JP6371077B2 - Difluoromethyl group-containing compound and use thereof - Google Patents
Difluoromethyl group-containing compound and use thereof Download PDFInfo
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- JP6371077B2 JP6371077B2 JP2014034419A JP2014034419A JP6371077B2 JP 6371077 B2 JP6371077 B2 JP 6371077B2 JP 2014034419 A JP2014034419 A JP 2014034419A JP 2014034419 A JP2014034419 A JP 2014034419A JP 6371077 B2 JP6371077 B2 JP 6371077B2
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- difluoromethyl
- mmol
- difluoro
- nmr
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- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 title claims description 36
- 150000001875 compounds Chemical class 0.000 title claims description 27
- -1 diphenyliodonium hexafluorophosphate Chemical compound 0.000 claims description 36
- QTQOPRNVTJILHT-UHFFFAOYSA-N 3,3-difluoroprop-2-enylsulfanylbenzene Chemical compound C1(=CC=CC=C1)SCC=C(F)F QTQOPRNVTJILHT-UHFFFAOYSA-N 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 12
- JJXFJTVSJBVPCV-VOTSOKGWSA-N [(E)-3,3-difluoroprop-1-enyl]sulfanylbenzene Chemical compound C1=CC=C(C=C1)S/C=C/C(F)F JJXFJTVSJBVPCV-VOTSOKGWSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- OZLBDYMWFAHSOQ-UHFFFAOYSA-N diphenyliodanium Chemical class C=1C=CC=CC=1[I+]C1=CC=CC=C1 OZLBDYMWFAHSOQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- SBQIJPBUMNWUKN-UHFFFAOYSA-M diphenyliodanium;trifluoromethanesulfonate Chemical group [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[I+]C1=CC=CC=C1 SBQIJPBUMNWUKN-UHFFFAOYSA-M 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical group O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 10
- ZFCFFNGBCVAUDE-UHFFFAOYSA-N 2-(benzenesulfonyl)acetonitrile Chemical compound N#CCS(=O)(=O)C1=CC=CC=C1 ZFCFFNGBCVAUDE-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 150000001942 cyclopropanes Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 230000002950 deficient Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- WHCQGCQEITVJOP-UHFFFAOYSA-N 2-(difluoromethyl)-5,7-dimethyl-5,7-diazaspiro[2.5]octane-4,6,8-trione Chemical compound FC(C1CC11C(N(C(N(C1=O)C)=O)C)=O)F WHCQGCQEITVJOP-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000012776 electronic material Substances 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WZRQGCPXBJKJDI-UHFFFAOYSA-N 1-(benzenesulfonyl)-2-(difluoromethyl)cyclopropane-1-carbonitrile Chemical compound FC(C1C(C1)(C#N)S(=O)(=O)C1=CC=CC=C1)F WZRQGCPXBJKJDI-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 235000002597 Solanum melongena Nutrition 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HNSAUKKLJXESCV-UHFFFAOYSA-N [1-(benzenesulfonyl)-2-(difluoromethyl)cyclopropyl]sulfonylbenzene Chemical compound FC(F)C1CC1(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1 HNSAUKKLJXESCV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- VBOGDLCGFBSZKS-UHFFFAOYSA-N phenylsulfanylbenzene;trifluoromethanesulfonic acid Chemical compound [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[SH+]C1=CC=CC=C1 VBOGDLCGFBSZKS-UHFFFAOYSA-N 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 2
- OVWINISJHZQCKW-UHFFFAOYSA-N 2-cyano-4-ethoxybutanoic acid Chemical compound CCOCCC(C#N)C(O)=O OVWINISJHZQCKW-UHFFFAOYSA-N 0.000 description 2
- XPSYZCWYRWHVCC-UHFFFAOYSA-N 3-o-tert-butyl 1-o-methyl propanedioate Chemical compound COC(=O)CC(=O)OC(C)(C)C XPSYZCWYRWHVCC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WAKLWPIEJANHFS-UHFFFAOYSA-N [1-cyano-2-(cyanomethyl)-3,3-difluoropropyl] diethyl phosphate Chemical compound P(=O)(OCC)(OCC)OC(C(CC#N)C(F)F)C#N WAKLWPIEJANHFS-UHFFFAOYSA-N 0.000 description 2
- HLAGCUKEHWIQQE-UHFFFAOYSA-N [1-cyano-2-(difluoromethyl)cyclopropyl] diethyl phosphate Chemical compound P(=O)(OCC)(OCC)OC1(C(C1)C(F)F)C#N HLAGCUKEHWIQQE-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- QCHNSJNRFSOCLJ-UHFFFAOYSA-N benzenesulfonylmethylsulfonylbenzene Chemical compound C=1C=CC=CC=1S(=O)(=O)CS(=O)(=O)C1=CC=CC=C1 QCHNSJNRFSOCLJ-UHFFFAOYSA-N 0.000 description 2
- RYFCSKVXWRJEOB-UHFFFAOYSA-N dibenzyl propanedioate Chemical compound C=1C=CC=CC=1COC(=O)CC(=O)OCC1=CC=CC=C1 RYFCSKVXWRJEOB-UHFFFAOYSA-N 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 2
- YVRLZZAZRUAIFE-UHFFFAOYSA-M diphenyl(3,3,3-trifluoroprop-1-enyl)sulfanium trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[S+](C=CC(F)(F)F)C1=CC=CC=C1 YVRLZZAZRUAIFE-UHFFFAOYSA-M 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- NLEAIFBNKPYTGN-UHFFFAOYSA-N methyl 2-(benzenesulfonyl)acetate Chemical compound COC(=O)CS(=O)(=O)C1=CC=CC=C1 NLEAIFBNKPYTGN-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- MCRZWYDXIGCFKO-UHFFFAOYSA-L 2-butylpropanedioate Chemical compound CCCCC(C([O-])=O)C([O-])=O MCRZWYDXIGCFKO-UHFFFAOYSA-L 0.000 description 1
- RCRZWVVBSRXXEF-UHFFFAOYSA-N 3,5-dioxooctanal Chemical compound CCCC(=O)CC(=O)CC=O RCRZWVVBSRXXEF-UHFFFAOYSA-N 0.000 description 1
- GDDNTTHUKVNJRA-UHFFFAOYSA-N 3-bromo-3,3-difluoroprop-1-ene Chemical compound FC(F)(Br)C=C GDDNTTHUKVNJRA-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 125000006418 4-methylphenylsulfonyl group Chemical group 0.000 description 1
- XLLOJUGNMZRWNZ-UHFFFAOYSA-N C1C(C1S(=O)(=O)C2=CC=CC=C2)C(F)F Chemical compound C1C(C1S(=O)(=O)C2=CC=CC=C2)C(F)F XLLOJUGNMZRWNZ-UHFFFAOYSA-N 0.000 description 1
- RLOHFIZRFWQLLM-UHFFFAOYSA-N CC(C(F)F)C(C#N)(C#N)S(=O)(=O)C1=CC=CC=C1 Chemical compound CC(C(F)F)C(C#N)(C#N)S(=O)(=O)C1=CC=CC=C1 RLOHFIZRFWQLLM-UHFFFAOYSA-N 0.000 description 1
- NCQMRTYWWJPIDK-UHFFFAOYSA-N CC(C)(C)C(C1)(C(F)F)C1(C(O)=O)C(OC)=O Chemical compound CC(C)(C)C(C1)(C(F)F)C1(C(O)=O)C(OC)=O NCQMRTYWWJPIDK-UHFFFAOYSA-N 0.000 description 1
- CKDMNTQHABSHPF-UHFFFAOYSA-N CCOCCC(C1)(C(F)F)C1(C(O)=O)C#N Chemical compound CCOCCC(C1)(C(F)F)C1(C(O)=O)C#N CKDMNTQHABSHPF-UHFFFAOYSA-N 0.000 description 1
- DFKXOVAOVPMKKW-CALJPSDSSA-M FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[Br-] Chemical compound FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[Br-] DFKXOVAOVPMKKW-CALJPSDSSA-M 0.000 description 1
- APEXEWGTELJENA-CALJPSDSSA-M FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[Cl-] Chemical compound FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[Cl-] APEXEWGTELJENA-CALJPSDSSA-M 0.000 description 1
- VSAQPZMSULHUDS-CALJPSDSSA-M FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[F-] Chemical compound FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[F-] VSAQPZMSULHUDS-CALJPSDSSA-M 0.000 description 1
- BBLYYNLSJAOFFY-CALJPSDSSA-M FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[I-] Chemical compound FC(/C=C/[S+](C1=CC=CC=C1)C1=CC=CC=C1)F.[I-] BBLYYNLSJAOFFY-CALJPSDSSA-M 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- IGMWDYQIKLLYQH-UHFFFAOYSA-N cyanomethyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OCC#N IGMWDYQIKLLYQH-UHFFFAOYSA-N 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- CEJVQBJYLUOFAS-NTMALXAHSA-N ethyl (z)-2-benzamido-4,4-difluorobut-2-enoate Chemical compound CCOC(=O)C(=C\C(F)F)\NC(=O)C1=CC=CC=C1 CEJVQBJYLUOFAS-NTMALXAHSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は新規なジフルオロメチル基含有化合物及びその用途に関する。本発明のジフルオロメチル基含有化合物は電子材料原料や医・農薬の製造中間体として有用な化合物である。また、本発明のジフルオロメチル基含有化合物と電子不足メチレン化合物との反応により得られるジフルオロメチル基含有シクロプロパン類も電子材料原料や医・農薬の製造中間体として有用な化合物である。 The present invention relates to a novel difluoromethyl group-containing compound and use thereof. The difluoromethyl group-containing compound of the present invention is a useful compound as a raw material for electronic materials and as a production intermediate for medicines and agricultural chemicals. In addition, difluoromethyl group-containing cyclopropanes obtained by the reaction of the difluoromethyl group-containing compound of the present invention and an electron-deficient methylene compound are also useful compounds as raw materials for electronic materials and as intermediates for production of medicines and agricultural chemicals.
従来より、本発明のジフルオロメチル基含有化合物は知られていない。
本発明のジフルオロメチル基含有化合物と類似のトリフルオロメチル基を含有化合物として（３，３，３−トリフルオロ−１−プロペン−１−イル）ジフェニルスルホニウム トリフルオロメタンスルホナートは知られており、各種アミンとの反応でアジリジン環が製造可能であることが報告されている（例えば、特許文献１参照）。
Conventionally, the difluoromethyl group-containing compound of the present invention has not been known.
(3,3,3-trifluoro-1-propen-1-yl) diphenylsulfonium trifluoromethanesulfonate is known as a compound containing a trifluoromethyl group similar to the difluoromethyl group-containing compound of the present invention. It has been reported that an aziridine ring can be produced by reaction with an amine (see, for example, Patent Document 1).
一方、ジフルオロメチル基を有するシクロプロパン類の製造方法も知られており、（Ｚ）−エチル ２−ベンゾイルアミノ−４，４−ジフルオロ−２−ブテノエートとジアゾメタンの反応によりジフルオロメチル基含有シクロプロパン類を得る方法が知られている（例えば、非特許文献１参照）。
特許文献１に記載の（３，３，３−トリフルオロ−１−プロペン−１−イル）ジフェニルスルホニウム トリフルオロメタンスルホナートは、アミン類との反応によりアジリジン環が形成される反応等が知られている。
On the other hand, a method for producing cyclopropanes having a difluoromethyl group is also known, and a difluoromethyl group-containing cyclopropane is obtained by reacting (Z) -ethyl 2-benzoylamino-4,4-difluoro-2-butenoate with diazomethane. Is known (see, for example, Non-Patent Document 1).
(3,3,3-trifluoro-1-propen-1-yl) diphenylsulfonium trifluoromethanesulfonate described in Patent Document 1 is known to undergo a reaction in which an aziridine ring is formed by reaction with amines. Yes.
一方、非特許文献１に記載の方法でジフルオロメチル基含有シクロプロパン類を得るには、爆発性を有するという課題があるジアゾメタンまたはその類似化合物の使用が必須で、工業的に実施が極めて困難な製造方法である。 On the other hand, in order to obtain difluoromethyl group-containing cyclopropanes by the method described in Non-Patent Document 1, it is essential to use diazomethane or a similar compound having a problem of explosive properties, and it is extremely difficult to implement industrially. It is a manufacturing method.
本発明の目的は、ジフルオロメチル基含有化合物の調製に有用な、新規ジフルオロメチル基含有化合物を提供するとともに、該試剤を用いたジフルオロメチル基含有シクロプロパン類の新規製造方法を提供することにある。 An object of the present invention is to provide a novel difluoromethyl group-containing compound useful for the preparation of a difluoromethyl group-containing compound and to provide a novel method for producing difluoromethyl group-containing cyclopropanes using the reagent. .
本発明者らは、新規なジフルオロメチル基導入剤について鋭意検討した結果、本発明の、ジフルオロメチル基含有化合物を見出した。さらに当該化合物を電子不足メチレン含有化合物と反応させることにより、容易にジフルオロメチル基含有シクロプロパン類の調製が可能であることを見出し、本発明を完成させるに至った。
すなわち本発明は、文献公知の方法で調製される（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドを塩基で処理し、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィドを調製した後、銅粉末存在下、ジフェニルヨードニウム塩を反応させ、下記一般式（１）
As a result of intensive studies on a novel difluoromethyl group-introducing agent, the present inventors have found the difluoromethyl group-containing compound of the present invention. Furthermore, it has been found that difluoromethyl group-containing cyclopropanes can be easily prepared by reacting the compound with an electron-deficient methylene-containing compound, and the present invention has been completed.
That is, the present invention treats (3,3-difluoro-2-propenyl) phenyl sulfide prepared by a method known in the literature with a base to produce [(1E) -3,3-difluoro-1-propen-1-yl. After the phenyl sulfide was prepared, the diphenyl iodonium salt was reacted in the presence of copper powder, and the following general formula (1)
（式（１）中、Ｘはハロゲン原子、トリフルオロメタンスルホン酸又はヘキサフルオロリン酸を示し、Ｐｈはフェニル基を示す。）
で表される新規ジフルオロメチル基含有化合物及びその製造方法並びに、それを用いた下記一般式（２）
Ｒ1−ＣＨ2−Ｒ2 （２）
（式（２）中、Ｒ1及びＲ2は各々独立して、アセチル基、メトキシカルボニル基、エトキシカルボニル基、ベンジルオキシカルボニル基、エトキシエトキシカルボニル基、シアノ基、フェニルスルホニル基、アミノカルボニル基、ジエトキシホスホリル基、フェニルスルホニル基、４−メチルフェニルスルホニル基、ジフェニルイミノ基又は、Ｒ1とＲ2が結合して環を形成したＮ，Ｎ−ジメチル尿素ジカルボニル基を示す。）
で表わされる電子不足メチレン化合物を、塩基存在下で反応させ、下記一般式（３）
(In formula (1), X represents a halogen atom, trifluoromethanesulfonic acid or hexafluorophosphoric acid, and Ph represents a phenyl group.)
A novel difluoromethyl group-containing compound represented by the formula, a process for producing the same, and the following general formula (2) using the same
R 1 —CH 2 —R 2 (2)
(In the formula (2), R 1 and R 2 are each independently an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group, an ethoxyethoxycarbonyl group, a cyano group, a phenylsulfonyl group, an aminocarbonyl group, A diethoxyphosphoryl group, a phenylsulfonyl group, a 4-methylphenylsulfonyl group, a diphenylimino group, or an N, N-dimethylurea dicarbonyl group in which R 1 and R 2 are bonded to form a ring.
The electron-deficient methylene compound represented by the formula is reacted in the presence of a base, and the following general formula (3)
（式（３）中、Ｒ1及びＲ2は前記式（２）と同じである。）
で表わされるジフルオロメチル基含有シクロプロパン類の製造方法を提供するものである。
なお、本明細書において、Ｐｈはフェニル基を示す。
(In Formula (3), R 1 and R 2 are the same as those in Formula (2).)
The manufacturing method of the difluoromethyl group containing cyclopropane represented by these is provided.
In the present specification, Ph represents a phenyl group.
本発明により、電子材料原料や医農薬及び電子材料の合成原料として有用な、ジフルオロメチル基含有化合物が提案され、それを用いたジフルオロメチル基含有シクロプロパン類の製造方法が提供された。 INDUSTRIAL APPLICABILITY According to the present invention, a difluoromethyl group-containing compound useful as a raw material for electronic materials, medical pesticides and electronic materials has been proposed, and a method for producing difluoromethyl group-containing cyclopropanes using the same has been provided.
以下、本発明を詳細に説明する。
本発明の一般式（１）で表されるジフルオロメチル基含有化合物としては、具体的には、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム フルオリド、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム クロリド、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム ブロミド、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム ヨージド、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム トリフルオロメタンスルホナート、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム ヘキサフルオロホスフェートなどが挙げられる。
Hereinafter, the present invention will be described in detail.
Specific examples of the difluoromethyl group-containing compound represented by the general formula (1) of the present invention include [(1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium fluoride, [( 1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium chloride, [(1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium bromide, [(1E) -3 , 3-Difluoro-1-propen-1-yl] diphenylsulfonium iodide, [(1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium trifluoromethanesulfonate, [(1E) -3, 3-difluoro-1-propen-1-yl] diphenylsulfonium hexafluorophosphate, etc. .
本発明の一般式（１）で表されるジフルオロメチル基含有化合物の製造方法としては、文献公知の方法で調製される（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドを塩基で処理し、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィドを調製した後、銅粉末存在下、ジフェニルヨードニウム塩を反応させることにより製造するか、予め製造が容易なトリフルオロメタンスルホン酸塩を調製の後、塩交換反応により陰イオンを目的とするものに交換することによっても可能である。 As a method for producing a difluoromethyl group-containing compound represented by the general formula (1) of the present invention, (3,3-difluoro-2-propenyl) phenyl sulfide prepared by a method known in the literature is treated with a base, After preparing [(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide, it is produced by reacting diphenyliodonium salt in the presence of copper powder, or trifluoromethane which is easy to produce in advance. It is also possible to prepare the sulfonate and then exchange the anion for the desired one by a salt exchange reaction.
ここで、（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドを塩基で処理するに際し、十分に異性化できる程度の塩基性を有しておればよい。またジフェニルヨードニウム塩を反応させる際に用いられる銅粉末としては本発明の目的を達しうるものであれば特に制限なく用いることができる。
本発明の一般式（１）で表されるジフルオロメチル基含有化合物の製造原料である［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィドの製造は、文献公知の方法で調製される（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドを、（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドに対して１〜２０重量倍のＮ，Ｎ−ジメチルホルムアミドやジメチルスルホキシド等の非プロトン性溶媒中、水素化ナトリウム、水素化カリウム、ソジウムメトキシド、カリウムメトキシド、カリウム−ｔｅｒｔ−ブトキシド、カリウムヘキサメチルジシラジド、４−（ジメチルアミノ）ピリジン、１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（ＤＢＵ）、１，５−ジアザビシクロ［４．３．０］−５−ノネン等の塩基を（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドに対して、０．０１〜０．３０モル％使用し、０〜４０℃の温度範囲で０．５〜４時間反応させることにより調製可能であり、通常の後処理の後、褐色液体として得られる。
Here, when (3,3-difluoro-2-propenyl) phenyl sulfide is treated with a base, it is sufficient to have a basicity sufficient to allow sufficient isomerization. Moreover, as a copper powder used when making a diphenyl iodonium salt react, if the objective of this invention can be achieved, it can use without a restriction | limiting especially.
The production of [(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide, which is a raw material for producing the difluoromethyl group-containing compound represented by the general formula (1) of the present invention, is well known in the literature. The (3,3-difluoro-2-propenyl) phenyl sulfide prepared by the method is 1 to 20 times as much N, N-dimethylformamide or dimethyl as (3,3-difluoro-2-propenyl) phenyl sulfide. In aprotic solvents such as sulfoxide, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, potassium tert-butoxide, potassium hexamethyldisilazide, 4- (dimethylamino) pyridine, 1,8 -Diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0 A base such as -5-nonene is used in an amount of 0.01 to 0.30 mol% with respect to (3,3-difluoro-2-propenyl) phenyl sulfide, and 0.5 to 4 in a temperature range of 0 to 40 ° C. It can be prepared by reacting for a period of time and is obtained as a brown liquid after normal post-treatment.
本発明の一般式（１）で表されるジフルオロメチル基含有化合物を［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィドより調製する方法としては、１〜２０重量倍量の１，２−ジクロロエタン又はトルエン等の溶媒中、反応に具する［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィドに対して、０．８〜１．５モル量のジフェニルヨードニウム塩及び２．０〜１０．０モル量の銅粉末を、７０〜１１０℃の温度範囲で、１〜６時間反応させることにより調製可能であり、通常の後処理及びシリカゲルカラム精製により、白色固体として得られる。 The method for preparing the difluoromethyl group-containing compound represented by the general formula (1) of the present invention from [(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide is 1 to 20 weights. 0.8 to 1. with respect to [(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide in the reaction in a solvent such as double amount of 1,2-dichloroethane or toluene. It can be prepared by reacting 5 mol amount of diphenyliodonium salt and 2.0-10.0 mol amount of copper powder in the temperature range of 70-110 ° C. for 1-6 hours. Obtained as a white solid by column purification.
本発明の一般式（１）で表わされるジフルオロメチル基含有化合物を塩交換反応により調製する方法としては、例えば比較的調製が容易な［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム トリフルオロメタンスルホナートを１〜１００重量倍量のアセトニトリル等の溶媒中、１．０〜１．５モル倍量の該当する陰イオンのカリウム塩等を、０〜６０℃の温度範囲で、１〜６時間反応させることにより調製可能である。 As a method for preparing the difluoromethyl group-containing compound represented by the general formula (1) of the present invention by a salt exchange reaction, for example, [(1E) -3,3-difluoro-1-propene-1 is relatively easy to prepare. -Yl] diphenylsulfonium trifluoromethanesulfonate in a solvent such as acetonitrile in an amount of 1 to 100 times by weight, a 1.0 to 1.5 molar amount of a potassium salt of an anion, etc. at a temperature of 0 to 60 ° C. In the range, it can be prepared by reacting for 1 to 6 hours.
本発明において用いられる一般式（２）で表わされる電子不足メチレン化合物としては、具体的には例えば、フェニルスルホニルアセトニトリル、２−エトキシエチル シアノ酢酸、てジエチル（シアノメチル）リン酸エステル、マロン酸ジメチル、マロン酸ジエチル、マロン酸−ｎ−ブチル、マロン酸ジ−ｔｅｒｔ−ブチル、マロン酸ｔｅｒｔ−ブチルメチル、フェニルスルホニル酢酸メチル、マロン酸ジベンジル、ビス（フェニルスルホニル）メタン、１，３−ジメチルバルビツル酸等を挙げることができる。 Specific examples of the electron-deficient methylene compound represented by the general formula (2) used in the present invention include phenylsulfonylacetonitrile, 2-ethoxyethyl cyanoacetic acid, diethyl (cyanomethyl) phosphate ester, dimethyl malonate, Diethyl malonate, n-butyl malonate, di-tert-butyl malonate, tert-butyl methyl malonate, methyl phenylsulfonylacetate, dibenzyl malonate, bis (phenylsulfonyl) methane, 1,3-dimethylbarbituric acid, etc. Can be mentioned.
本発明において用いられる一般式（３）で表わされるジフルオロメチル基含有シクロプロパン類としては、具体的には例えば、１−（フェニルスルホニル）−２−（ジフルオロメチル）シアノプロパンカルボニトリル、エトキシエチル １−シアノ−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル、ジエチル ［１−シアノ−２−（ジフルオロメチル）シアノプロピル］ホスフェート、ｔｅｒｔ−ブチル １−メトキシカルボニル−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル、１−フェニルスルホニル−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル、ジベンジル ２−（ジフルオロメチル）シクロプロパンジカルボン酸エステル、１，１−ビス（フェニルスルホニル）−２−（ジフルオロメチル）シクロプロパン、５，７−ジメチル−１−（ジフルオロメチル）−５，７−ジアザスピロ［２，５］オクタン−４，６，８−トリオン等を挙げることができる。 Specific examples of the difluoromethyl group-containing cyclopropanes represented by the general formula (3) used in the present invention include 1- (phenylsulfonyl) -2- (difluoromethyl) cyanopropanecarbonitrile, ethoxyethyl 1 -Cyano-2- (difluoromethyl) cyclopropanecarboxylic acid ester, diethyl [1-cyano-2- (difluoromethyl) cyanopropyl] phosphate, tert-butyl 1-methoxycarbonyl-2- (difluoromethyl) cyclopropanecarboxylic acid Ester, 1-phenylsulfonyl-2- (difluoromethyl) cyclopropanecarboxylic acid ester, dibenzyl 2- (difluoromethyl) cyclopropanedicarboxylic acid ester, 1,1-bis (phenylsulfonyl) -2- (difluoromethyl) Le) cyclopropane, 5,7-dimethyl-1- (difluoromethyl) -5,7-diazaspiro [2,5] can be exemplified octane-4,6,8-trione, and the like.
本発明において用いられる一般式（３）で表わされるジフルオロメチル基含有シクロプロパン類の製造方法としては、一般式（２）で表わされる電子不足メチレン化合物類と、一般式（２）で表わされる電子不足メチレン化合物類に対して１．０〜１．５モル量の一般式（１）で表わされるジフルオロメチル基含有化合物及び１．０〜５．０モル倍量の炭酸ナトリウム又は炭酸カリウム等のアルカリを、１０〜２００重量倍量のアセトン等の溶媒中、０〜６０℃の温度範囲で、０．５〜４時間反応させることにより調製可能で、通常の後処理の後、シリカゲルカラムクロマトグラフィー等の公知の方法で精製することにより目的物のジフルオロメチル基含有シクロプロパン類を得ることができる。 The method for producing the difluoromethyl group-containing cyclopropane represented by the general formula (3) used in the present invention includes an electron-deficient methylene compound represented by the general formula (2) and an electron represented by the general formula (2). 1.0-1.5 mol amount of the difluoromethyl group-containing compound represented by the general formula (1) and 1.0-5.0 mol amount of alkali such as sodium carbonate or potassium carbonate with respect to the deficient methylene compounds. Can be prepared by reacting in a solvent such as acetone in an amount of 10 to 200 times by weight in a temperature range of 0 to 60 ° C. for 0.5 to 4 hours. After usual post-treatment, silica gel column chromatography, etc. The target difluoromethyl group-containing cyclopropane can be obtained by purifying by the known method.
以下実施例により本発明を具体的に説明するが、本発明はこれらの実施例のみに限定されるものではない。
なお、生成物の分析に当たっては、下記装置を使用した。
ＮＭＲ：バリアン社製ＮＭＲ Ｓｙｓｔｅｍ ４００ＨＦＸ
ＩＲ：パーキン・エルマー社製Ｓｐｅｃｔｒｕｍ ２０００ ＦＴ−ＩＲ ｓｐｅｃｔｒｏｍｅｔｅｒ
ＧＣ−ＭＳ：アジレント社製５９７５Ｃ ｓｐｅｃｔｒｏｍｅｔｅｒ
元素分析：ヤナコ社製ＣＨＮコーダー ＭＴ−６
〔参考例１〕 （３，３−ジフルオロ−２−プロペン−１−イル）フェニルスルフィド（４）の調製
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited only to these examples.
In the analysis of the product, the following apparatus was used.
NMR: Varian's NMR System 400HFX
IR: Spectrum 2000 FT-IR spectrometer manufactured by Perkin Elmer
GC-MS: 5975C spectrometer manufactured by Agilent
Elemental analysis: CHN coder MT-6 manufactured by Yanaco
[Reference Example 1] Preparation of (3,3-difluoro-2-propen-1-yl) phenyl sulfide (4)
撹拌子を備えた３００ｍＬの二口ナスフラスコを乾燥アルゴン置換後、水素化ナトリウム（５０％油性，１．５５ｇ，３８．２ｍｍｏｌ，１．５ｅｑ）を入れ、適当量のヘキサンで３回洗浄し鉱油を除いた後、１，４−ジオキサン（３０ｍＬ）を加え、超音波洗浄機を用い超音波で１０分間分散させた。次いで、ベンゼンチオール（３．０ｍＬ，２９．４ｍｍｏｌ）を添加し、５分程撹拌の後、３−ブロモ３，３−ジフルオロプロペン（４．５ｍＬ，４４．１ｍｍｏｌ，１．５ｅｑ）を添加し、撹拌しながら室温下、１時間反応を行った。反応終了後、反応液に飽和の塩化アンモニウム水溶液を添加、ヘキサン／酢酸エチル混合溶剤（３／１ ｖｏｌ／ｖｏｌ）で３回抽出、有機層を合わせて硫酸ナトリウム上で乾燥、ろ過、濃縮し、粗製物を得た。 A 300 mL two-necked eggplant flask equipped with a stir bar was substituted with dry argon, and then sodium hydride (50% oily, 1.55 g, 38.2 mmol, 1.5 eq) was added, washed three times with an appropriate amount of hexane, and mineral oil Then, 1,4-dioxane (30 mL) was added, and the mixture was dispersed with an ultrasonic wave for 10 minutes using an ultrasonic cleaner. Then, benzenethiol (3.0 mL, 29.4 mmol) was added, and after stirring for about 5 minutes, 3-bromo-3,3-difluoropropene (4.5 mL, 44.1 mmol, 1.5 eq) was added, The reaction was carried out at room temperature for 1 hour with stirring. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted three times with a hexane / ethyl acetate mixed solvent (3/1 vol / vol), the organic layers were combined, dried over sodium sulfate, filtered, concentrated, A crude product was obtained.
得られた粗製物は、シリカゲルｋラムクロマトグラフィー（ヘキサン）で精製し、目的物の（３，３−ジフルオロ−２−プロペン−１−イル）フェニルスルフィド（４）を無色透明液体として得た（５．３９ｇ，２９．４ｍｍｏｌ，収率９９％）。
なお、生成物は物性測定の結果、下記文献に記載の物性値と一致し目的物であることを確認した。
The obtained crude product was purified by silica gel k-ram chromatography (hexane) to obtain the desired product (3,3-difluoro-2-propen-1-yl) phenyl sulfide (4) as a colorless transparent liquid ( 5.39 g, 29.4 mmol, 99% yield).
As a result of measuring physical properties, the product was confirmed to be the target product in accordance with the physical property values described in the following documents.
Yuan-yao Xu, et. al., J. Fluorine Chem., 70(1995), 5-6。
〔参考例２〕 ［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィド（５）の調製
Yuan-yao Xu, et. Al., J. Fluorine Chem., 70 (1995), 5-6.
Reference Example 2 Preparation of [(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide (5)
撹拌子を備えた３００ｍＬの二口ナスフラスコを乾燥アルゴン置換後、参考例１で調製した（３，３−ジフルオロ−２−プロペニル）フェニルスルフィド（４）（５．３２ｇ，２８．６ｍｍｏｌ）及びジメチルスルホキシド（１０ｍＬ）を入れ、撹拌した。次いで、ｔｅｒｔ−ブトキシカリウム（１６３．２ｍｇ，１．４３ｍｍｏｌ，０．０５ｅｑ）を添加し、撹拌しながら室温下、１時間反応を行った。反応終了後、反応液に水を添加、ヘキサンで３回抽出、有機層を合わせて硫酸ナトリウム上で乾燥、ろ過、濃縮し、目的物の［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィド（５）を褐色液体として得た（４．９５ｇ，２６．６ｍｍｏｌ，収率９３％）。
ＩＲ（ＡＲＴ）：２９２５，１６１６，１３７６，１１３０，１０６０，１１０８，９３６，８２８，７４２，６９０ｃｍ-1。
１Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝７．４７−７．４１（ｍ，２Ｈ），７．４１−７．３４（ｍ，３Ｈ），６．８４（ｄｔｄ，Ｊ＝１５．３，３．２，０．６Ｈｚ，１Ｈ），６．０９（ｔｄｄ，Ｊ＝５６．２，５．５，０．６Ｈｚ，１Ｈ），５．６０−５．５３（ｍ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１３６．１（ｔ，Ｊ＝１２．４Ｈｚ），１３２．５，１３１．２，１２９．５，１２８．７，１１９．２（ｔ，Ｊ＝２４．９Ｈｚ），１１４．３（ｔ，Ｊ＝２３４．３Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１０．４（ｄｄｄ，Ｊ＝５６．０，８．３，３．６Ｈｚ，２Ｆ）。
ＧＣ−ＭＳ（ｍ/ｚ）：１８６（９２，Ｍ+），１６５（２５），１４７（１２），１３５（１００），１３４（１９），１０９（２１），９１（３５），７７（２５），６５（１２），５１（２４）。
A 300 mL two-necked eggplant flask equipped with a stir bar was substituted with dry argon, and then (3,3-difluoro-2-propenyl) phenyl sulfide (4) (5.32 g, 28.6 mmol) and dimethyl prepared in Reference Example 1 were used. Sulfoxide (10 mL) was added and stirred. Subsequently, tert-butoxy potassium (163.2 mg, 1.43 mmol, 0.05 eq) was added, and the reaction was performed at room temperature for 1 hour with stirring. After completion of the reaction, water was added to the reaction solution, extracted three times with hexane, and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to obtain the desired product [(1E) -3,3-difluoro-1-propene. -1-yl] phenyl sulfide (5) was obtained as a brown liquid (4.95 g, 26.6 mmol, 93% yield).
IR (ART): 2925, 1616, 1376, 1130, 1060, 1108, 936, 828, 742, 690 cm −1 .
1H-NMR (400 MHz): δ = 7.47-7.41 (m, 2H), 7.41-7.34 (m, 3H), 6.84 (dtd, J = 15.3, 3.2) , 0.6 Hz, 1H), 6.09 (tdd, J = 56.2, 5.5, 0.6 Hz, 1H), 5.60-5.53 (m, 1H).
13 C-NMR (100 MHz): δ = 136.1 (t, J = 12.4 Hz), 132.5, 131.2, 129.5, 128.7, 119.2 (t, J = 24.9 Hz) ), 114.3 (t, J = 234.3 Hz).
19 F-NMR (376 MHz): δ = −110.4 (ddd, J = 56.0, 8.3, 3.6 Hz, 2F).
GC-MS (m / z): 186 (92, M + ), 165 (25), 147 (12), 135 (100), 134 (19), 109 (21), 91 (35), 77 (25 ), 65 (12), 51 (24).
〔実施例１〕 ［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニ ルスルホニウム トリフルオロメタンスルホナート（６）の調製 Example 1 Preparation of [(1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium trifluoromethanesulfonate (6)
乾燥アルゴンで置換した３００ｍＬの二口ナスフラスコに、室温下、参考例２で調製した［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィド（５）（４．８３ｇ，２５．９ｍｍｏｌ，１．０５ｅｑ）及び１，２−ジクロロエタン（３０ｍＬ）を入れ、撹拌しながら溶解させた後、次いでこれにジフェニルヨードニウム トリフルオロメタンスルホナート（１０．６０ｇ，２４．７ｍｍｏｌ，１．０ｅｑ）及び銅粉末（７．９０ｇ，１２３．５ｍｍｏｌ，５．０ｅｑ）を添加した。油浴上で８０℃に加熱し、２時間反応を行った後、室温まで冷却、固形物をセライトろ過のよりろ別し、濃縮することにより粗製物を得た。得られた粗製物は、シリカゲルカラムクロマトグラフィー（ジクロロメタン→ジクロロメタン／アセトン＝２／１ ｖｏｌ／ｖｏｌ）で精製することにより、目的物（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム トリフルオロメタンスルホナート（６）を白色結晶として得た（９．６２ｇ，２４．３ｍｍｏｌ，収率９４％）。
融点：５１．３−５２．４℃。
ＩＲ（ＡＴＲ）：３０４６，１７０９，１４４８，１２５３，１１５１，１０２７，７４６，６８２，６２５，５７３，５１６，５００ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝７．９４−７．９０（ｍ，４Ｈ），７．８２（ｄｔ，Ｊ＝１４．８，２．３Ｈｚ，１Ｈ），７．７７−７．７２（ｍ，２Ｈ），７．７０−７．６５（ｍ，４Ｈ），７．０４−６．９０（ｍ，１Ｈ），６５．８（ｔｄ，Ｊ＝５４．０，４．３Ｈｚ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１４３．３（ｔ，Ｊ＝２６．４Ｈｚ），１３５．０，１３１．７，１３０．７，１２４．２， １２３．３（ｔ，Ｊ＝２４．１Ｈｚ），１２０．６（ｑ，Ｊ＝３２０．７Ｈｚ），１１１．０（ｔ，Ｊ＝２３９．８Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−７９．６（ｓ，３Ｆ），−１１７．５（ｄｄｄ，Ｊ＝５３．６，８．３，２．３Ｈｚ，２Ｆ）。
元素分析 計算値Ｃ，４６．６０、Ｈ，３．１８、測定値Ｃ，４６．６８，Ｈ，３．２３。
[(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide (5) (4.83 g) prepared in Reference Example 2 was added to a 300 mL two-necked eggplant flask substituted with dry argon at room temperature. , 25.9 mmol, 1.05 eq) and 1,2-dichloroethane (30 mL), dissolved with stirring, and then diphenyliodonium trifluoromethanesulfonate (10.60 g, 24.7 mmol, 1.0 eq). ) And copper powder (7.90 g, 123.5 mmol, 5.0 eq) were added. After heating to 80 ° C. on an oil bath and reacting for 2 hours, the mixture was cooled to room temperature, the solid was filtered off through celite, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (dichloromethane → dichloromethane / acetone = 2/1 vol / vol) to give the desired product (1E) -3,3-difluoro-1-propen-1-yl. Diphenylsulfonium trifluoromethanesulfonate (6) was obtained as white crystals (9.62 g, 24.3 mmol, 94% yield).
Melting point: 51.3-52.4 ° C.
IR (ATR): 3046, 1709, 1448, 1253, 1151, 1027, 746, 682, 625, 573, 516, 500 cm −1 .
1 H-NMR (400 MHz): δ = 7.94-7.90 (m, 4H), 7.82 (dt, J = 14.8, 2.3 Hz, 1H), 7.77-7.72 ( m, 2H), 7.70-7.65 (m, 4H), 7.04-6.90 (m, 1H), 65.8 (td, J = 54.0, 4.3 Hz, 1H).
13 C-NMR (100 MHz): δ = 143.3 (t, J = 26.4 Hz), 135.0, 131.7, 130.7, 124.2, 123.3 (t, J = 24.1 Hz) ), 120.6 (q, J = 320.7 Hz), 111.0 (t, J = 239.8 Hz).
19 F-NMR (376 MHz): δ = −79.6 (s, 3F), −117.5 (ddd, J = 53.6, 8.3, 2.3 Hz, 2F).
Elemental analysis Calculated value C, 46.60, H, 3.18, measured value C, 46.68, H, 3.23.
〔実施例２〕 ［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム ヘキサフルオロホスフェート（７）の調製 Example 2 Preparation of [(1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium hexafluorophosphate (7)
アルゴン気流下、撹拌子を備えた５０ｍｌのナフ型二口フラスコに、実施例１で調製した［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム トリフルオロメタンスルホナート（６）（４３３ｍｇ，１．０５ｍｍｏｌ，１．０５ｅｑ．）及びアセトニトリル（４ｍＬ）を入れ、溶解させた後、次いで、カリウム ヘキサフルオロホスフェート（１８４ｍｇ，１．００ｍｍｏｌ）を添加し、室温下、２時間反応を行った。反応終了後、濃縮し得られた残査をシリカゲルカラムクロマトグラフィー（ジクロロメタン／アセトン＝２／１ ｖｏｌ／ｖｏｌ）で精製し、目的物の［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム ヘキサフルオロホスフェート（７）を白色固体として得た（３９４．６ｍｇ，０．９６０ｍｍｏｌ，収率９６％）。
白色結晶。
融点：９２．５−９３．７℃。
ＩＲ（ＡＴＲ）：３０７８，１４４９，１３５９，１１３４，１０５３，８４２，８２２，７４６，７３０，５５５ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝７．９０（ｄ，Ｊ＝７．５Ｈｚ，４Ｈ），７．８３（ｔ，Ｊ＝７．４Ｈｚ，４Ｈ），７．７５（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝１５．１Ｈｚ，１Ｈ），６．８９（ｍ，１Ｈ），６．５５（ｔ，Ｊ＝５３．９Ｈｚ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１４３．１（ｔ，Ｊ＝２４．９Ｈｚ），１３４．９，１３１．６，１３０．４，１２３．４，１２２．１（ｔ，Ｊ＝１１．６Ｈｚ），１１０．６（ｔ，Ｊ＝２３９．８Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−７３．２（ｄ，Ｊ＝７１．４Ｈｚ，６Ｆ），−１１８．９（ｄ，Ｊ＝７．１Ｈｚ，１Ｆ），−１１９．１（ｄ，Ｊ＝７．２Ｈｚ，1Ｈ）。
[(1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium trifluoromethanesulfonate (prepared in Example 1) was added to a 50 ml naphth type two-necked flask equipped with a stir bar under an argon stream. 6) (433 mg, 1.05 mmol, 1.05 eq.) And acetonitrile (4 mL) were added and dissolved, then potassium hexafluorophosphate (184 mg, 1.00 mmol) was added, and the reaction was performed at room temperature for 2 hours. Went. After completion of the reaction, the residue obtained by concentration was purified by silica gel column chromatography (dichloromethane / acetone = 2/1 vol / vol), and the desired product [(1E) -3,3-difluoro-1-propene- 1-yl] diphenylsulfonium hexafluorophosphate (7) was obtained as a white solid (394.6 mg, 0.960 mmol, 96% yield).
White crystals.
Melting point: 92.5-93.7 ° C.
IR (ATR): 3078, 1449, 1359, 1134, 1053, 842, 822, 746, 730, 555 cm −1 .
1 H-NMR (400 MHz): δ = 7.90 (d, J = 7.5 Hz, 4H), 7.83 (t, J = 7.4 Hz, 4H), 7.75 (t, J = 7. 5 Hz, 2H), 7.53 (d, J = 15.1 Hz, 1H), 6.89 (m, 1H), 6.55 (t, J = 53.9 Hz, 1H).
13 C-NMR (100 MHz): δ = 143.1 (t, J = 24.9 Hz), 134.9, 131.6, 130.4, 123.4, 122.1 (t, J = 11.6 Hz) ), 110.6 (t, J = 239.8 Hz).
19 F-NMR (376 MHz): δ = −73.2 (d, J = 71.4 Hz, 6F), −118.9 (d, J = 7.1 Hz, 1F), −119.1 (d, J = 7.2 Hz, 1H).
〔実施例３〕 １−（フェニルスルホニル）−２−（ジフルオロメチル）シクロプロパンカルボニトリル（８）の調製 Example 3 Preparation of 1- (phenylsulfonyl) -2- (difluoromethyl) cyclopropanecarbonitrile (8)
撹拌子を備えた２５ｍＬの丸底フラスコに、室温、大気下、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）、塩基として炭酸カリウム（１２４．４ｍｇ，０．９ｍｍｏｌ，３．０ｅｑ）及びアセトン（３．０ｍＬ）を仕込み、溶解させた後、次いでこれに実施例１で調製した（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］ジフェニルスルホニウム トリフルオロメタンスルホナート（６）（１２９．９０ｍｇ，０．３１５ｍｍｏｌ，１．０５ｅｑ）を添加し、１時間反応を行った。 To a 25 mL round bottom flask equipped with a stir bar, at room temperature and in the atmosphere, phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol), potassium carbonate (124.4 mg, 0.9 mmol, 3.0 eq) and acetone (base) 3.0 mL) was prepared and dissolved, and then (1E) -3,3-difluoro-1-propen-1-yl] diphenylsulfonium trifluoromethanesulfonate (6) (129) prepared in Example 1 was added thereto. .90 mg, 0.315 mmol, 1.05 eq) was added and the reaction was carried out for 1 hour.
反応終了後、反応液をセライトろ過により固形物をろ別、濃縮し、粗製物を得た。
得られた粗製物は、シリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝１／１ ｖｏｌ／ｖｏｌ）で精製し、目的物の１−（フェニルスルホニル）−２−（ジフルオロメチル）シクロプロパンカルボニトリル（８）を白色固体として得た（７３．０ｍｇ，０．２８３ｍｍｏｌ，収率９８％）。
融点：６２．８−６３．１℃。
ＩＲ（ＡＴＲ）：３１０９，３０４８，２２４８，２２３６，１９７７，１３３４，１１４６，１０７８，１０５５，７６２，７２８，６８５，６０８，５６１ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝８．０２−７．９６（ｍ，２Ｈ），７．８３−７．７５（ｍ，１Ｈ），７．７１−７．６４（ｍ，２Ｈ），５．８３（ｔｄ，Ｊ＝５４．８，４．３Ｈｚ，１Ｈ），２．７１−２．６３（ｍ，１Ｈ），２．２２−２．１５（ｍ，１Ｈ），１．９２（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１３６．０，１３５．５，１２９．９，１２９．０，１１２．８，１１２．５（ｔ，Ｊ＝２４２．９Ｈｚ），３５．１（ｄ，Ｊ＝３．２Ｈｚ），２８．０（ｔ，Ｊ＝３０．４Ｈｚ），１６．５（ｔ，Ｊ＝４．７Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１５．８（ｄｄｄ，Ｊ＝２９５．７，５４．９，９．８Ｈｚ，１Ｆ），
−１１８．８（ｄｄｄ，Ｊ＝２９５．６，５６．０，９．５Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：２５７（１７，Ｍ+），１４３（４），１４２（７），１４１（８５），７７（１００），５１（２５），５０（６）。
元素分析 計算値Ｃ，５１．３６、Ｈ，３．５３、Ｎ，５．４４、測定値Ｃ，５１．３９，Ｈ，３．２３、Ｎ，５．４２。
After completion of the reaction, the reaction mixture was filtered through celite and the solid was filtered and concentrated to obtain a crude product.
The obtained crude product was purified by silica gel column chromatography (hexane / diethyl ether = 1/1 vol / vol), and the desired product 1- (phenylsulfonyl) -2- (difluoromethyl) cyclopropanecarbonitrile (8 ) Was obtained as a white solid (73.0 mg, 0.283 mmol, 98% yield).
Melting point: 62.8-63.1 ° C.
IR (ATR): 3109, 3048, 2248, 2236, 1977, 1334, 1146, 1078, 1055, 762, 728, 685, 608, 561 cm −1 .
1 H-NMR (400 MHz): δ = 8.02-7.96 (m, 2H), 7.83-7.75 (m, 1H), 7.71-7.64 (m, 2H), 5 .83 (td, J = 54.8, 4.3 Hz, 1H), 2.71-2.63 (m, 1H), 2.22-2.15 (m, 1H), 1.92 (t, J = 6.8 Hz, 1H).
13 C-NMR (100 MHz): δ = 136.0, 135.5, 129.9, 129.0, 112.8, 112.5 (t, J = 242.9 Hz), 35.1 (d, J = 3.2 Hz), 28.0 (t, J = 30.4 Hz), 16.5 (t, J = 4.7 Hz).
19 F-NMR (376 MHz): δ = −115.8 (ddd, J = 295.7, 54.9, 9.8 Hz, 1F),
-118.8 (ddd, J = 295.6, 56.0, 9.5 Hz, 1F).
GC-MS (m / z): 257 (17, M + ), 143 (4), 142 (7), 141 (85), 77 (100), 51 (25), 50 (6).
Elemental analysis Calculated values C, 51.36, H, 3.53, N, 5.44, measured values C, 51.39, H, 3.23, N, 5.42.
〔実施例４〕 エトキシエチル １−シアノ−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル（９）の調製 [Example 4] Preparation of ethoxyethyl 1-cyano-2- (difluoromethyl) cyclopropanecarboxylic acid ester (9)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えて２−エトキシエチル シアノ酢酸を（４２．１μＬ，０．２９ｍｍｏｌ）を用いた以外、実施例２と同じ操作により粗製物を得、次いでシリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝１／１ ｖｏｌ／ｖｏｌ）で単離精製し、目的物のエトキシエチル １−シアノ−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル（９）を無色透明液体として得た（６１．５ｍｇ，０．２６４ｍｍｏｌ、収率９１％）。
ＩＲ（ＡＴＲ）：２９７８，２８７４，２２５２，１７４０，１２９３，１１７６，１１０３，１０４３，８６２，７５９ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝５．８１（ｔｄ，Ｊ＝４８．５，５．２Ｈｚ，１Ｈ），４．４８−４．２２（ｍ，２Ｈ），３７．１（ｔ，Ｊ＝３．４Ｈｚ，２Ｈ），３．５７，３．６２−３．４３（ｍ，２Ｈ），２．５８−２．４８（ｍ，１Ｈ），２．０２−１．９５（ｍ，１Ｈ），１．８５（ｔ，Ｊ＝６．５Ｈｚ，１Ｈ），１．２３（ｔ，Ｊ＝５．７Ｈｚ，３Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１６５．６，１１４．７（ｔ，Ｊ＝２４０．６Ｈｚ），１１３．８，６７．３，６６．５，６６．４，３０．０（ｔ，Ｊ＝３０．３Ｈｚ），１９．３（ｔ，Ｊ＝２．３Ｈｚ），１６．７（ｄ，Ｊ＝６．２Ｈｚ），１４．８。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１３．９（ｄｄ，Ｊ＝２９６．９，５４．９Ｈｚ，１Ｆ），−１１８．０（ｄｄ，Ｊ＝２９４．４，５４．８Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：１８８（３３），１６２（８），１４４（２６），１１６（１９），８９（１０），８０（１２），７２（２８），５９（１００），５１（９）。
Same as Example 2 except that 2-ethoxyethyl cyanoacetic acid (42.1 μL, 0.29 mmol) was used instead of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol) in the same reactor as in Example 3. The crude product was obtained by the operation, and then isolated and purified by silica gel column chromatography (hexane / diethyl ether = 1/1 vol / vol), and the desired product ethoxyethyl 1-cyano-2- (difluoromethyl) cyclopropanecarboxylic acid The ester (9) was obtained as a colorless transparent liquid (61.5 mg, 0.264 mmol, 91% yield).
IR (ATR): 2978, 2874, 2252, 1740, 1293, 1176, 1103, 1043, 862, 759 cm −1 .
1 H-NMR (400 MHz): δ = 5.81 (td, J = 48.5, 5.2 Hz, 1H), 4.48-4.22 (m, 2H), 37.1 (t, J = 3.4 Hz, 2H), 3.57, 3.62-3.43 (m, 2H), 2.58-2.48 (m, 1H), 2.02-1.95 (m, 1H), 1.85 (t, J = 6.5 Hz, 1H), 1.23 (t, J = 5.7 Hz, 3H).
13 C-NMR (100 MHz): δ = 165.6, 114.7 (t, J = 240.6 Hz), 113.8, 67.3, 66.5, 66.4, 30.0 (t, J = 30.3 Hz), 19.3 (t, J = 2.3 Hz), 16.7 (d, J = 6.2 Hz), 14.8.
19 F-NMR (376 MHz): δ = −113.9 (dd, J = 296.9, 54.9 Hz, 1F), −118.0 (dd, J = 294.4, 54.8 Hz, 1F).
GC-MS (m / z): 188 (33), 162 (8), 144 (26), 116 (19), 89 (10), 80 (12), 72 (28), 59 (100), 51 (9).
〔実施例５〕 ジエチル ［１−シアノ−２−（ジフルオロメチル）シクロプロピル］ホスフェート（１０）の調製 Example 5 Preparation of diethyl [1-cyano-2- (difluoromethyl) cyclopropyl] phosphate (10)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えてジエチル （シアノメチル）リン酸エステル（４７．２μＬ，０．２９ｍｍｏｌ）を用いた以外、実施例２と同じ操作により粗製物を得、次いでシリカゲルカラムクロマトグラフィー（ジクロロメタン／アセトン＝１０／１ ｖｏｌ／ｖｏｌ）で単離精製し、目的物のジエチル ［１−シアノ−２−（ジフルオロメチル）シアノプロピル］ホスフェート（１０）を無色透明液体として得た（５７．４ｍｇ，０．１５４ｍｍｏｌ、収率５３％）。
ＩＲ（ＡＴＲ）：２９８８，２９２０，２２４１，１２６３，１１６５，１１００，１０１２，９８２，７９６，６０２，５５３ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝５．７９（ｔｄ，Ｊ＝５４．７，５．６Ｈｚ，１Ｈ），４．２６（ｑｕｉｎ，Ｊ＝７．０Ｈｚ，４Ｈ），２．４４−２．２９（ｍ，１Ｈ），１．８９−１．８０（ｍ，１Ｈ），１．７４−１．６６（ｍ，１Ｈ），１．４６−１．３８（ｍ，６Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１１５．４，１１４．４（ｔｄ，Ｊ＝２４０．５，２．４Ｈｚ），６４．４（ｔ，Ｊ＝６．２Ｈｚ），２６．１（ｔ，Ｊ＝３０．４Ｈｚ），１６．２（ｔ，Ｊ＝５．１Ｈｚ），１５．３（ｑｕｉｎ，Ｊ＝３．１Ｈｚ），８．３１（ｄｄ，Ｊ＝１９５．４，３．９Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１４．２（ｄｄｄ，Ｊ＝２９４．５，５４．９，９．６Ｈｚ，１Ｆ），−１１６．８（ｄｄｄ，Ｊ＝２９３．２，５４．８，６．０Ｈｚ，１Ｈ）。
ＧＣ−ＭＳ（ｍ／ｚ）：２２６（７７），１９８（１００），１８０（５３），１７８（２４），１５７（３６），１４６（３５），１３２（１３），１１６（１８），１０９（４９），９７（２０），８１（４２），６５（１７）。
Same as Example 2, except that diethyl (cyanomethyl) phosphate (47.2 μL, 0.29 mmol) was used in the same reactor as in Example 3 instead of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol). The crude product was obtained by the operation, followed by isolation and purification by silica gel column chromatography (dichloromethane / acetone = 10/1 vol / vol), and the target diethyl [1-cyano-2- (difluoromethyl) cyanopropyl] phosphate ( 10) was obtained as a colorless transparent liquid (57.4 mg, 0.154 mmol, yield 53%).
IR (ATR): 2988, 2920, 2241, 1263, 1165, 1100, 1012, 982, 796, 602, 553 cm −1 .
1 H-NMR (400 MHz): δ = 5.79 (td, J = 54.7, 5.6 Hz, 1H), 4.26 (quin, J = 7.0 Hz, 4H), 2.44-2. 29 (m, 1H), 1.89-1.80 (m, 1H), 1.74-1.66 (m, 1H), 1.46-1.38 (m, 6H).
13 C-NMR (100 MHz): δ = 115.4, 114.4 (td, J = 240.5, 2.4 Hz), 64.4 (t, J = 6.2 Hz), 26.1 (t, J = 30.4 Hz), 16.2 (t, J = 5.1 Hz), 15.3 (quin, J = 3.1 Hz), 8.31 (dd, J = 195.4, 3.9 Hz).
19 F-NMR (376 MHz): δ = −114.2 (ddd, J = 294.5, 54.9, 9.6 Hz, 1F), −116.8 (ddd, J = 293.2, 54.8) , 6.0 Hz, 1H).
GC-MS (m / z): 226 (77), 198 (100), 180 (53), 178 (24), 157 (36), 146 (35), 132 (13), 116 (18), 109 (49), 97 (20), 81 (42), 65 (17).
〔実施例６〕 ｔｅｒｔ−ブチル １−メトキシカルボニル−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル（１１）の調製 Example 6 Preparation of tert-butyl 1-methoxycarbonyl-2- (difluoromethyl) cyclopropanecarboxylic acid ester (11)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えてマロン酸ｔｅｒｔ−ブチルメチル（４９．０μＬ，０．２９ｍｍｏｌ）を用いた以外、実施例２と同じ操作により粗製物を得、次いでシリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝５／１ ｖｏｌ／ｖｏｌ）で単離精製し、目的物のｔｅｒｔ−ブチル １−メトキシカルボニル−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル（１１）を無色透明液体として得た（６７．３ｍｇ，０．２８７ｍｍｏｌ、収率９９％）。
ＩＲ（ＡＴＲ）：２９８１，１７０５，１３７０，１３２８，１２５２，１２１０，１１６０，１２２２，１０９１，１０４２，８４０ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝５．６９（ｔｄ，Ｊ＝５５．８Ｈｚ，１Ｈ），２．４０（ｓ，３Ｈ），２．４２−２．２９（ｍ，１Ｈ），１．７１−１．６５（ｍ，１Ｈ），１．５１（ｓ，９Ｈ），１．４４−１．３８（ｍ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝２００．６，１６７．１，１１５．１（ｄｄ，Ｊ＝２３７．４，２３６．６Ｈｚ），８３．４，３９．９（ｄ，Ｊ＝４．７Ｈｚ），２８．９４，２８．９０（ｔ，Ｊ＝３０．４Ｈｚ），２７．８，１８．１（ｄｄ，Ｊ＝６．２，１．５Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１０．９（ｄｄ，Ｊ＝２９３．２，５７．１Ｈｚ，１Ｆ），−１１６．９（ｄｄｄ，Ｊ＝２９２．１，５６．０，１０．７Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：１７９（２９），１６１（６３），１１９（２９），１１４（１５），９０（７），５７（１００）。
By the same operation as in Example 2, except that tert-butylmethyl malonate (49.0 μL, 0.29 mmol) was used instead of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol) in the same reaction apparatus as in Example 3. A crude product was obtained, and then isolated and purified by silica gel column chromatography (hexane / diethyl ether = 5/1 vol / vol) to obtain the desired product, tert-butyl 1-methoxycarbonyl-2- (difluoromethyl) cyclopropanecarboxylic acid. The ester (11) was obtained as a colorless transparent liquid (67.3 mg, 0.287 mmol, 99% yield).
IR (ATR): 2981, 1705, 1370, 1328, 1252, 1210, 1160, 1222, 1091, 1042, 840 cm −1 .
1 H-NMR (400 MHz): δ = 5.69 (td, J = 55.8 Hz, 1H), 2.40 (s, 3H), 2.42-2.29 (m, 1H), 1.71 -1.65 (m, 1H), 1.51 (s, 9H), 1.44-1.38 (m, 1H).
13 C-NMR (100 MHz): δ = 200.6, 167.1, 115.1 (dd, J = 237.4, 236.6 Hz), 83.4, 39.9 (d, J = 4.7 Hz) ), 28.94, 28.90 (t, J = 30.4 Hz), 27.8, 18.1 (dd, J = 6.2, 1.5 Hz).
19 F-NMR (376 MHz): δ = −110.9 (dd, J = 293.2, 57.1 Hz, 1F), −116.9 (ddd, J = 292.1, 56.0, 10.7 Hz) , 1F).
GC-MS (m / z): 179 (29), 161 (63), 119 (29), 114 (15), 90 (7), 57 (100).
〔実施例７〕 １−フェニルスルホニル−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル（１２）の調製 Example 7 Preparation of 1-phenylsulfonyl-2- (difluoromethyl) cyclopropanecarboxylic acid ester (12)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えてフェニルスルホニル酢酸メチル（７４．７μＬ，０．４５ｍｍｏｌ）を用い、他の試剤を１．５５倍のスケールで用いた以外、実施例２と同じ操作により粗製物を得、次いで、シリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝１／１ ｖｏｌ／ｖｏｌ）で単離精製することにより目的物の１−フェニルスルホニル−２−（ジフルオロメチル）シクロプロパンカルボン酸エステル（１２）を無色透明液体として得た（１１２．５ｍｇ，０．３８７ｍｍｏｌ，収率８６％）。
ＩＲ（ＡＴＲ）：２９５９，１７３６，１４４７，１３１０，１１３５，１０８２，１０４８，９２９，７４３，６８６，６０２，５６４ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝７９．４（ｄ，Ｊ＝７．４Ｈｚ，２Ｈ），７５．８（ｔ，Ｊ＝７．４Ｈｚ，２Ｈ），５７．７（ｔｄ，Ｊ＝５５．５，６．４Ｈｚ，１Ｈ），３．６８（ｓ，３Ｈ），２．７８−２．６６（ｍ，１Ｈ），２．３２−２．２４（ｍ，１Ｈ），２．１７（ｓ，１Ｈ），２．０６−１．９９（ｍ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１６４．８，１３８．８，１３４．１，１２９．０，１２８．９，１１３．９（ｔ，Ｊ＝２３８．２Ｈｚ），５３．３，４７．４（ｔ，Ｊ＝６．２Ｈｚ），２９．６（ｄｄ，Ｊ＝３５．８，３０．３Ｈｚ），１６．２（ｄ，Ｊ＝７．０Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１１．５（ｄｄ，Ｊ＝２９６．８，５４．８Ｈｚ，１Ｆ），−１１７．２（ｄｄｄ，Ｊ＝２９６．８，５４．８，１０．７Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：２５９（１０），２２６（２４），１７５（６），１５９（１８），１４７（２９），１４１（２０），１２５（１２），７７（１００），５９（１２），５１（２５）。
In the same reactor as in Example 3, methyl phenylsulfonylacetate (74.7 μL, 0.45 mmol) was used instead of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol), and other reagents were scaled 1.55 times. The crude product was obtained in the same manner as in Example 2 except that it was used in Step 1. Then, the product was isolated and purified by silica gel column chromatography (hexane / diethyl ether = 1/1 vol / vol) to obtain the target 1-phenylsulfonyl. -2- (Difluoromethyl) cyclopropanecarboxylic acid ester (12) was obtained as a colorless transparent liquid (112.5 mg, 0.387 mmol, yield 86%).
IR (ATR): 2959, 1736, 1447, 1310, 1135, 1082, 1048, 929, 743, 686, 602, 564 cm −1 .
1 H-NMR (400 MHz): δ = 79.4 (d, J = 7.4 Hz, 2H), 75.8 (t, J = 7.4 Hz, 2H), 57.7 (td, J = 55. 5,6.4 Hz, 1H), 3.68 (s, 3H), 2.78-2.66 (m, 1H), 2.32-2.24 (m, 1H), 2.17 (s, 1H), 2.06-1.99 (m, 1H).
13 C-NMR (100 MHz): δ = 164.8, 138.8, 134.1, 129.0, 128.9, 113.9 (t, J = 238.2 Hz), 53.3, 47.4 (T, J = 6.2 Hz), 29.6 (dd, J = 35.8, 30.3 Hz), 16.2 (d, J = 7.0 Hz).
19 F-NMR (376 MHz): δ = −111.5 (dd, J = 296.8, 54.8 Hz, 1F), −117.2 (ddd, J = 296.8, 54.8, 10.7 Hz) , 1F).
GC-MS (m / z): 259 (10), 226 (24), 175 (6), 159 (18), 147 (29), 141 (20), 125 (12), 77 (100), 59 (12), 51 (25).
〔実施例８〕 ジベンジル ２−（ジフルオロメチル）シクロプロパンジカルボン酸エステル（１３）の調製 Example 8 Preparation of dibenzyl 2- (difluoromethyl) cyclopropanedicarboxylic acid ester (13)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えてマロン酸ジベンジル（７１．７μＬ，０．３ｍｍｏｌ）を用い、他の試剤を１．０７倍のスケールで用いた以外、実施例２と同じ操作により粗製物を得、次いで、シリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝３／１ ｖｏｌ／ｖｏｌ）で単離精製することにより目的物のジベンジル ２−（ジフルオロメチル）シクロプロパンジカルボン酸エステル（１３）を無色透明液体として得た（９９．９ｍｇ，０．２９１ｍｍｏｌ，収率９４％）。
ＩＲ（ＡＴＲ）：３０３６，２９５８，１７２６，１４５６，１３７９，１３１５，１２６６，１１９８，１１２７，１０９６，１０３２，９６１，９０５，７３６，６９５，５８４ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝７．４０−７．２０（ｍ，１０Ｈ），５．６９（ｔｄ，Ｊ＝５５．７，５．２Ｈｚ，１Ｈ），５．２２−５．０９（ｍ，４Ｈ），２．４５−２．３４（ｍ，１Ｈ），１．８０（ｔｄ，Ｊ＝５．５，１．２Ｈｚ，１Ｈ），１．６２−１．５４（ｍ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１６７．８，１６６．１，１３４．６０，１３４．５６，１２８．３，１２８．２，１２８．１４，１２８．１２，１２８．０，１２７．８，１１４．０（ｔ，Ｊ＝２３８．２Ｈｚ），６７．７，６７．５，３２．０（ｄｄ，Ｊ＝５．４，２．４Ｈｚ），２８．０（ｔ，Ｊ＝３１．１Ｈｚ），１５．９（ｑ，Ｊ＝３．１Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１１２．４（ｄｄ，Ｊ＝２９２．０，５６．０Ｈｚ，１Ｆ），−１１８．７（ｄｄｄ，Ｊ＝２９２．１，５６．０，１０．７Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：２６９（９），１８０（６），１６３（５４），１２３（５），１１９（５），１０７（５５），９２（１０），９１（１００），７７（６），６５（１１），５１（３）。
In the same reactor as in Example 3, dibenzyl malonate (71.7 μL, 0.3 mmol) was used instead of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol), and other reagents were scaled at 1.07 times. The crude product was obtained by the same operation as in Example 2 except that it was used, and then isolated and purified by silica gel column chromatography (hexane / diethyl ether = 3/1 vol / vol) to obtain the target dibenzyl 2- (difluoro Methyl) cyclopropanedicarboxylic acid ester (13) was obtained as a colorless transparent liquid (99.9 mg, 0.291 mmol, 94% yield).
IR (ATR): 3036, 2958, 1726, 1456, 1379, 1315, 1266, 1198, 1127, 1096, 1032, 961, 905, 736, 695, 584 cm −1 .
1 H-NMR (400 MHz): δ = 7.40-7.20 (m, 10H), 5.69 (td, J = 55.7, 5.2 Hz, 1H), 5.22-5.09 ( m, 4H), 2.45-2.34 (m, 1H), 1.80 (td, J = 5.5, 1.2 Hz, 1H), 1.62-1.54 (m, 1H).
13 C-NMR (100 MHz): δ = 167.8, 166.1, 134.60, 134.56, 128.3, 128.2, 128.14, 128.12, 128.0, 127.8, 114.0 (t, J = 238.2 Hz), 67.7, 67.5, 32.0 (dd, J = 5.4, 2.4 Hz), 28.0 (t, J = 31.1 Hz) , 15.9 (q, J = 3.1 Hz).
19 F-NMR (376 MHz): δ = −112.4 (dd, J = 292.0, 56.0 Hz, 1F), −118.7 (ddd, J = 292.1, 56.0, 10.7 Hz) , 1F).
GC-MS (m / z): 269 (9), 180 (6), 163 (54), 123 (5), 119 (5), 107 (55), 92 (10), 91 (100), 77 (6), 65 (11), 51 (3).
〔実施例９〕 １，１−ビス（フェニルスルホニル）−２−（ジフルオロメチル）シクロプロパン（１４）の調製 Example 9 Preparation of 1,1-bis (phenylsulfonyl) -2- (difluoromethyl) cyclopropane (14)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えてビス（フェニルスルホニル）メタン（９１．９ｍｇ，０．３ｍｍｏｌ）を用い、他の試剤を１．０３倍のスケールで用いた以外、実施例２と同じ操作により粗製物を得、次いで、シリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝１／１ ｖｏｌ／ｖｏｌ）で単離精製することにより目的物の１，１−ビス（フェニルスルホニル）−２−（ジフルオロメチル）シクロプロパン（１４）を無色透明液体として得た（１１２．２ｍｇ，０．２９１ｍｍｏｌ，収率９７％）。
ＩＲ（ＡＴＲ）：３１０４，３０７０，１７３０，１４４８，１３２５，１２４３，１１５５，１０５０，９５０，７９１，７４９，７２２，６１３ｃｍ-1。
1Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝７．９８（ｄ，Ｊ＝７．６Ｈｚ，２Ｈ），７．９１（ｄ，Ｊ＝７．５Ｈｚ，２Ｈ），７．７４−７．６８（ｍ，２Ｈ），７．５９−７．５５（ｍ，４Ｈ），６．４０（ｔｄ，Ｊ＝５４．８，７．３Ｈｚ，１Ｈ），２．９４−２．８０（ｍ，１Ｈ），２．３８−２．３１（ｍ，１Ｈ），２．３０−２．２４（ｍ，１Ｈ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１３８．７，１３７．６，１３４．８，１３４．６，１２９．５，１２９．３，１２９．０，１２８．９，１１３．４（ｄｄ，Ｊ＝２４０．６，２３６．７Ｈｚ），６１．８（ｄ，Ｊ＝７．８Ｈｚ），３２．３（ｄｄ，Ｊ＝３９．７，３２．７Ｈｚ），１６．９（ｔ，Ｊ＝７．０Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）：δ＝−１０８．２（ｄｄｄ，Ｊ＝３００．４，５４．８，３．６Ｈｚ，１Ｆ），−１１１．２（ｄｄｄｄ，Ｊ＝２９９．２，５４．９，１１．９，３．６Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：３０８（６），１８３（１３），１６７（１１），１６３（１７），１４７（１５），１４１（２３），１２５（４５），１０５（９），９７（１０），７７（１００）。
In the same reactor as in Example 3, bis (phenylsulfonyl) methane (91.9 mg, 0.3 mmol) was used instead of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol), and other reagents were added 1.03 times. The crude product was obtained in the same manner as in Example 2 except that it was used at a scale of 1, and then isolated and purified by silica gel column chromatography (hexane / diethyl ether = 1/1 vol / vol). 1-bis (phenylsulfonyl) -2- (difluoromethyl) cyclopropane (14) was obtained as a colorless transparent liquid (112.2 mg, 0.291 mmol, yield 97%).
IR (ATR): 3104, 3070, 1730, 1448, 1325, 1243, 1155, 1050, 950, 791, 749, 722, 613 cm- 1 .
1 H-NMR (400 MHz): δ = 7.98 (d, J = 7.6 Hz, 2H), 7.91 (d, J = 7.5 Hz, 2H), 7.74-7.68 (m, 2H), 7.59-7.55 (m, 4H), 6.40 (td, J = 54.8, 7.3 Hz, 1H), 2.94-2.80 (m, 1H), 2. 38-2.31 (m, 1H), 2.30-2.24 (m, 1H).
13 C-NMR (100 MHz): δ = 138.7, 137.6, 134.8, 134.6, 129.5, 129.3, 129.0, 128.9, 113.4 (dd, J = 240.6, 236.7 Hz), 61.8 (d, J = 7.8 Hz), 32.3 (dd, J = 39.7, 32.7 Hz), 16.9 (t, J = 7.0 Hz) ).
19 F-NMR (376 MHz): δ = −108.2 (ddd, J = 300.4, 54.8, 3.6 Hz, 1F), −111.2 (dddd, J = 299.2, 54.9) 11.9, 3.6 Hz, 1F).
GC-MS (m / z): 308 (6), 183 (13), 167 (11), 163 (17), 147 (15), 141 (23), 125 (45), 105 (9), 97 (10), 77 (100).
〔実施例１０〕 ５，７−ジメチル−１−（ジフルオロメチル）−５，７−ジアザスピロ［２，５］オクタン−４，６，８−トリオン（１５）の調製 Example 10 Preparation of 5,7-dimethyl-1- (difluoromethyl) -5,7-diazaspiro [2,5] octane-4,6,8-trione (15)
実施例３と同じ反応装置に、フェニルスルホニルアセトニトリル（５２．５ｍｇ，０．２９ｍｍｏｌ）に替えて１，３−ジメチルバルビツル酸（６８．７ｍｇ，０．４４ｍｍｏｌ）を用い、他の試剤を１．５２倍のスケールで用いた以外、実施例２と同じ操作により粗製物を得、次いで、シリカゲルカラムクロマトグラフィー（ヘキサン／ジエチルエーテル＝１／１ ｖｏｌ／ｖｏｌ）で単離精製することにより目的物の５，７−ジメチル−１−（ジフルオロメチル）−５，７−ジアザスピロ［２，５］オクタン−４，６，８−トリオン（１５）を白色結晶として得た（８３．７ｍｇ，０．３６１ｍｍｏｌ，収率８２％）。
融点：８９．６−９１．２℃。
ＩＲ（ＡＴＲ）：３１０５，１６６７，１４４７，１３８６，１２９８，１２２７，１０８９，１０３６，８５２，７５２ｃｍ-1。
１Ｈ−ＮＭＲ（４００ＭＨｚ）：δ＝６．０９（ｄｔ，Ｊ＝５５．４，７．５Ｈｚ，１Ｈ），３．３３９（ｓ，３Ｈ），３．３３６（ｓ，３Ｈ），２．７４−２．６２（ｍ，１Ｈ），２．１８（ｄ，Ｊ＝３．７Ｈｚ,１Ｈ），２．１６（ｄ，Ｊ＝３．３Ｈｚ）。
13Ｃ−ＮＭＲ（１００ＭＨｚ）：δ＝１６６．９，１６６．５，１５１．１，１１４．１（ｄｄ，Ｊ＝２３８．２，２３６．７Ｈｚ），３７．６（ｄｄ，Ｊ＝３８．９，３０．４Ｈｚ），３０．６（ｄ，Ｊ＝６．２Ｈｚ），２８．９９７，２８．９０４，２５．０（ｄ，Ｊ＝９．４Ｈｚ）。
19Ｆ−ＮＭＲ（３７６ＭＨｚ）δ＝−１１１．０（ｄｄ，Ｊ＝２９９．２，５４．９Ｈｚ，１Ｆ），１１７．４（ｄｄｄ，Ｊ＝２９９．２，５６．０，９．５Ｈｚ，１Ｆ）。
ＧＣ−ＭＳ（ｍ／ｚ）：２３２（２３，Ｍ+），２１２（６０），１８１（１００），１７４（２０），１４７（１７），１２４（２７），９９（２３），９０（３５），５６（２１）。
元素分析 計算値Ｃ，４６．５６、Ｈ，４．３４、Ｎ，１２．０７、測定値Ｃ，４６．６６，Ｈ，４．３５、Ｎ，１２．０７。
In the same reaction apparatus as in Example 3, 1,3-dimethylbarbituric acid (68.7 mg, 0.44 mmol) was used in place of phenylsulfonylacetonitrile (52.5 mg, 0.29 mmol), and other reagents were used as 1. A crude product was obtained by the same operation as in Example 2 except that it was used at a scale of 52 times, and then isolated and purified by silica gel column chromatography (hexane / diethyl ether = 1/1 vol / vol). 5,7-dimethyl-1- (difluoromethyl) -5,7-diazaspiro [2,5] octane-4,6,8-trione (15) was obtained as white crystals (83.7 mg, 0.361 mmol, Yield 82%).
Melting point: 89.6-91.2 ° C.
IR (ATR): 3105, 1667, 1447, 1386, 1298, 1227, 1089, 1036, 852, 752 cm −1 .
1H-NMR (400 MHz): δ = 6.09 (dt, J = 55.4, 7.5 Hz, 1H), 3.3339 (s, 3H), 3.336 (s, 3H), 2.74- 2.62 (m, 1H), 2.18 (d, J = 3.7 Hz, 1H), 2.16 (d, J = 3.3 Hz).
13 C-NMR (100 MHz): δ = 166.9, 166.5, 151.1, 114.1 (dd, J = 238.2, 236.7 Hz), 37.6 (dd, J = 38.9) 30.4 Hz), 30.6 (d, J = 6.2 Hz), 28.997, 28.904, 25.0 (d, J = 9.4 Hz).
19 F-NMR (376 MHz) δ = −111.0 (dd, J = 299.2, 54.9 Hz, 1F), 117.4 (ddd, J = 299.2, 56.0, 9.5 Hz, 1F) ).
GC-MS (m / z): 232 (23, M + ), 212 (60), 181 (100), 174 (20), 147 (17), 124 (27), 99 (23), 90 (35 ), 56 (21).
Elemental analysis Calculated value C, 46.56, H, 4.34, N, 12.07, measured value C, 46.66, H, 4.35, N, 12.07.
本発明により提案された新規ジフルオロメチル基含有化合物は電子不足メチレンとの反応が可能で、工業的に有用なジフルオロメチル基含有シクロプロパン化合物の製造が可能となる。 The novel difluoromethyl group-containing compound proposed by the present invention can be reacted with electron-deficient methylene, and industrially useful difluoromethyl group-containing cyclopropane compounds can be produced.
Claims (2)
で表されるジフルオロメチル基含有化合物の製造方法であって、
（３，３−ジフルオロ−２−プロペニル）フェニルスルフィドを塩基で処理し、［（１Ｅ）−３，３−ジフルオロ−１−プロペン−１−イル］フェニルスルフィドを調製した後、銅粉末存在下、ジフェニルヨードニウム塩を反応させる、ジフルオロメチル基含有化合物の製造方法。 The following general formula (1)
A process for producing a difluoromethyl group-containing compound represented by:
After treating (3,3-difluoro-2-propenyl) phenyl sulfide with a base to prepare [(1E) -3,3-difluoro-1-propen-1-yl] phenyl sulfide, in the presence of copper powder, A method for producing a difluoromethyl group-containing compound, wherein a diphenyliodonium salt is reacted.
The method for producing a difluoromethyl group-containing compound according to claim 1 , wherein the diphenyliodonium salt is diphenyliodonium trifluoromethanesulfonate or diphenyliodonium hexafluorophosphate.
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