JP2017075120A - Reagent for turning material into difluoromethylthio and method for producing difluoromethylthio-enamine derivative - Google Patents
Reagent for turning material into difluoromethylthio and method for producing difluoromethylthio-enamine derivative Download PDFInfo
- Publication number
- JP2017075120A JP2017075120A JP2015203685A JP2015203685A JP2017075120A JP 2017075120 A JP2017075120 A JP 2017075120A JP 2015203685 A JP2015203685 A JP 2015203685A JP 2015203685 A JP2015203685 A JP 2015203685A JP 2017075120 A JP2017075120 A JP 2017075120A
- Authority
- JP
- Japan
- Prior art keywords
- group
- difluoromethylthio
- compound
- phenyl
- reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 difluoromethylthio Chemical group 0.000 title claims abstract description 47
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 15
- 239000000463 material Substances 0.000 title abstract 3
- 238000004519 manufacturing process Methods 0.000 title description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 150000002081 enamines Chemical class 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 8
- 239000003905 agrochemical Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- RRZMGYGGSPGCAB-UHFFFAOYSA-N 2-(difluoromethylsulfonyl)-1-phenylethanone Chemical compound FC(S(=O)(=O)CC(=O)C1=CC=CC=C1)F RRZMGYGGSPGCAB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- RODBEKUWCLMBSW-FGZHOGPDSA-M (3r,5r)-7-[1-cyclohexyl-4-(4-fluorophenyl)-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC(C)C1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=CN1C1CCCCC1 RODBEKUWCLMBSW-FGZHOGPDSA-M 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- OKIRBHVFJGXOIS-UHFFFAOYSA-N 1,2-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC=C1C(C)C OKIRBHVFJGXOIS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JXYCCKVJTSXZRI-UHFFFAOYSA-N 1,4-dioxane;heptane Chemical compound C1COCCO1.CCCCCCC JXYCCKVJTSXZRI-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- QFVRYGXAHXDPHE-UHFFFAOYSA-N [acetyloxy-(2,4,6-trimethylphenyl)-$l^{3}-iodanyl] acetate Chemical group CC(=O)OI(OC(C)=O)C1=C(C)C=C(C)C=C1C QFVRYGXAHXDPHE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- KSCRVOKQPYZBHZ-IXPOFIJOSA-N benzyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@H]1C(NCC1)=O)C(=O)C=1SC2=CC=CC=C2N=1)C(C)C)C(=O)OCC1=CC=CC=C1 KSCRVOKQPYZBHZ-IXPOFIJOSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- ZLRROLLKQDRDPI-UHFFFAOYSA-L disodium;4,5-dihydroxybenzene-1,3-disulfonate;hydrate Chemical compound O.[Na+].[Na+].OC1=CC(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C1O ZLRROLLKQDRDPI-UHFFFAOYSA-L 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical class N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、各種反応基質を容易にジフルオロメチルチオ化することが可能な、ジフルオロメチルチオ化試薬およびジフルオロメチルチオ−エナミン誘導体の製造方法に関するものである。 The present invention relates to a difluoromethylthiolation reagent and a method for producing a difluoromethylthio-enamine derivative capable of easily difluoromethylthiolating various reaction substrates.
フッ素原子は全原子中で最大の電気陰性度を持つ等、その特異的な性質から医薬、農薬分野において注目を集め、生理活性物質への導入が盛んに研究されている。特に農薬分野においては、その利用が盛んに行われ、上市されている農薬の約半数近くにフッ素原子が含まれているといわれている。その中の一つにジフルオロメチルチオ基（SCF2H基）があり、生理活性を変化、改善する官能基として、医薬、農薬の開発に関して非常に重要な部分構造である。最近では徐々にジフルオロメチルチオ化反応が報告されつつあるが、直接的にターゲット分子に対してジフルオロメチルチオ基を導入する反応の報告例は非常に少ない。それゆえ、直接的にジフルオロメチルチオ基を導入できる試薬が開発できれば非常に有用な化合物ツールとなる。
特許文献１には、カルボニル化合物またはマロノニトリル誘導体を、塩基存在下、フェニル（２，３，４，５−テトラメチルフェニル）ブロモジフルオロメチルチオフェニウムテトラフルオロボラート、又はフェニル（２，３，４，５−テトラメチルフェニル）ブロモジフルオロメチルチオフェニウムトリフルオロメタンスルホナートを反応させて作製したジフルオロメチル基含有化合物が示されており、その反応温度は−８０℃〜０℃であることが記載されている。
最近１例のみではあるが、各種求核剤に対して直接的にジフルオロメチルチオ基を導入できる、フタルイミド型の試薬が報告された(非特許文献１)。この試薬は様々な基質に対して直接的なジフルオロメチルチオ基の導入が可能である。しかしながら、ほとんどの反応基質をジフルオロメチルチオ化する場合に加熱条件下での反応が必要であり、より広範囲な反応基質を想定した場合、より温和な条件下でのジフルオロメチルチオ化が可能な新規試薬の開発が望まれる。
The fluorine atom has the highest electronegativity among all atoms, and has attracted attention in the fields of medicine and agricultural chemicals due to its unique properties, and its introduction into physiologically active substances has been actively studied. In particular, in the agricultural chemical field, it is said that fluorine atom is contained in nearly half of the agricultural chemicals that have been actively used and marketed. One of them is a difluoromethylthio group (SCF 2 H group), which is a very important partial structure for the development of pharmaceuticals and agricultural chemicals as a functional group that changes and improves physiological activity. Recently, difluoromethylthiolation reactions are gradually being reported, but there are very few reports of reactions in which difluoromethylthio groups are directly introduced into target molecules. Therefore, if a reagent capable of directly introducing a difluoromethylthio group can be developed, it becomes a very useful compound tool.
Patent Document 1 discloses that a carbonyl compound or a malononitrile derivative is phenyl (2,3,4,5-tetramethylphenyl) bromodifluoromethylthiophenium tetrafluoroborate or phenyl (2,3,4,4) in the presence of a base. 5-tetramethylphenyl) bromodifluoromethylthiophenium trifluoromethanesulfonate produced by reaction with a difluoromethyl group-containing compound is shown, and the reaction temperature is described to be -80 ° C to 0 ° C. .
Recently, although only in one example, a phthalimide-type reagent that can directly introduce a difluoromethylthio group into various nucleophiles has been reported (Non-patent Document 1). This reagent can directly introduce difluoromethylthio groups to various substrates. However, when most reaction substrates are difluoromethylthiolated, a reaction under heating conditions is required. When a wider range of reaction substrates is assumed, a new reagent capable of difluoromethylthiolation under milder conditions is required. Development is desired.
本発明は上記点に鑑みて、様々な医・農薬製造過程において重要である合成中間体として有用なエナミン化合物を提供するため、ジフルオロメチルチオ基をより温和な反応条件（常温、常圧）下で分子内に導入することが可能な試薬およびジフルオロメチルチオ−エナミン誘導体の製造方法である。 In view of the above points, the present invention provides a diaminomethylthio group under milder reaction conditions (normal temperature and normal pressure) in order to provide an enamine compound useful as a synthetic intermediate that is important in various medical and agricultural chemical production processes. A reagent that can be introduced into a molecule and a method for producing a difluoromethylthio-enamine derivative.
従来のものより反応性の高い活性構造を形成することができるジフルオロメチルチオ化試薬として、下記（化１）で示される本発明化合物は、上記目的を達成することができる。すなわち、請求項１記載の本発明は、（化１）で表されるジフルオロメチルチオ化試薬（ヨードニウムイリド化合物）である。また、（化１）で表されるジフルオロメチルチオを用いることで、温和な条件（常温、常圧）下において下記（化２）で示される化合物群へのジフルオロメチルチオ化が可能である。すなわち、請求項２記載の本発明は、（化２）で表されるジフルオロメチルチオ−エナミン誘導体の製造方法である。 The compound of the present invention represented by the following (Chemical Formula 1) as a difluoromethylthiolation reagent capable of forming an active structure having a higher reactivity than the conventional one can achieve the above-mentioned object. That is, the present invention described in claim 1 is a difluoromethylthiolation reagent (iodonium ylide compound) represented by (Chemical Formula 1). In addition, by using difluoromethylthio represented by (Chemical Formula 1), difluoromethylthiolation to a compound group represented by the following (Chemical Formula 2) can be performed under mild conditions (normal temperature, normal pressure). That is, the present invention according to claim 2 is a method for producing a difluoromethylthio-enamine derivative represented by (Chemical Formula 2).
（式中、Ｒ1は水素原子，ハロゲン原子，ニトロ基，C１−C３アルキル基またはC１−C３アルコキシ基を表し、Ｒ２はフェニル基またはメシチル基を表す。）
(In the formula, R 1 represents a hydrogen atom, a halogen atom, a nitro group, a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group, and R 2 represents a phenyl group or a mesityl group.)
（式中、Ｒ3，Ｒ４は、それぞれ独立してC１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いベンジル基，C１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基，水素原子およびC１−C６アルキル基を表し、Ｒ５はC１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基およびC１−C６アルキル基を表し、Ｒ６はC１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基およびC１−C３アルキル基を表す。）
(In the formula, R 3 and R 4 are each independently a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a benzyl group optionally substituted with a halogen atom, or a C 1 -C 3 alkyl group. , C 1 -C 3 alkoxy group or a phenyl group which may be substituted with a halogen atom, a hydrogen atom and a C 1 -C 6 alkyl group, R 5 is a C 1 -C 3 alkyl group, C 1 -C 3 an alkoxy group or a phenyl group which may be substituted with a halogen atom and C 1 -C 6 alkyl group, R 6 is optionally substituted C 1 -C 3 alkyl groups, C 1 -C 3 alkoxy group or a halogen atom even represents a phenyl group and C 1 -C 3 alkyl group.)
本明細書において、C１−C３アルキル基としては、例えば、炭素数１〜３のアルキル基を用いることができる。具体的には、メチル基，エチル基，プロピル基，イソプロピル基を表す。
C１−C６アルキル基としては、メチル基，エチル基，プロピル基，イソプロピル基，ブチル基，ペンチル基，ヘキシル基，iso-ブチル基，tert-ブチル基を表す。
C１−C３アルコキシ基としては、メトキシ基，エトキシ基，プロピルオキシ基，イソプロポキシ基を表す。
ハロゲン原子としては、フッ素原子，塩素原子，臭素原子，ヨウ素原子を表す。
C１−C３アルキル基，C１-C３アルコキシ基またはハロゲン原子に置換されていても良いベンジル基としては、２−メチル−フェニルメチル基，３−メチル−フェニルメチル基，４−メチル−フェニルメチル基，２−エチル−フェニルメチル基，３−エチル−フェニルメチル基，４−エチル−フェニルメチル基，２−メトキシ−フェニルメチル基，３−メトキシ−フェニルメチル基，４−メトキシ−フェニルメチル基，２−エトキシ−フェニルメチル基，３−エトキシ−フェニルメチル基，４−エトキシ−フェニルメチル基，２−フルオロ−フェニルメチル基，３−フルオロ−フェニルメチル基，４−フルオロ−フェニルメチル基，２−クロロ−フェニルメチル基，３−クロロ−フェニルメチル基，４−クロロ−フェニルメチル基，２−ブロモ−フェニルメチル基，３−ブロモ−フェニルメチル基，４−ブロモ−フェニルメチル基，２−ヨード−フェニルメチル基，３−ヨード−フェニルメチル基，４−ヨード−フェニルメチル基を表す。
C１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基としては、２−メチル−フェニル基，３−メチル−フェニル基，４−メチル−フェニル基，２−エチル−フェニル基，３−エチル−フェニル基，４−エチル−フェニル基，２−メトキシ−フェニル基，３−メトキシ−フェニル基，４−メトキシ−フェニル基，２−エトキシ−フェニル基，３−エトキシ−フェニル基，４−エトキシ−フェニル基，２−フルオロ−フェニル基，３−フルオロ−フェニル基，４−フルオロ−フェニル基，２−クロロ−フェニル基，３−クロロ−フェニル基，４−クロロ−フェニル基，２−ブロモ−フェニル基，３−ブロモ−フェニル基，４−ブロモ−フェニル基，２−ヨード−フェニル基，３−ヨード−フェニル基，４−ヨード−フェニル基を表す。
溶媒の種類は特に限定されないが、ジエチルエーテル，ジイソプロピルエーテル，n-ブチルメチルエーテル，tert−ブチルメチルエーテル，テトラヒドロフラン，１，４-ジオキサン等のエーテル系溶媒；ヘプタン，ヘキサン，シクロペンタン，シクロヘキサン等の炭化水素系溶媒；クロロホルム，四塩化炭素，塩化メチレン，ジクロロエタン，トリクロロエタン等のハロゲン化炭化水素系溶媒；ベンゼン，トルエン，キシレン，クメン，シメン，メシチレン，ジイソプロピルベンゼン，ピリジン等の芳香族系溶媒；ジメチルスルホキシド，ジメチルホルムアミド等の溶媒；メタノール，エタノール，プロパノール，イソプロピルアルコール，アミノエタノール，N,N-ジメチルアミノエタノール等のアルコール系溶媒；アセトニトリル，プロピオニトリル等が挙げられる。これらは単独で使用し得るのみならず、２種類以上を混合して用いることも可能である。
銅試薬としては、フッ化銅(II)，塩化銅(I)，塩化銅(II)，臭化銅(I)，臭化銅(II)，ヨウ化銅(I)，酢酸銅(I)，酢酸銅(II)を用いることが可能であるが、臭化銅(I)を用いることが最も好ましい。使用量は化（２）の（2-a）に対し0.1〜2.0当量が可能であるが、好ましくは0.20当量である。
ヨードニウムイリド化合物の使用量は、（化２）の（2-a）に対し1.0〜10.0当量が可能であるが、好ましくは2.0当量である。
反応温度は特に限定されるものではないが通常−８０℃〜１２０℃であり、より好ましくは室温付近である。反応器は大気開放型の反応器、またはオートクレーブ等の密閉型の反応器のいずれも可能である。反応圧力は大気圧下、または加圧下のいずれも可能である。反応時間は特に限定されるものではないが、通常0.1〜24時間で反応は完結する。
反応後、前記（化１）および（化２）で示される化合物は一般的な手法によって反応液から単離および精製することができ、例えば濾取での単離や、反応液を濃縮した後、シリカゲル，アルミナ等の吸着剤を用いたカラムクロマトグラフ法での精製、塩析、再結晶等が挙げられる。
In this specification, the C 1 -C 3 alkyl group, for example, may be used an alkyl group having 1 to 3 carbon atoms. Specifically, it represents a methyl group, an ethyl group, a propyl group, or an isopropyl group.
The C 1 -C 6 alkyl group represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, an iso-butyl group, or a tert-butyl group.
The C 1 -C 3 alkoxy group represents a methoxy group, an ethoxy group, a propyloxy group, or an isopropoxy group.
The halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group or benzyl group which may be substituted with a halogen atom include 2-methyl-phenylmethyl group, 3-methyl-phenylmethyl group, 4-methyl- Phenylmethyl group, 2-ethyl-phenylmethyl group, 3-ethyl-phenylmethyl group, 4-ethyl-phenylmethyl group, 2-methoxy-phenylmethyl group, 3-methoxy-phenylmethyl group, 4-methoxy-phenylmethyl group Group, 2-ethoxy-phenylmethyl group, 3-ethoxy-phenylmethyl group, 4-ethoxy-phenylmethyl group, 2-fluoro-phenylmethyl group, 3-fluoro-phenylmethyl group, 4-fluoro-phenylmethyl group, 2-chloro-phenylmethyl group, 3-chloro-phenylmethyl group, 4-chloro-phenylmethyl group, 2-butyl Mode - a phenyl methyl group - phenylmethyl group, 3-bromo - phenylmethyl group, 4-bromo - phenylmethyl group, 2-iodo - phenylmethyl group, 3-iodo - phenylmethyl group, 4-iodo.
The C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group or phenyl group optionally substituted by a halogen atom includes a 2-methyl-phenyl group, a 3-methyl-phenyl group, and a 4-methyl-phenyl group. 2-ethyl-phenyl group, 3-ethyl-phenyl group, 4-ethyl-phenyl group, 2-methoxy-phenyl group, 3-methoxy-phenyl group, 4-methoxy-phenyl group, 2-ethoxy-phenyl group, 3-ethoxy-phenyl group, 4-ethoxy-phenyl group, 2-fluoro-phenyl group, 3-fluoro-phenyl group, 4-fluoro-phenyl group, 2-chloro-phenyl group, 3-chloro-phenyl group, 4 -Chloro-phenyl group, 2-bromo-phenyl group, 3-bromo-phenyl group, 4-bromo-phenyl group, 2-iodo-phenyl group, 3-iodo-phenyl Represents a sulfur group and a 4-iodo-phenyl group.
The type of solvent is not particularly limited, but ether solvents such as diethyl ether, diisopropyl ether, n-butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane; heptane, hexane, cyclopentane, cyclohexane, etc. Hydrocarbon solvents; Halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride, methylene chloride, dichloroethane, and trichloroethane; Aromatic solvents such as benzene, toluene, xylene, cumene, cymene, mesitylene, diisopropylbenzene, and pyridine; Solvents such as sulfoxide and dimethylformamide; alcohol solvents such as methanol, ethanol, propanol, isopropyl alcohol, aminoethanol, N, N-dimethylaminoethanol; acetonitrile, propio Tolyl, and the like. These can be used alone or in combination of two or more.
Copper reagents include copper fluoride (II), copper chloride (I), copper chloride (II), copper bromide (I), copper bromide (II), copper iodide (I), copper acetate (I) Copper (II) acetate can be used, but copper (I) bromide is most preferred. The amount used can be 0.1 to 2.0 equivalents relative to (2-a) in Chemical Formula (2), but is preferably 0.20 equivalents.
The amount of the iodonium ylide compound used may be 1.0 to 10.0 equivalents to (2-a) in (Chemical Formula 2), but is preferably 2.0 equivalents.
Although reaction temperature is not specifically limited, Usually, it is -80 degreeC-120 degreeC, More preferably, it is room temperature vicinity. The reactor can be either an open-air reactor or a closed reactor such as an autoclave. The reaction pressure can be either atmospheric pressure or pressurized. The reaction time is not particularly limited, but the reaction is usually completed in 0.1 to 24 hours.
After the reaction, the compounds represented by the above (Chemical Formula 1) and (Chemical Formula 2) can be isolated and purified from the reaction solution by a general method. For example, after isolation by filtration or concentration of the reaction solution. And purification by column chromatography using an adsorbent such as silica gel and alumina, salting out, recrystallization and the like.
以下、本発明の実施形態をさらに具体的に説明するが、本発明の特許請求の範囲は下記の実施形態に限定されることはない。
（化学式１の一般的な製造方法）
窒素雰囲気下、1−フェニル-2-[（ジフルオロメチル）スルホニル]エタノン（3.22 g），水酸化カリウム（1.16 g）およびアセトニトリル（100 ml）混合物に対し、室温下でフェニルヨードジアセテート（4.87 g）を加え、5時間撹拌した後，水（200 ml）を加えた。さらに0.5時間撹拌した後、沈殿物を濾取し、水およびジエチルエーテルで洗浄し、減圧下溶媒および水分を留去し、下記化合物構造式で表される本発明化合物（1a）を4.26 g得た。
Hereinafter, although the embodiment of the present invention will be described more specifically, the scope of the claims of the present invention is not limited to the following embodiment.
(General production method of Formula 1)
Under a nitrogen atmosphere, 1-phenyl-2-[(difluoromethyl) sulfonyl] ethanone (3.22 g), potassium hydroxide (1.16 g) and acetonitrile (100 ml) were mixed with phenyliododiacetate (4.87 g) at room temperature. ) And stirred for 5 hours, and then water (200 ml) was added. After further stirring for 0.5 hour, the precipitate was collected by filtration, washed with water and diethyl ether, and the solvent and water were distilled off under reduced pressure to obtain 4.26 g of the present compound (1a) represented by the following compound structural formula. It was.
本発明化合物1a: 1H NMR (300 MHz, (CD3)2SO): d ppm 7.85 (d, J = 7.8 Hz, 2H), 7.62−7.57 (m, 1H), 7.53−7.47 (m, 2H), 7.39−7.29 (m, 5H), 6.70 (t, J = 53.1 Hz, 1H).
Compound 1a of the present invention: 1 H NMR (300 MHz, (CD 3 ) 2 SO): d ppm 7.85 (d, J = 7.8 Hz, 2H), 7.62-7.57 (m, 1H), 7.53-7.47 (m, 2H ), 7.39-7.29 (m, 5H), 6.70 (t, J = 53.1 Hz, 1H).
窒素雰囲気下、1−フェニル-2-[（ジフルオロメチル）スルホニル]エタノン（0.50 g），水酸化カリウム（0.18 g）およびアセトニトリル（10 ml）混合物に対し、室温下で2-(ジアセトキシヨード)メシチレン（0.85 g）を加え、1時間撹拌した後，氷水（20ml）を加えた。さらに0.5時間撹拌した後、沈殿物を濾取し、氷水およびジエチルエーテルで洗浄し、減圧下溶媒および水分を留去し、下記化合物構造式で表される本発明化合物（1b）を0.40ｇを得た。 2- (diacetoxyiodo) at room temperature against a mixture of 1-phenyl-2-[(difluoromethyl) sulfonyl] ethanone (0.50 g), potassium hydroxide (0.18 g) and acetonitrile (10 ml) under nitrogen atmosphere Mesitylene (0.85 g) was added and stirred for 1 hour, followed by ice water (20 ml). After further stirring for 0.5 hour, the precipitate was collected by filtration, washed with ice water and diethyl ether, the solvent and water were distilled off under reduced pressure, and 0.40 g of the present compound (1b) represented by the following compound structural formula was obtained. Obtained.
本発明化合物1b: 1H NMR (300 MHz, CDCl3): d ppm 7.49 (d, J = 6.2 Hz, 2H), 7.40−7.33 (m, 3H), 7.06 (s, 2H), 5.92 (t, J = 55.2 Hz, 1H), 2.72 (s, 6H), 2.37 (s, 3H).
Compound 1b of the present invention: 1 H NMR (300 MHz, CDCl 3 ): d ppm 7.49 (d, J = 6.2 Hz, 2H), 7.40-7.33 (m, 3H), 7.06 (s, 2H), 5.92 (t, J = 55.2 Hz, 1H), 2.72 (s, 6H), 2.37 (s, 3H).
窒素雰囲気下、1−(4-ニトロフェニル)-2-[（ジフルオロメチル）スルホニル]エタノン（0.50 g），水酸化カリウム（0.15 g）およびアセトニトリル（10 ml）混合物に対し、室温下でフェニルヨードジアセテート（0.64 g）を加え、5時間撹拌した後，水（20 ml）を加えた。さらに0.5時間撹拌した後、沈殿物を濾取し、水およびジエチルエーテルで洗浄し、減圧下溶媒および水分を留去し、下記化合物構造式で表される本発明化合物（1c）を0.73 gを得た。 Phenyl iodide at room temperature against a mixture of 1- (4-nitrophenyl) -2-[(difluoromethyl) sulfonyl] ethanone (0.50 g), potassium hydroxide (0.15 g) and acetonitrile (10 ml) under nitrogen atmosphere After adding diacetate (0.64 g) and stirring for 5 hours, water (20 ml) was added. After further stirring for 0.5 hour, the precipitate was collected by filtration, washed with water and diethyl ether, the solvent and water were distilled off under reduced pressure, and 0.73 g of the present compound (1c) represented by the following compound structural formula was obtained. Obtained.
本発明化合物1c: 1H NMR (300 MHz, (CD3)2SO): d ppm 8.19 (d, J = 6.6 Hz, 2H), 7.96 (d, J = 7.5 Hz, 2H), 7.64−7.49 (m, 5H), 6.70 (t, J = 54.0 Hz, 1H).
Compound 1c of the present invention: 1 H NMR (300 MHz, (CD 3 ) 2 SO): d ppm 8.19 (d, J = 6.6 Hz, 2H), 7.96 (d, J = 7.5 Hz, 2H), 7.64-7.49 ( m, 5H), 6.70 (t, J = 54.0 Hz, 1H).
窒素雰囲気下、1−(4−ニトロフェニル)-2-[（ジフルオロメチル）スルホニル]エタノン（0.50 g），水酸化カリウム（0.15 g）およびアセトニトリル（10 ml）混合物に対し、室温下で2-(ジアセトキシヨード)メシチレン（0.72 g）を加え、5時間撹拌した後、水（50 ml）を加えた。さらに0.5時間撹拌した後、沈殿物を濾取し、水およびジエチルエーテルで洗浄し、減圧下溶媒および水分を留去し、下記化合物構造式で表される本発明化合物（1d）を0.87 gを得た。 In a nitrogen atmosphere, a mixture of 1- (4-nitrophenyl) -2-[(difluoromethyl) sulfonyl] ethanone (0.50 g), potassium hydroxide (0.15 g) and acetonitrile (10 ml) (Diacetoxyiodo) mesitylene (0.72 g) was added, stirred for 5 hours, and then water (50 ml) was added. After further stirring for 0.5 hour, the precipitate was collected by filtration, washed with water and diethyl ether, the solvent and water were distilled off under reduced pressure, and 0.87 g of the present compound (1d) represented by the following compound structural formula was obtained. Obtained.
本発明化合物1d: 1H NMR (300 MHz, (CD3)2SO): d ppm 8.16 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.12 (s, 2H), 6.50 (t, J = 53.4 Hz, 1H), 2.59 (s, 6H), 2.30 (s, 3H). 19F NMR (282 MHz, CDCl3): d ppm−120.2 (d, J = 55.5 Hz, 2F).
Compound 1d of the present invention: 1 H NMR (300 MHz, (CD 3 ) 2 SO): d ppm 8.16 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.12 (s, . 2H), 6.50 (t, J = 53.4 Hz, 1H), 2.59 (s, 6H), 2.30 (s, 3H) 19 F NMR (282 MHz, CDCl 3): d ppm-120.2 (d, J = 55.5 Hz, 2F).
（化２の一般的な製造方法）
窒素雰囲気下、３−フェニルメチルアミノ−３−ブテノン酸メチルエステル (41.0 mg, 0.2 mmol)、臭化銅(I) (5.7 mg, 0.04 mmol)、１，４−ジオキサン(2.5 ml)の混合物に対し、室温下で本発明化合物(1a) (174.5 mg, 0.4 mmol)を加え、5 時間撹拌した。反応混合物を濾過した後、濾液を減圧下濃縮し、シリカゲルカラムクロマトグラフィーに付し、化合物2aを47.2 mgを得た。
(General production method of chemical formula 2)
Under a nitrogen atmosphere, to a mixture of 3-phenylmethylamino-3-butenonic acid methyl ester (41.0 mg, 0.2 mmol), copper (I) bromide (5.7 mg, 0.04 mmol), 1,4-dioxane (2.5 ml) On the other hand, this invention compound (1a) (174.5 mg, 0.4 mmol) was added at room temperature, and it stirred for 5 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 47.2 mg of compound 2a.
化合物2a: 1H NMR (300 MHz, CDCl3): d ppm 10.61 (brs, 1H), 7.37−7.33 (m, 5H), 6.53 (t, J = 58.5 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H), 2.39 (s, 3H).
Compound 2a: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.61 (brs, 1H), 7.37-7.33 (m, 5H), 6.53 (t, J = 58.5 Hz, 1H), 4.53 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H), 2.39 (s, 3H).
実施例５と同様にして、化合物2b−2oを得た。 In the same manner as in Example 5, compound 2b-2o was obtained.
化合物2b: 1H NMR (300 MHz, CDCl3): d ppm 10.52 (brs, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.53 (t, J = 58.2 Hz, 1H), 4.45 (d, J = 5.4 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.40 (s, 3H).
Compound 2b: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.52 (brs, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.53 (t , J = 58.2 Hz, 1H), 4.45 (d, J = 5.4 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.40 (s, 3H).
化合物2c: 1H NMR (300 MHz, CDCl3): d ppm 10.60 (brs, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.53 (t, J = 58.2 Hz, 1H), 4.48 (d, J = 5.4 Hz, 2H), 3.74 (s, 3H), 2.37 (s, 3H).
Compound 2c: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.60 (brs, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.53 (t , J = 58.2 Hz, 1H), 4.48 (d, J = 5.4 Hz, 2H), 3.74 (s, 3H), 2.37 (s, 3H).
化合物2d: 1H NMR (300 MHz, CDCl3): d ppm 10.26 (brs, 1H), 6.51 (t, J = 58.8 Hz, 1H), 3.73 (s, 3H), 3.31 (d, J = 6.0 Hz, 2H), 2.37 (s, 3H), 1.64−1.59 (m, 2H), 1.47−1.42 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).
Compound 2d: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.26 (brs, 1H), 6.51 (t, J = 58.8 Hz, 1H), 3.73 (s, 3H), 3.31 (d, J = 6.0 Hz , 2H), 2.37 (s, 3H), 1.64−1.59 (m, 2H), 1.47−1.42 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).
化合物2e: 1H NMR (300 MHz, CDCl3): d ppm 10.84 (brs, 1H), 7.39−7.36 (m, 2H), 7.29−7.26 (m, 1H), 7.12 (d, J = 6.9 Hz, 2H), 6.61 (t, J = 58.5 Hz, 1H), 3.79 (s, 3H), 2.34 (s, 3H).
Compound 2e: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.84 (brs, 1H), 7.39-7.36 (m, 2H), 7.29-7.26 (m, 1H), 7.12 (d, J = 6.9 Hz, 2H), 6.61 (t, J = 58.5 Hz, 1H), 3.79 (s, 3H), 2.34 (s, 3H).
化合物2f: 1H NMR (300 MHz, CDCl3): d ppm 11.75 (brs, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.00 (d, J＝7.5 Hz, 2H), 6.60 (t, J = 58.2 Hz, 1H), 3.79 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H).
Compound 2f: 1 H NMR (300 MHz, CDCl 3 ): d ppm 11.75 (brs, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 7.5 Hz, 2H), 6.60 (t , J = 58.2 Hz, 1H), 3.79 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H).
化合物2g: 1H NMR (300 MHz, CDCl3): d ppm 10.44 (brs, 1H), 7.42 (brs, 3H), 7.31−7.28 (m, 2H), 7.12 (brs, 5H), 6.42 (t, J = 58.2 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H).
Compound 2g: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.44 (brs, 1H), 7.42 (brs, 3H), 7.31-7.28 (m, 2H), 7.12 (brs, 5H), 6.42 (t, J = 58.2 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H).
化合物2h: 1H NMR (300 MHz, CDCl3): d ppm 10.43 (brs, 1H), 7.42 (brs, 3H), 7.30−7.28 (m, 3H), 7.12 (brs, 4H), 6.43 (t, J = 58.2 Hz, 1H), 4.26 (q, J = 6.9 Hz, 2H), 4.12 (d, J = 5.7 Hz, 2H), 1.34 (t J = 6.9 Hz, 3H).
Compound 2h: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.43 (brs, 1H), 7.42 (brs, 3H), 7.30-7.28 (m, 3H), 7.12 (brs, 4H), 6.43 (t, J = 58.2 Hz, 1H), 4.26 (q, J = 6.9 Hz, 2H), 4.12 (d, J = 5.7 Hz, 2H), 1.34 (t J = 6.9 Hz, 3H).
化合物2i: 1H NMR (300 MHz, CDCl3): d ppm 9.35 (brs, 1H), 7.44-7.41 (m, 2H), 7.39−7.32 (m, 3H), 6.50 (t, J = 58.5 Hz, 1H), 5.38 (brs, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H).
Compound 2i: 1 H NMR (300 MHz, CDCl 3 ): d ppm 9.35 (brs, 1H), 7.44-7.41 (m, 2H), 7.39-7.32 (m, 3H), 6.50 (t, J = 58.5 Hz, 1H), 5.38 (brs, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H).
化合物2j: 1H NMR (300 MHz, CDCl3): d ppm 10.40 (brs, 1H), 7.41 (brs, 1H), 7.29−7.26 (m, 3H), 7.12 (d, J = 6.3 Hz, 2H), 7.02 (brs, 2H), 6.93 (d, J = 6.3 Hz, 1H), 6.45 (t, J = 58.5 Hz, 1H), 4.14 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H).
Compound 2j: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.40 (brs, 1H), 7.41 (brs, 1H), 7.29-7.26 (m, 3H), 7.12 (d, J = 6.3 Hz, 2H) , 7.02 (brs, 2H), 6.93 (d, J = 6.3 Hz, 1H), 6.45 (t, J = 58.5 Hz, 1H), 4.14 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H).
化合物2k: 1H NMR (300 MHz, CDCl3): d ppm 10.41 (brs, 1H), 7.33−7.26 (m, 4H), 7.13−7.11 (m, 2H), 6.95 (d, J = 6.6 Hz, 1H), 6.72 (d, J = 8.1, 1H), 6.64 (s, 1H), 6.45 (t, J = 58.5 Hz, 1H), 4.14 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H).
Compound 2k: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.41 (brs, 1H), 7.33−7.26 (m, 4H), 7.13−7.11 (m, 2H), 6.95 (d, J = 6.6 Hz, 1H), 6.72 (d, J = 8.1, 1H), 6.64 (s, 1H), 6.45 (t, J = 58.5 Hz, 1H), 4.14 (s, 2H), 3.80 (s, 3H), 3.74 (s , 3H).
化合物2l:1H NMR (300 MHz, CDCl3): d ppm 10.44 (brs, 1H), 7.33−7.26 (m, 3H), 7.13−7.04 (m, 4H), 6.93 (d, J = 8.4 Hz, 1H), 6.43 (t, J = 58.2 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H).
Compound 2l: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.44 (brs, 1H), 7.33−7.26 (m, 3H), 7.13−7.04 (m, 4H), 6.93 (d, J = 8.4 Hz, 1H), 6.43 (t, J = 58.2 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H).
化合物2m:1H NMR (300 MHz, CDCl3): d ppm 10.42 (brs, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.32−7.26 (m, 3H), 7.09 (d, J = 6.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.43 (t, J = 58.8 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H).
Compound 2m: 1 H NMR (300 MHz, CDCl 3 ): d ppm 10.42 (brs, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.32−7.26 (m, 3H), 7.09 (d, J = 6.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.43 (t, J = 58.8 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H).
化合物2n:1H NMR (300 MHz, CDCl3): d ppm 12.86 (brs, 1H), 7.37−7.30 (m 5H), 6.50 (t, J = 56.7 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 2.43 (s, 3H), 2.37 (s, 3H).
Compound 2n: 1 H NMR (300 MHz, CDCl 3 ): d ppm 12.86 (brs, 1H), 7.37-7.30 (m 5H), 6.50 (t, J = 56.7 Hz, 1H), 4.55 (d, J = 5.7 Hz, 2H), 2.43 (s, 3H), 2.37 (s, 3H).
化合物2o:1H NMR (300 MHz, CDCl3): d ppm 13.01 (brs, 1H), 7.40−7.34 (m, 10H), 6.25 (t, J = 56.7 Hz, 1H), 4.64 (d, J = 5.4 Hz, 2H), 2.49 (s, 3H).
Compound 2o: 1 H NMR (300 MHz, CDCl 3 ): d ppm 13.01 (brs, 1H), 7.40−7.34 (m, 10H), 6.25 (t, J = 56.7 Hz, 1H), 4.64 (d, J = 5.4 Hz, 2H), 2.49 (s, 3H).
なお、全例において、混合攪拌は窒素雰囲気下で行うものであるが、収率は低下するが空気雰囲気下（大気中）で行うことも可能である。 In all cases, the mixing and stirring is performed in a nitrogen atmosphere, but the yield is reduced, but it can also be performed in an air atmosphere (in the air).
本発明に係るジフルオロメチルチオ化試薬およびジフルオロメチルチオ−エナミン誘導体の製造方法により得られるエナミン化合物は、様々な医・農薬の製造過程に見られる合成中間体であり、そのため、ジフルオロメチルチオ基を持つエナミンは、新しい合成中間体として有用である。
The enamine compound obtained by the production method of the difluoromethylthiolation reagent and the difluoromethylthio-enamine derivative according to the present invention is a synthetic intermediate found in various medical and agrochemical production processes. Therefore, an enamine having a difluoromethylthio group is It is useful as a new synthetic intermediate.
Claims (2)
（式中、Ｒ1は水素原子，ハロゲン原子，ニトロ基，C１−C３アルキル基またはC１−C３アルコキシ基を表し、Ｒ２はフェニル基またはメシチル基を表す。） A difluoromethylthiolation reagent represented by the formula (1).
(In the formula, R 1 represents a hydrogen atom, a halogen atom, a nitro group, a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxy group, and R 2 represents a phenyl group or a mesityl group.)
（式中、Ｒ3，Ｒ４は、それぞれ独立して、C１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いベンジル基，C１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基，水素原子およびC１−C６アルキル基を表し、Ｒ５はC１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基およびC１−C６アルキル基を表し、Ｒ６はC１−C３アルキル基，C１−C３アルコキシ基またはハロゲン原子に置換されていても良いフェニル基およびC１−C３アルキル基を表す。）
The difluoromethylthiolation reagent represented by Chemical Formula (1) is reacted with a catalytic amount of a copper reagent and the enamine derivative (2-a) represented by Chemical Formula (2), and the enamine compound represented by Chemical Formula (2) ( A process for producing a difluoromethylthio-enamine derivative, characterized in that 2) is obtained.
(Wherein R 3 and R 4 are each independently a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a benzyl group optionally substituted by a halogen atom, or C 1 -C 3 alkyl. group, C 1 -C 3 alkoxy group or an optionally substituted phenyl group with a halogen atom, a hydrogen atom and C1-C6 alkyl group, R 5 is C 1 -C 3 alkyl group, C 1 -C 3 alkoxy represents a group or a phenyl group which may be substituted with a halogen atom and C 1 -C 6 alkyl group, R 6 is substituted by a C 1 -C 3 alkyl groups, C 1 -C 3 alkoxy group or a halogen atom also represents a phenyl group and C 1 -C 3 alkyl group.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015203685A JP2017075120A (en) | 2015-10-15 | 2015-10-15 | Reagent for turning material into difluoromethylthio and method for producing difluoromethylthio-enamine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015203685A JP2017075120A (en) | 2015-10-15 | 2015-10-15 | Reagent for turning material into difluoromethylthio and method for producing difluoromethylthio-enamine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2017075120A true JP2017075120A (en) | 2017-04-20 |
Family
ID=58550045
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015203685A Pending JP2017075120A (en) | 2015-10-15 | 2015-10-15 | Reagent for turning material into difluoromethylthio and method for producing difluoromethylthio-enamine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2017075120A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11098036B2 (en) * | 2017-09-29 | 2021-08-24 | The Royal Institution For The Advancement Of Learning/Mcgill University | Catalyst-free and redox-neutral innate trifluoromethylation and alkylation of (hetero)aromatics enabled by light |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014065678A (en) * | 2012-09-26 | 2014-04-17 | Nagoya Institute Of Technology | Method for manufacturing difluoromethyl group-containing compound |
| JP2014234376A (en) * | 2013-06-04 | 2014-12-15 | 国立大学法人 名古屋工業大学 | Trifluoromethylthiolation method using a hypervalent iodine ylide including a trifluoromethanesulfonyl group |
-
2015
- 2015-10-15 JP JP2015203685A patent/JP2017075120A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014065678A (en) * | 2012-09-26 | 2014-04-17 | Nagoya Institute Of Technology | Method for manufacturing difluoromethyl group-containing compound |
| JP2014234376A (en) * | 2013-06-04 | 2014-12-15 | 国立大学法人 名古屋工業大学 | Trifluoromethylthiolation method using a hypervalent iodine ylide including a trifluoromethanesulfonyl group |
Non-Patent Citations (3)
| Title |
|---|
| DIANHU ZHU ET AL.: "N-Difluoromethylthiophthalimide: A Shelf-Stable, Electrophilic Reagent for Difluoromethylthiolation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 137(33), JPN6019024906, 15 July 2015 (2015-07-15), pages 10547 - 10553, ISSN: 0004066512 * |
| YANG, YU-DONG; AZUMA, AYAKA; TOKUNAGA, ETSUKO; YAMASAKI, MIKIO; SHIRO, MOTOO; SHIBATA, NORIO: "Trifluoromethanesulfonyl Hypervalent Iodonium Ylide for Copper-Catalyzed Trifluoromethylthiolati", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 135(24), JPN6019024905, 2013, pages 8782 - 8785, ISSN: 0004066511 * |
| 有森貞幸 他: "医薬品開発を志向した求電子的トリフルオロメチルチオ化およびジフルオロメチルチオ化試薬の開発とその利用", 反応と合成の進歩シンポジウム講演要旨集, vol. 41, JPN6019024904, 9 October 2015 (2015-10-09), pages 98, ISSN: 0004188007 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11098036B2 (en) * | 2017-09-29 | 2021-08-24 | The Royal Institution For The Advancement Of Learning/Mcgill University | Catalyst-free and redox-neutral innate trifluoromethylation and alkylation of (hetero)aromatics enabled by light |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhou et al. | Air oxidative radical hydroxysulfurization of styrenes leading to β-hydroxysulfides | |
| Manna et al. | Remarkable influence of secondary catalyst site on enantioselective desymmetrization of cyclopentenedione | |
| US20120095218A1 (en) | Optically active quaternary ammonium salt having axial asymmetry, and method for producing alpha-amino acid and derivative thereof by using the same | |
| Li et al. | An efficient enantioselective synthesis of florfenicol via a vanadium-catalyzed asymmetric epoxidation | |
| Scott et al. | Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide− Olefin Cycloaddition | |
| JPWO2010067824A1 (en) | Process for producing optically active carboxylic acid | |
| JP5412742B2 (en) | Process for producing 4-perfluoroisopropylanilines | |
| JP6746802B2 (en) | A scalable method for the preparation of indoxacarb | |
| CN112041298A (en) | Method for producing aromatic nitrile compound | |
| JP4384635B2 (en) | Asymmetric urea compound and method for producing asymmetric compound by asymmetric conjugate addition reaction using the same | |
| JP2017075120A (en) | Reagent for turning material into difluoromethylthio and method for producing difluoromethylthio-enamine derivative | |
| WO2013089188A1 (en) | Optical resolution method for bicyclic compound using asymmetric catalyst | |
| JP2013245215A (en) | Method for producing optically active bicyclic compound based on asymmetric cyclization reaction | |
| JP2017160158A (en) | Process for producing optically active 4-nitro-butanoic acid ester and pregabalin | |
| Fioravanti et al. | Trifluoromethyl syn-or anti-γ-amino alcohols by one-pot solvent-free Mannich-type reactions under temperature control | |
| JP4793976B2 (en) | Optically active hydrazine compound and method for producing optically active amine compound | |
| JP6235783B2 (en) | Asymmetric azadirs-alder reaction catalyst and method for producing optically active tetrahydropyridine compound using the same | |
| JP2012097041A (en) | Tetrahydropyrazolopyrazolone derivative having fluoroalkyl group and method of producing the same | |
| JP4414759B2 (en) | Method for producing ethene derivative | |
| Müller et al. | Desymmetrization of spiro-activated meso-cyclopropanes via nucleophilic substitution | |
| JP5396841B2 (en) | Process for producing α-trifluoromethyl-β-substituted-β-amino acids | |
| JP4923630B2 (en) | Method for producing 4-substituted tetrahydropyran | |
| JP4896476B2 (en) | Methyloxymethylaminopyridine derivative and method for producing the same | |
| KR20170080190A (en) | Method for preparing eight-membered heterocycles using catalytic cycloaddition of 1,5-dipole and eight-membered heterocycles prepared thereby | |
| JP2006096692A (en) | Manufacturing method of optically active trifluoromethyl carbinol derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180925 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190620 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190709 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190904 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20200114 |