 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 21.9, 86.3 (d, J = 314.0 Hz), 106.2 (d, J = 3.2 Hz), 116.3, 124.9 (d, J = 10.9 Hz), 131.3, 135.4, 143.8, 145.5 (d, J = 20.3 Hz). GC-MS (m / z) 40 (0.9), 50 (9.8), 51 (9.8), 63 (13.4), 75 (15.5), 94 (8.1), 99 (11.7), 100 (11.4), 120 (18.5), 121 (12.2), 126 (12.2), 147 (86.3), 226 (100), 228 (95 .1).
実施例−１８ Example-18
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、４−ブロモ−２−メチルベンゾニトリル（１９６．０ｍｇ，１．０ｍｍｏｌ）を用いて３−メチル−４−シアノフェニルマグネシウムクロリドのＴＨＦ溶液を調製した。調製した３−メチル−４−シアノフェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、４−（ジブロモフルオロメチル）−２−メチルベンゾニトリル（７２．５ｍｇ、３９％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．６９（ｓ，３Ｈ），７．５５−７．５７（ｍ，２Ｈ），７．５５（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５０．４４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２０．９，８８．６，１１４．５，１１７．６，１２４．８，（ｄ，Ｊ＝１３．１Ｈｚ），１２９．５，１３６．２，１３６．３，１４５．３（ｄ，Ｊ＝１８．６Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（０．８），５０（１７．６），５１（１３．７），６３（１３．４），７５（１５．５），９４（８．１），９９（１１．７），１００（１１．４），１２０（１８．５），１２１（１２．２），１２６（１２．２），１４７（８６．３），２２６（１００），２２８（９５．１）． In the same manner as in Example-14, 4-methyl-2-methylbenzonitrile (196.0 mg, 1.0 mmol) was used in the presence of lithium bromide (208.4 mg, 2.4 mmol) to give 3-methyl-4 -A THF solution of cyanophenyl magnesium chloride was prepared. The prepared 3-methyl-4-cyanophenylmagnesium bromide in THF was reacted with dibromodifluoromethane to give 4- (dibromofluoromethyl) -2-methylbenzonitrile (72.5 mg, 39%) as a yellow oily substance. Obtained. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.69 (s, 3H), 7.55-7.57 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-50.44 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 20.9, 88.6, 114.5, 117.6, 124.8, (d, J = 13.1 Hz), 129.5, 136.2, 136. 3, 145.3 (d, J = 18.6 Hz). GC-MS (m / z) 40 (0.8), 50 (17.6), 51 (13.7), 63 (13.4), 75 (15.5), 94 (8.1), 99 (11.7), 100 (11.4), 120 (18.5), 121 (12.2), 126 (12.2), 147 (86.3), 226 (100), 228 (95 .1).
実施例−１９ Example-19
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、４−ブロモ−３−メチルベンゾニトリル（１９６．０ｍｇ，１．０ｍｍｏｌ）を用いて２−メチル−４−シアノフェニルマグネシウムクロリドのＴＨＦ溶液を調製した。調製した２−メチル−４−シアノフェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、４−（ジブロモフルオロメチル）−３−メチルベンゾニトリル（６７．２ｍｇ、２２％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．６９（ｓ，３Ｈ），７．５５−７．５７（ｍ，２Ｈ），７．７５（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５０．４４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２０．９，８８．６，１１４．５，１１７．６，１２４．８，（ｄ，Ｊ＝１３．１Ｈｚ），１２９．５，１３６．２，１３６．３，１４５．２（ｄ，Ｊ＝１８．４Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（０．７），５０（１５．２），６３（１１．９），７５（１３．８），８１（６．２），９６（７．６），９９（１０．５），１００（１０．５），１２０（１６．８），１２６（１１．２），１４７（８１．８），２２６（１００），２２８（９８．１）． In the same manner as in Example-14, in the presence of lithium bromide (208.4 mg, 2.4 mmol), 4-bromo-3-methylbenzonitrile (196.0 mg, 1.0 mmol) was used to give 2-methyl-4. -A THF solution of cyanophenyl magnesium chloride was prepared. The prepared 2-methyl-4-cyanophenylmagnesium bromide in THF was reacted with dibromodifluoromethane to give 4- (dibromofluoromethyl) -3-methylbenzonitrile (67.2 mg, 22%) as a yellow oily substance. Obtained. 1 H-NMR (400MHz, CDCl 3) δ2.69 (s, 3H), 7.55-7.57 (m, 2H), 7.75 (d, J = 8.8Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-50.44 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 20.9, 88.6, 114.5, 117.6, 124.8, (d, J = 13.1 Hz), 129.5, 136.2, 136. 3, 145.2 (d, J = 18.4 Hz). GC-MS (m / z) 40 (0.7), 50 (15.2), 63 (11.9), 75 (13.8), 81 (6.2), 96 (7.6), 99 (10.5), 100 (10.5), 120 (16.8), 126 (11.2), 147 (81.8), 226 (100), 228 (98.1).
実施例−２０ Example-20
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、４−ヨード安息香酸メチル（２６２．０ｍｇ，１．０ｍｍｏｌ）を用いて４−（メトキシカルボニル）フェニルマグネシウムブロミドのＴＨＦ溶液を調製した。調製した４−（メトキシカルボニル）フェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、４−（ジブロモフルオロメチル）安息香酸メチル（９０．０ｍｇ，２８％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ３．９５（ｓ，３Ｈ），７．７３（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），８．０８（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ５２．５，８９．５（ｄ，Ｊ＝３１５Ｈｚ），１２４．１（ｄ，Ｊ＝６．９Ｈｚ，２Ｃ），１２９．７（ｓ，２Ｃ），１３２．０，１４８．３（ｄ，Ｊ＝２０．４Ｈｚ），１６５．８．ＧＣ−ＭＳ（ｍ／ｚ）５０（８．２），５７（２１．９），８１（１５．６），９４（６．２），１０７（６０．９），１２３（２．６），１３７（１．３），１５１（２．４），１６７（４．７），１８６（１１．７），１８８（１１．７），２１７（１９．０），２１９（１９．２），２４５（１００），２４７（９７．８），２９２（２．７），２９５（５．３），２９７（２．５）．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ９Ｈ８Ｂｒ２ＦＯ２：３２４．８８７５（ＭＨ＋）；Ｆｏｕｎｄ：３２４．８８７６． In the same manner as in Example-14, 4- (methoxycarbonyl) phenylmagnesium was used with methyl 4-iodobenzoate (262.0 mg, 1.0 mmol) in the presence of lithium bromide (208.4 mg, 2.4 mmol). A solution of bromide in THF was prepared. The prepared 4- (methoxycarbonyl) phenylmagnesium bromide in THF was reacted with dibromodifluoromethane to obtain methyl 4- (dibromofluoromethyl) benzoate (90.0 mg, 28%) as a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 3.95 (s, 3H), 7.73 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.4 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 52.5, 89.5 (d, J = 315 Hz), 124.1 (d, J = 6.9 Hz, 2C), 129.7 (s, 2C), 132 0.0, 148.3 (d, J = 20.4 Hz), 165.8. GC-MS (m / z) 50 (8.2), 57 (21.9), 81 (15.6), 94 (6.2), 107 (60.9), 123 (2.6), 137 (1.3), 151 (2.4), 167 (4.7), 186 (11.7), 188 (11.7), 217 (19.0), 219 (19.2), 245 (100), 247 (97.8), 292 (2.7), 295 (5.3), 297 (2.5). HRMS (FAB, m / z) Calcd for C 9 H 8 Br 2 FO 2: 324.8875 (MH +); Found: 324.8876.
実施例−２１ Example-21
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、１−ヨード−４−（４−メチルフェニルスルホニル）ベンゼン（３５８．１９ｍｇ，１．０ｍｍｏｌ）を用いて４−（４−メチルフェニルスルホニル）フェニルマグネシウムブロミドのＴＨＦ溶液を調製した。調製した４−（４−メチルフェニルスルホニル）フェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、１−（ジブロモフルオロメチル）−４−（４−メチルフェニルスルホニル）ベンゼン（１３２．０ｍｇ，３１％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．４２（ｓ，３Ｈ），７．３３（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．７６（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．８４（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．９７（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５７．３（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２１．６，８８．５（ｄ，Ｊ＝３１４．７Ｈｚ），１２５．０（ｄ，Ｊ＝７．０Ｈｚ，２Ｃ），１２７．７（ｓ，２Ｃ），１２７．９（ｓ，２Ｃ），１３０．２（ｓ，２Ｃ），１３７．７，１４４．０，１４４．８，１４８．３（ｄ，Ｊ＝２１．０Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）４０（０．４），５１（４．４），６５（２２．１），７７（１０．８），９１（１９．２），１０７（３７．４），１３９（１００），１４０（８．３），１７０（０．５），１８６（３．６），１８８（３．５），２３４（１．２）２３６（１．３），２６３（７．９），３４１（３６．８），３４３（３７．４）．ｍｐ１５８．８−１６０．８℃．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ１４Ｈ１２Ｂｒ２ＦＯ２Ｓ：４２０．８９０９（ＭＨ＋）；Ｆｏｕｎｄ：４２０．８９１０． In the same manner as in Example-14, 1-iodo-4- (4-methylphenylsulfonyl) benzene (358.19 mg, 1.0 mmol) was used in the presence of lithium bromide (208.4 mg, 2.4 mmol). A THF solution of 4- (4-methylphenylsulfonyl) phenylmagnesium bromide was prepared. The prepared 4- (4-methylphenylsulfonyl) phenylmagnesium bromide in THF was reacted with dibromodifluoromethane to give 1- (dibromofluoromethyl) -4- (4-methylphenylsulfonyl) benzene (132.0 mg, 31 %) As a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.42 (s, 3H), 7.33 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7 .84 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H). 19 F-NMR (376 MHz, CDCl 3 ) δ-57.3 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 21.6, 88.5 (d, J = 314.7 Hz), 125.0 (d, J = 7.0 Hz, 2C), 127.7 (s, 2C) , 127.9 (s, 2C), 130.2 (s, 2C), 137.7, 144.0, 144.8, 148.3 (d, J = 21.0 Hz). GC-MS (m / z) 40 (0.4), 51 (4.4), 65 (22.1), 77 (10.8), 91 (19.2), 107 (37.4), 139 (100), 140 (8.3), 170 (0.5), 186 (3.6), 188 (3.5), 234 (1.2) 236 (1.3), 263 (7. 9), 341 (36.8), 343 (37.4). mp 158.8-160.8 ° C. HRMS (FAB, m / z) Calcd for C 14 H 12 Br 2 FO 2 S: 420.8909 (MH +); Found: 420.8910.
実施例−２２ Example-22
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、１−ヨード−４−（４−フルオロフェニルスルホニル）ベンゼン（３６２．１６ｍｇ，１．０ｍｍｏｌ）を用いて、４−（４−フルオロフェニルスルホニル）フェニルマグネシウムブロミドのＴＨＦ溶液を調製した。調製した４−（４−フルオロフェニルスルホニル）フェニルマグネシウムブロミドのＴＨＦ溶液とジブロモジフルオロメタンを反応させて、１−（ジブロモフルオロメチル）−４−（４−フルオロフェニルスルホニル）ベンゼン（２０７．０ｍｇ，４９％）を白色固体として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ．７．２２（ｄｄ，Ｊ＝８．５，８．７Ｈｚ，２Ｈ），７．８０（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．９６−８．０１（ｍ，４Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５７．６（ｓ，１Ｆ），−１０４．４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ８８．４（ｄ，Ｊ＝３１４．７Ｈｚ），１１６．９（ｄ，Ｊ＝２２．６Ｈｚ，２Ｃ），１２５．１（ｄ，Ｊ＝７．２Ｈｚ），１２７．８（ｓ，２Ｃ），１３０．７（ｄ，Ｊ＝９．５Ｈｚ，２Ｃ），１３６．８（ｄ，Ｊ＝３．０Ｈｚ，２Ｃ），１４３．５，１４８．７（ｄ，Ｊ＝２１．２Ｈｚ），１６５．８（ｄ，Ｊ＝２２５Ｈｚ）．ＧＣ−ＭＳ（ｍ／ｚ）５７（１７．９），７５（１８．３），８１（１２．３），９５（２２．９），１０７（５３．１），１１５（１８．６）１２７（３．０），１４３（１００），１４６（１．１），１８６（４．８），１８８（５．２），２６７（１１．２），３４５（４３．６），３４７（４３．８）．ｍｐ９１．１−９２．８℃．ＨＲＭＳ（ＦＡＢ，ｍ／ｚ）Ｃａｌｃｄ ｆｏｒ Ｃ１３Ｈ９Ｂｒ２ＦＯ２Ｓ：４２４．８６５８（ＭＨ＋）；Ｆｏｕｎｄ：４２４．８６５５． In the same manner as in Example-14, 1-iodo-4- (4-fluorophenylsulfonyl) benzene (362.16 mg, 1.0 mmol) was used in the presence of lithium bromide (208.4 mg, 2.4 mmol). 4- (4-fluorophenylsulfonyl) phenylmagnesium bromide in THF was prepared. The prepared 4- (4-fluorophenylsulfonyl) phenylmagnesium bromide in THF was reacted with dibromodifluoromethane to give 1- (dibromofluoromethyl) -4- (4-fluorophenylsulfonyl) benzene (207.0 mg, 49 %) As a white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ. 7.22 (dd, J = 8.5, 8.7 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.96-8.01 (m, 4H). 19 F-NMR (376 MHz, CDCl 3 ) δ-57.6 (s, 1F), -104.4 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 88.4 (d, J = 314.7 Hz), 116.9 (d, J = 22.6 Hz, 2C), 125.1 (d, J = 7.2 Hz) , 127.8 (s, 2C), 130.7 (d, J = 9.5 Hz, 2C), 136.8 (d, J = 3.0 Hz, 2C), 143.5, 148.7 (d, J = 21.2 Hz), 165.8 (d, J = 225 Hz). GC-MS (m / z) 57 (17.9), 75 (18.3), 81 (12.3), 95 (22.9), 107 (53.1), 115 (18.6) 127 (3.0), 143 (100), 146 (1.1), 186 (4.8), 188 (5.2), 267 (11.2), 345 (43.6), 347 (43. 8). mp 91.1-92.8 ° C. HRMS (FAB, m / z) Calcd for C 13 H 9 Br 2 FO 2 S: 424.8658 (MH +); Found: 424.8655.
実施例−２３ Example-23
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、４−ヨード−２−メチル安息香酸メチル（３１８．１ｍｇ， １．０ｍｍｏｌ）を用いて４−（メトキシカルボニル）−３−メチルフェニルマグネシウムブロミドのテトラヒドロフラン溶液を調製した。調製した４−（メトキシカルボニル）−３−メチルフェニルマグネシウムブロミドのテトラヒドロフラン溶液とジブロモジフルオロメタンを反応させて、４−（ジブロモフルオロメチル）−２−メチル安息香酸メチル（１９．７ｍｇ，６％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ２．６４（ｓ，３Ｈ），３．９２（ｓ，３Ｈ），７．５２（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．５３（ｓ，１Ｈ），７．９４（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．２（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ２１．８，５２．１，８９．６（ｄ，Ｊ＝３１５．０Ｈｚ），１２１．４（ｄ，Ｊ＝６．８Ｈｚ），１２７．０（ｄ，Ｊ＝６．８Ｈｚ），１３０．７，１３１．５，１４０．６，１４７．１（ｄ，Ｊ＝２０．２Ｈｚ），１６６．９．ＧＣ−ＭＳ（７０ｅＶ，ｍ／ｚ）５１（１２．１），６０（１１．９），７５（１７．３），１０１（３０．８），１２０（１３．９），１２１（１２．２），１３７（２．１），１５３（１．４），１６５（１．９），１８１（６．４），２００（１１．５），２０２（１１．６），２３１（２２．２），２３３（２０．７），２５９（１００），２６１（９９．８），３０６（２．９），３０９（５．６），３１１（３．１），３３９（０．４）． In the same manner as in Example-14, 4- (methoxy) was obtained using methyl 4-iodo-2-methylbenzoate (318.1 mg, 1.0 mmol) in the presence of lithium bromide (208.4 mg, 2.4 mmol). A tetrahydrofuran solution of carbonyl) -3-methylphenylmagnesium bromide was prepared. The prepared tetrahydrofuran solution of 4- (methoxycarbonyl) -3-methylphenylmagnesium bromide and dibromodifluoromethane were reacted to give methyl 4- (dibromofluoromethyl) -2-methylbenzoate (19.7 mg, 6%). Obtained as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 2.64 (s, 3H), 3.92 (s, 3H), 7.52 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H ), 7.94 (d, J = 9.0 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.2 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 21.8, 52.1, 89.6 (d, J = 315.0 Hz), 121.4 (d, J = 6.8 Hz), 127.0 (d, J = 6.8 Hz), 130.7, 131.5, 140.6, 147.1 (d, J = 20.2 Hz), 166.9. GC-MS (70 eV, m / z) 51 (12.1), 60 (11.9), 75 (17.3), 101 (30.8), 120 (13.9), 121 (12.2) ), 137 (2.1), 153 (1.4), 165 (1.9), 181 (6.4), 200 (11.5), 202 (11.6), 231 (22.2) , 233 (20.7), 259 (100), 261 (99.8), 306 (2.9), 309 (5.6), 311 (3.1), 339 (0.4).
実施例−２４ Example-24
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、２−（アリルオキシ）−４−ブロモベンゾニトリル（２３８．１ｍｇ，１．０ｍｍｏｌ）を用いて３−（アリルオキシ）−４−シアノフェニルマグネシウムブロミドのテトラヒドロフラン溶液を調製した。調製した３−（アリルオキシ）−４−シアノフェニルマグネシウムブロミドのテトラヒドロフラン溶液とジブロモジフルオロメタンを反応させて、２−（アリルオキシ）−４−（ジブロモフルオロメチル）ベンゾニトリル（２８．０ｍｇ，８％）を黄色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ４．７４（ｄｄｄ，Ｊ＝１．５，１．５，５．１Ｈｚ，２Ｈ），５．３９（ｔｄｄ，Ｊ＝１．５，１．５，１０．５Ｈｚ，１Ｈ），５．５１（ｔｄｄ，Ｊ＝１．５，１．５，１７．２Ｈｚ，１Ｈ），６．０６（ｍ，１Ｈ），７．２０（ｄ，Ｊ＝１．７Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝１．７，８．２Ｈｚ，１Ｈ），７．６４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５７．４（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ７０．０，８８．４（ｄ，Ｊ＝３１４．５Ｈｚ），１０４．４，１０８．５（ｄ，Ｊ＝７．６Ｈｚ），１１５．２，１１６．６（ｄ，Ｊ＝７．２Ｈｚ），１１９．１，１３１．２，１３３．９，１４９．６（ｄ，Ｊ＝２０．７Ｈｚ），１５９．９．ＧＣ−ＭＳ（ｍ／ｚ）４１（１００），６９（２．３），７５（１．７），９４（２．９），１００（３．７），１２０（４．４），１６１（１．８），２６８（１２．６），２７０（１２．５），３４７（１．４），３４９（２．７），３５１（１．４）． In the same manner as in Example-14, 3- (allyloxy) -4-bromobenzonitrile (238.1 mg, 1.0 mmol) was used in the presence of lithium bromide (208.4 mg, 2.4 mmol). A tetrahydrofuran solution of allyloxy) -4-cyanophenylmagnesium bromide was prepared. The prepared tetrahydrofuran solution of 3- (allyloxy) -4-cyanophenylmagnesium bromide and dibromodifluoromethane were reacted to give 2- (allyloxy) -4- (dibromofluoromethyl) benzonitrile (28.0 mg, 8%). Obtained as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 4.74 (ddd, J = 1.5, 1.5, 5.1 Hz, 2H), 5.39 (tdd, J = 1.5, 1.5, 10 .5 Hz, 1 H), 5.51 (tdd, J = 1.5, 1.5, 17.2 Hz, 1 H), 6.06 (m, 1 H), 7.20 (d, J = 1.7 Hz, 1H), 7.30 (dd, J = 1.7, 8.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-57.4 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 70.0, 88.4 (d, J = 314.5 Hz), 104.4, 108.5 (d, J = 7.6 Hz), 115.2, 116. 6 (d, J = 7.2 Hz), 119.1, 131.2, 133.9, 149.6 (d, J = 20.7 Hz), 159.9. GC-MS (m / z) 41 (100), 69 (2.3), 75 (1.7), 94 (2.9), 100 (3.7), 120 (4.4), 161 ( 1.8), 268 (12.6), 270 (12.5), 347 (1.4), 349 (2.7), 351 (1.4).
実施例−２５ Example-25
実施例−１４と同様にして、臭化リチウム（２０８．４ｍｇ，２．４ｍｍｏｌ）存在下、２−（アリルオキシ）−４−ブロモ安息香酸メチル（３１８．１１ｍｇ，１．０ｍｍｏｌ）を用いて３−（アリルオキシ）−４−（メトキシカルボニル）フェニルマグネシウムブロミドのテトラヒドロフラン溶液を調製した。調製した３−アリルオキシ−４−シアノフェニルマグネシウムブロミドのテトラヒドロフラン溶液とジブロモジフルオロメタンを反応させて、２−（アリルオキシ）−４−（ジブロモフルオロメチル）安息香酸メチル（３０．６ｍｇ，８％）を無色油状物質として得た。１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ ３．９１（ｓ，３Ｈ），４．６８（ｄｄｄ，Ｊ＝１．５，１．５，４．９Ｈｚ，２Ｈ），５．３４（ｔｄｄ，Ｊ＝１．５，１．５，１０．６Ｈｚ，１Ｈ），５．５３（ｔｄｄ，Ｊ＝１．５，１．５，１７．２Ｈｚ，１Ｈ），６．０７（ｍ，１Ｈ），７．２２（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝１．８，８．２Ｈｚ，１Ｈ），７．８１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ３）δ−５６．２（ｓ，１Ｆ）．１３Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ３）δ５２．３，６９．８，８９．３（ｄ，Ｊ＝３１４．８Ｈｚ），１０９．４（ｄ，Ｊ＝７．２Ｈｚ），１１６．０（ｄ，Ｊ＝７．２Ｈｚ），１１８．１，１２２．６，１３１．７，１３２．０，１４８．６（ｄ，Ｊ＝２０．５Ｈｚ），１５７．５，１６５．７．ＧＣ−ＭＳ（ｍ／ｚ）４１（１００），５９（１５．１），７１（１２．７），９４（３０．１），１０７（６．６），１１５（５．３），１３３（７．０），１３５（６．２），２０１（２１．８），２０３（２２．４），２４１（１８．５），２４３（１８．１），３０１（３２．１），３０３（３２．０），３０５（２．７），３５１（３．３），３８０（１．２），３８２（２．３），３８４（１．２）． In the same manner as in Example-14, 3- (allyloxy) -4-bromobenzoate (318.11 mg, 1.0 mmol) was used in the presence of lithium bromide (208.4 mg, 2.4 mmol) in the presence of 3- A tetrahydrofuran solution of (allyloxy) -4- (methoxycarbonyl) phenylmagnesium bromide was prepared. The prepared tetrahydrofuran solution of 3-allyloxy-4-cyanophenylmagnesium bromide and dibromodifluoromethane were reacted to give methyl 2- (allyloxy) -4- (dibromofluoromethyl) benzoate (30.6 mg, 8%) colorless Obtained as an oil. 1 H-NMR (400 MHz, CDCl 3 ) δ 3.91 (s, 3H), 4.68 (ddd, J = 1.5, 1.5, 4.9 Hz, 2H), 5.34 (tdd, J = 1.5, 1.5, 10.6 Hz, 1H), 5.53 (tdd, J = 1.5, 1.5, 17.2 Hz, 1H), 6.07 (m, 1H), 7. 22 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 1.8, 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H). 19 F-NMR (376 MHz, CDCl 3 ) δ-56.2 (s, 1F). 13 C-NMR (100 MHz, CDCl 3 ) δ 52.3, 69.8, 89.3 (d, J = 314.8 Hz), 109.4 (d, J = 7.2 Hz), 116.0 (d, J = 7.2 Hz), 118.1, 122.6, 131.7, 132.0, 148.6 (d, J = 20.5 Hz), 157.5, 165.7. GC-MS (m / z) 41 (100), 59 (15.1), 71 (12.7), 94 (30.1), 107 (6.6), 115 (5.3), 133 ( 7.0), 135 (6.2), 201 (21.8), 203 (22.4), 241 (18.5), 243 (18.1), 301 (32.1), 303 (32 .0), 305 (2.7), 351 (3.3), 380 (1.2), 382 (2.3), 384 (1.2).
Claims (7)
以上
General formula (2)
that's all
（式中、Ｒ１は炭素数１から６のフルオロアルキル基；（炭素数１から６のアルコキシ）カルボニル基；シアノ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基；フッ素原子；又はペンタフルオロスルファニル基を表し、Ｒ２は炭素数１から６のフルオロアルキル基；（炭素数１から６のアルコキシ）カルボニル基；シアノ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよいフェニルスルホニル基；フッ素原子；ペンタフルオロスルファニル基；炭素数１から６のアルキル基；炭素数１から６のアルコキシ基；炭素数３から６のアルケニルオキシ基；炭素数１から６のアルキル基、炭素数１から６のフルオロアルキル基又はフッ素原子で置換されていてもよい炭素数６から１２の芳香族炭化水素基；又は塩素原子を表す。ｎは０から３の整数を表し、ｎが２又は３の整数の場合、複数のＲ２は同一又は相異なっていてもよい。Ｘはハロゲン原子を表す。）で表されるアリールマグネシウム試薬を、一般式（５）［ＭＱ（５）］（式中、Ｍはアルカリ金属、Ｑは塩素原子又は臭素原子を表す。）で表されるハロゲン化アルカリ金属塩又は一般式（６）［ＭｇＱ２（６）］（式中、Ｑは塩素原子又は臭素原子を表す。）で表されるハロゲン化マグネシウム存在下、ジブロモジフルオロメタンと反応させることを特徴とする、一般式（２）
（式中、Ｒ１、Ｒ２、Ｑ及びｎは前記と同じ意味を表す。）で表される（トリハロメチル）ベンゼン誘導体の製造方法。 General formula (1)
(Wherein R 1 is a fluoroalkyl group having 1 to 6 carbon atoms; (alkoxy having 1 to 6 carbon atoms) carbonyl group; cyano group; an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms) Or a phenylsulfonyl group optionally substituted with a fluorine atom; a fluorine atom; or a pentafluorosulfanyl group, wherein R 2 is a fluoroalkyl group having 1 to 6 carbon atoms; (an alkoxy having 1 to 6 carbon atoms) carbonyl group; A cyano group; an alkyl group having 1 to 6 carbon atoms, a fluoroalkyl group having 1 to 6 carbon atoms, or a phenylsulfonyl group optionally substituted with a fluorine atom; a fluorine atom; a pentafluorosulfanyl group; an alkyl having 1 to 6 carbon atoms Group: an alkoxy group having 1 to 6 carbon atoms; an alkenyloxy group having 3 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms; 6 represents an aromatic hydrocarbon group having 6 to 12 carbon atoms which may be substituted with a fluoroalkyl group or a fluorine atom; or represents a chlorine atom, n represents an integer of 0 to 3, and n represents 2 or 3 In the case of an integer, a plurality of R 2 may be the same or different. X represents a halogen atom.) An arylmagnesium reagent represented by the general formula (5) [MQ (5)] (wherein M represents an alkali metal, Q represents a chlorine atom or a bromine atom) or a halogenated alkali metal salt represented by the general formula (6) [MgQ 2 (6)] (wherein Q represents a chlorine atom or a bromine atom) And represented by the general formula (2), characterized by reacting with dibromodifluoromethane in the presence of magnesium halide represented by formula (2)
(Wherein R 1 , R 2 , Q and n represent the same meaning as described above). A method for producing a (trihalomethyl) benzene derivative represented by:
（式中、Ｒ１、Ｒ２及びｎは前記と同じ意味を表す。Ｙはハロゲン原子を表す。）で表されるハロゲン化ベンゼン誘導体と、一般式（４）［ｉ−ＰｒＭｇＺ（４）］（式中、Ｚはハロゲン原子を表す。）で表されるイソプロピルマグネシウムハライドとを反応させて調製した一般式（１）
（式中、Ｒ１、Ｒ２及びｎは前記と同じ意味を表す。ＸはＹ又はＺを表す。）で表されるアリールマグネシウム試薬を、一般式（５）［ＭＱ（５）］（式中、Ｍはアルカリ金属、Ｑは塩素原子又は臭素原子を表す。）で表されるハロゲン化アルカリ金属塩又は一般式（６）［ＭｇＱ２（６）］（式中、Ｑは塩素原子又は臭素原子を表す。）で表されるハロゲン化マグネシウム存在下、ジブロモジフルオロメタンと反応させることを特徴とする、請求項２に記載の一般式（２）
（式中、Ｒ１、Ｒ２、Ｑ及びｎは前記と同じ意味を表す。）で表される（トリハロメチル）ベンゼン誘導体の製造方法。 General formula (3)
(Wherein R 1 , R 2 and n represent the same meaning as described above. Y represents a halogen atom) and a general formula (4) [i-PrMgZ (4)] (Wherein Z represents a halogen atom) General formula (1) prepared by reacting with isopropylmagnesium halide represented by
(Wherein R 1 , R 2 and n represent the same meaning as described above. X represents Y or Z). An arylmagnesium reagent represented by the general formula (5) [MQ (5)] (formula Wherein M represents an alkali metal, Q represents a chlorine atom or a bromine atom) or a general formula (6) [MgQ 2 (6)] (wherein Q represents a chlorine atom or bromine) It is reacted with dibromodifluoromethane in the presence of a magnesium halide represented by the general formula (2) according to claim 2.
(Wherein R 1 , R 2 , Q and n represent the same meaning as described above). A method for producing a (trihalomethyl) benzene derivative represented by:
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