JP2016147812A - (2,2,2−トリフルオロエチル)ケトンの製造方法 - Google Patents
(2,2,2−トリフルオロエチル)ケトンの製造方法 Download PDFInfo
- Publication number
- JP2016147812A JP2016147812A JP2015023856A JP2015023856A JP2016147812A JP 2016147812 A JP2016147812 A JP 2016147812A JP 2015023856 A JP2015023856 A JP 2015023856A JP 2015023856 A JP2015023856 A JP 2015023856A JP 2016147812 A JP2016147812 A JP 2016147812A
- Authority
- JP
- Japan
- Prior art keywords
- trifluoromethyl
- acid
- mmol
- added
- acid ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- QGYHOLFDHMQCKG-UHFFFAOYSA-N 1,1,1,5,5,5-hexafluoropentan-3-one Chemical compound FC(F)(F)CC(=O)CC(F)(F)F QGYHOLFDHMQCKG-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title claims description 30
- 239000002253 acid Substances 0.000 claims abstract description 26
- OPUQYFOVJNXOQI-UHFFFAOYSA-N 3,3,3-trifluoro-2-formylpropanoic acid Chemical compound O=CC(C(=O)O)C(F)(F)F OPUQYFOVJNXOQI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 18
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 82
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 78
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 51
- -1 3-amino-2-propenoic acid ester Chemical class 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 48
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000002506 iron compounds Chemical class 0.000 claims description 9
- 150000003462 sulfoxides Chemical class 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011737 fluorine Substances 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 105
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 90
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 87
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 51
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 45
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 35
- 229910052786 argon Inorganic materials 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 26
- 235000011054 acetic acid Nutrition 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000007788 liquid Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- GGHASBGAYFRVGL-UHFFFAOYSA-J S(=O)(=O)([O-])[O-].S(=O)(=O)(O)O.S(=O)(=O)([O-])[O-].[Fe+2].[Fe+2] Chemical compound S(=O)(=O)([O-])[O-].S(=O)(=O)(O)O.S(=O)(=O)([O-])[O-].[Fe+2].[Fe+2] GGHASBGAYFRVGL-UHFFFAOYSA-J 0.000 description 13
- QOSATHPSBFQAML-UHFFFAOYSA-N hydrogen peroxide;hydrate Chemical compound O.OO QOSATHPSBFQAML-UHFFFAOYSA-N 0.000 description 13
- 239000011369 resultant mixture Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 12
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 12
- 235000019345 sodium thiosulphate Nutrition 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 8
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 7
- ACIGNEBKPMVJMT-UHFFFAOYSA-N ethyl 2-benzoyl-3,3,3-trifluoropropanoate Chemical compound CCOC(=O)C(C(F)(F)F)C(=O)C1=CC=CC=C1 ACIGNEBKPMVJMT-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 229910000358 iron sulfate Inorganic materials 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- LBWMQVOHFPLVBY-UHFFFAOYSA-N 3,3,3-trifluoro-1-phenylpropan-1-one Chemical compound FC(F)(F)CC(=O)C1=CC=CC=C1 LBWMQVOHFPLVBY-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- OAKURXIZZOAYBC-UHFFFAOYSA-N 3-Oxopropanoic acid Natural products OC(=O)CC=O OAKURXIZZOAYBC-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- CGULTTSJZGXDBD-UHFFFAOYSA-N ethyl 3-amino-3-phenylprop-2-enoate Chemical compound CCOC(=O)C=C(N)C1=CC=CC=C1 CGULTTSJZGXDBD-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- AQRYRSMBPVPPMZ-UHFFFAOYSA-N ethyl 3-oxo-2-(trifluoromethyl)butanoate Chemical compound CCOC(=O)C(C(C)=O)C(F)(F)F AQRYRSMBPVPPMZ-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 229940071870 hydroiodic acid Drugs 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 3
- 125000005009 perfluoropropyl group Chemical group FC(C(C(F)(F)F)(F)F)(F)* 0.000 description 3
- 238000004262 preparative liquid chromatography Methods 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 3
- 238000000638 solvent extraction Methods 0.000 description 3
- 238000000859 sublimation Methods 0.000 description 3
- 230000008022 sublimation Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- VTWOEWWPTCRJEC-UHFFFAOYSA-N 1,1,1,4,4,4-hexafluorobutane-2,2-diol Chemical compound FC(C(CC(F)(F)F)(O)O)(F)F VTWOEWWPTCRJEC-UHFFFAOYSA-N 0.000 description 2
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PLTVOBWRGAWZOU-UHFFFAOYSA-N 1-(4-chlorophenyl)-3,3,3-trifluoropropan-1-one Chemical compound FC(F)(F)CC(=O)C1=CC=C(Cl)C=C1 PLTVOBWRGAWZOU-UHFFFAOYSA-N 0.000 description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- JJHHIJFTHRNPIK-UHFFFAOYSA-N Diphenyl sulfoxide Chemical compound C=1C=CC=CC=1S(=O)C1=CC=CC=C1 JJHHIJFTHRNPIK-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- YPMPTULBFPFSEQ-SNAWJCMRSA-N ethyl (e)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(/C)N YPMPTULBFPFSEQ-SNAWJCMRSA-N 0.000 description 2
- LHFJBGSSFFJXCW-UHFFFAOYSA-N ethyl 3-amino-2-(trifluoromethyl)but-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C LHFJBGSSFFJXCW-UHFFFAOYSA-N 0.000 description 2
- WXFFUFPJWCCJKD-UHFFFAOYSA-N ethyl 3-amino-3-phenyl-2-(trifluoromethyl)prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=CC=CC=C1 WXFFUFPJWCCJKD-UHFFFAOYSA-N 0.000 description 2
- OOIRRXMPCORKCC-UHFFFAOYSA-N ethyl 3-amino-4,4,4-trifluoro-2-(trifluoromethyl)but-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C(F)(F)F OOIRRXMPCORKCC-UHFFFAOYSA-N 0.000 description 2
- DBGNGAPVYJEOEE-UHFFFAOYSA-N ethyl 3-oxo-2-(trifluoromethyl)heptanoate Chemical compound CCCCC(=O)C(C(=O)OCC)C(F)(F)F DBGNGAPVYJEOEE-UHFFFAOYSA-N 0.000 description 2
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N ethyl but-2-enoate Chemical compound CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- HMDRYDOGLSACSY-UHFFFAOYSA-N 1,1,1-trifluoro-4-methylpentan-3-one Chemical compound CC(C)C(=O)CC(F)(F)F HMDRYDOGLSACSY-UHFFFAOYSA-N 0.000 description 1
- YMFPDHRTDDCTME-UHFFFAOYSA-N 1,1,1-trifluoroheptan-3-one Chemical compound CCCCC(=O)CC(F)(F)F YMFPDHRTDDCTME-UHFFFAOYSA-N 0.000 description 1
- ZNPTZZRIBUAVRB-UHFFFAOYSA-N 1,1,1-trifluorohexan-3-one Chemical compound CCCC(=O)CC(F)(F)F ZNPTZZRIBUAVRB-UHFFFAOYSA-N 0.000 description 1
- IPRROFRGPQGDOX-UHFFFAOYSA-K 1,2,3,4,5-pentamethylcyclopenta-1,3-diene;trichlorotitanium Chemical group Cl[Ti](Cl)Cl.CC=1C(C)=C(C)[C-](C)C=1C IPRROFRGPQGDOX-UHFFFAOYSA-K 0.000 description 1
- LOWMYOWHQMKBTM-UHFFFAOYSA-N 1-butylsulfinylbutane Chemical compound CCCCS(=O)CCCC LOWMYOWHQMKBTM-UHFFFAOYSA-N 0.000 description 1
- BQCCJWMQESHLIT-UHFFFAOYSA-N 1-propylsulfinylpropane Chemical compound CCCS(=O)CCC BQCCJWMQESHLIT-UHFFFAOYSA-N 0.000 description 1
- SSORSZACHCNXSJ-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NCC(C)O SSORSZACHCNXSJ-UHFFFAOYSA-N 0.000 description 1
- DILISPNYIVRDBP-UHFFFAOYSA-N 2-[3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile Chemical compound OC(CNC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=CC2=CC=CC=C2C=C1)C DILISPNYIVRDBP-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- PARCUCWFQOWGFX-UHFFFAOYSA-N 2-butan-2-ylsulfinylbutane Chemical compound CCC(C)S(=O)C(C)CC PARCUCWFQOWGFX-UHFFFAOYSA-N 0.000 description 1
- MCDJZKPTBCWNSJ-UHFFFAOYSA-N 2-methyl-1-(2-methylpropylsulfinyl)propane Chemical compound CC(C)CS(=O)CC(C)C MCDJZKPTBCWNSJ-UHFFFAOYSA-N 0.000 description 1
- WFJXYIUAMJAURQ-UHFFFAOYSA-N 2-propan-2-ylsulfinylpropane Chemical compound CC(C)S(=O)C(C)C WFJXYIUAMJAURQ-UHFFFAOYSA-N 0.000 description 1
- JBCXLODHZJAKDB-UHFFFAOYSA-N 3,3,3-trifluoro-1-(2-methoxyphenyl)propan-1-one Chemical compound COC1=CC=CC=C1C(=O)CC(F)(F)F JBCXLODHZJAKDB-UHFFFAOYSA-N 0.000 description 1
- LJDWIMORXWXHMU-UHFFFAOYSA-N 3,3,3-trifluoro-1-(3-methoxyphenyl)propan-1-one Chemical compound COC1=CC=CC(C(=O)CC(F)(F)F)=C1 LJDWIMORXWXHMU-UHFFFAOYSA-N 0.000 description 1
- LPDOSBVQJBUGLG-UHFFFAOYSA-N 3,3,3-trifluoro-1-(4-methylphenyl)propan-1-one Chemical compound CC1=CC=C(C(=O)CC(F)(F)F)C=C1 LPDOSBVQJBUGLG-UHFFFAOYSA-N 0.000 description 1
- IVKPNYAMBOJGKI-UHFFFAOYSA-N 3,3,3-trifluoro-1-(4-nitrophenyl)propan-1-one Chemical compound [O-][N+](=O)C1=CC=C(C(=O)CC(F)(F)F)C=C1 IVKPNYAMBOJGKI-UHFFFAOYSA-N 0.000 description 1
- HVAPLSNCVYXFDQ-UHFFFAOYSA-N 3,3-dimethyl-1-(trifluoromethyl)-1$l^{3},2-benziodoxole Chemical compound C1=CC=C2C(C)(C)OI(C(F)(F)F)C2=C1 HVAPLSNCVYXFDQ-UHFFFAOYSA-N 0.000 description 1
- BTXXTMOWISPQSJ-UHFFFAOYSA-N 4,4,4-trifluorobutan-2-one Chemical compound CC(=O)CC(F)(F)F BTXXTMOWISPQSJ-UHFFFAOYSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- ONPGOSVDVDPBCY-CQSZACIVSA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ONPGOSVDVDPBCY-CQSZACIVSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VAXGBFLZNLRUHS-UHFFFAOYSA-N C(C)OC(C=C(C1=CC(=CC=C1)OC)N)=O Chemical compound C(C)OC(C=C(C1=CC(=CC=C1)OC)N)=O VAXGBFLZNLRUHS-UHFFFAOYSA-N 0.000 description 1
- SZLFTHJWEOZKAQ-QPJJXVBHSA-N C/C(/C(CN)=O)=N\C Chemical compound C/C(/C(CN)=O)=N\C SZLFTHJWEOZKAQ-QPJJXVBHSA-N 0.000 description 1
- TUOKKOLYJIAYRY-YFHOEESVSA-N CCOC(/C=C(/c(cc1)ccc1Cl)\N)=O Chemical compound CCOC(/C=C(/c(cc1)ccc1Cl)\N)=O TUOKKOLYJIAYRY-YFHOEESVSA-N 0.000 description 1
- APUIHBJDWFHDFP-UHFFFAOYSA-N CCOC(C(C(F)(F)F)C(c(cc1)ccc1Cl)=O)=O Chemical compound CCOC(C(C(F)(F)F)C(c(cc1)ccc1Cl)=O)=O APUIHBJDWFHDFP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- ZFDIRQKJPRINOQ-HWKANZROSA-N Ethyl crotonate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 1
- JBNRHDLQTVLVCY-UHFFFAOYSA-N FC(C(C(=O)O)=CN)(F)F Chemical compound FC(C(C(=O)O)=CN)(F)F JBNRHDLQTVLVCY-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021579 Iron(II) iodide Inorganic materials 0.000 description 1
- KUMCSMBDLMXYBM-UHFFFAOYSA-N NC(=CC(=O)OCC)C1=C(C=CC=C1)OC Chemical compound NC(=CC(=O)OCC)C1=C(C=CC=C1)OC KUMCSMBDLMXYBM-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- ODUIXUGXPFKQLG-QWRGUYRKSA-N [2-(4-chloro-2-fluoroanilino)-5-methyl-1,3-thiazol-4-yl]-[(2s,3s)-2,3-dimethylpiperidin-1-yl]methanone Chemical compound C[C@H]1[C@@H](C)CCCN1C(=O)C1=C(C)SC(NC=2C(=CC(Cl)=CC=2)F)=N1 ODUIXUGXPFKQLG-QWRGUYRKSA-N 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- FTXHRXNIBVONLO-UHFFFAOYSA-N benzyl 3,3,3-trifluoro-2-formylpropanoate Chemical compound C(C1=CC=CC=C1)OC(C(C=O)C(F)(F)F)=O FTXHRXNIBVONLO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- WJYJULOBJLLPER-UHFFFAOYSA-N copper(1+);trifluoromethane Chemical compound [Cu+].F[C-](F)F WJYJULOBJLLPER-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- FXIXJKOVGVATTM-UHFFFAOYSA-N diphenyl(trifluoromethyl)sulfanium Chemical class C=1C=CC=CC=1[S+](C(F)(F)F)C1=CC=CC=C1 FXIXJKOVGVATTM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- UUAOTFRYFNIJQW-UHFFFAOYSA-N ethyl 3-amino-2-(trifluoromethyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=CC(=CC=C1)C(F)(F)F UUAOTFRYFNIJQW-UHFFFAOYSA-N 0.000 description 1
- OAGKFKRMXWTRLJ-UHFFFAOYSA-N ethyl 3-amino-2-(trifluoromethyl)hept-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)CCCC OAGKFKRMXWTRLJ-UHFFFAOYSA-N 0.000 description 1
- HJRXZINSSJBUSU-UHFFFAOYSA-N ethyl 3-amino-2-(trifluoromethyl)hex-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)CCC HJRXZINSSJBUSU-UHFFFAOYSA-N 0.000 description 1
- ZEEJKQDPOAPNHD-UHFFFAOYSA-N ethyl 3-amino-3-(2-methoxyphenyl)-2-(trifluoromethyl)prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=C(C=CC=C1)OC ZEEJKQDPOAPNHD-UHFFFAOYSA-N 0.000 description 1
- AUNHNNJBBATWGM-UHFFFAOYSA-N ethyl 3-amino-3-(3-methoxyphenyl)-2-(trifluoromethyl)prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=CC(=CC=C1)OC AUNHNNJBBATWGM-UHFFFAOYSA-N 0.000 description 1
- ISDNHUKDVRTCDD-UHFFFAOYSA-N ethyl 3-amino-3-(4-chlorophenyl)-2-(trifluoromethyl)prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=CC=C(C=C1)Cl ISDNHUKDVRTCDD-UHFFFAOYSA-N 0.000 description 1
- TUOKKOLYJIAYRY-UHFFFAOYSA-N ethyl 3-amino-3-(4-chlorophenyl)prop-2-enoate Chemical compound CCOC(=O)C=C(N)C1=CC=C(Cl)C=C1 TUOKKOLYJIAYRY-UHFFFAOYSA-N 0.000 description 1
- GJKVXXFINFFLHC-UHFFFAOYSA-N ethyl 3-amino-3-(4-methylphenyl)-2-(trifluoromethyl)prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=CC=C(C=C1)C GJKVXXFINFFLHC-UHFFFAOYSA-N 0.000 description 1
- UBGYTDILSOBSKQ-UHFFFAOYSA-N ethyl 3-amino-3-(4-methylphenyl)prop-2-enoate Chemical compound CCOC(=O)C=C(N)C1=CC=C(C)C=C1 UBGYTDILSOBSKQ-UHFFFAOYSA-N 0.000 description 1
- OJUYLAQLJPWIQJ-UHFFFAOYSA-N ethyl 3-amino-3-(4-nitrophenyl)-2-(trifluoromethyl)prop-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C1=CC=C(C=C1)[N+](=O)[O-] OJUYLAQLJPWIQJ-UHFFFAOYSA-N 0.000 description 1
- WDECUCWUDKVIAV-UHFFFAOYSA-N ethyl 3-amino-3-(4-nitrophenyl)prop-2-enoate Chemical compound CCOC(=O)C=C(N)C1=CC=C([N+]([O-])=O)C=C1 WDECUCWUDKVIAV-UHFFFAOYSA-N 0.000 description 1
- TXYYKFPFZHQYDQ-UHFFFAOYSA-N ethyl 3-amino-3-[3-(trifluoromethyl)phenyl]prop-2-enoate Chemical compound CCOC(=O)C=C(N)C1=CC=CC(C(F)(F)F)=C1 TXYYKFPFZHQYDQ-UHFFFAOYSA-N 0.000 description 1
- HPMIGBCEBWYKPO-UHFFFAOYSA-N ethyl 3-amino-4-methyl-2-(trifluoromethyl)pent-2-enoate Chemical compound NC(=C(C(=O)OCC)C(F)(F)F)C(C)C HPMIGBCEBWYKPO-UHFFFAOYSA-N 0.000 description 1
- AEXYGJRYLCZIJM-UHFFFAOYSA-N ethyl 3-amino-4-methylpent-2-enoate Chemical compound CCOC(=O)C=C(N)C(C)C AEXYGJRYLCZIJM-UHFFFAOYSA-N 0.000 description 1
- SKOURRNNESBPHU-UHFFFAOYSA-N ethyl 3-aminohept-2-enoate Chemical compound CCCCC(N)=CC(=O)OCC SKOURRNNESBPHU-UHFFFAOYSA-N 0.000 description 1
- WLIGDZJHZGUCTD-UHFFFAOYSA-N ethyl 3-aminohex-2-enoate Chemical compound CCCC(N)=CC(=O)OCC WLIGDZJHZGUCTD-UHFFFAOYSA-N 0.000 description 1
- MQLVWQSVRZVNIP-UHFFFAOYSA-L ferrous ammonium sulfate hexahydrate Chemical compound [NH4+].[NH4+].O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O MQLVWQSVRZVNIP-UHFFFAOYSA-L 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- OWZIYWAUNZMLRT-UHFFFAOYSA-L iron(2+);oxalate Chemical compound [Fe+2].[O-]C(=O)C([O-])=O OWZIYWAUNZMLRT-UHFFFAOYSA-L 0.000 description 1
- LNOZJRCUHSPCDZ-UHFFFAOYSA-L iron(ii) acetate Chemical compound [Fe+2].CC([O-])=O.CC([O-])=O LNOZJRCUHSPCDZ-UHFFFAOYSA-L 0.000 description 1
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 0.000 description 1
- BQZGVMWPHXIKEQ-UHFFFAOYSA-L iron(ii) iodide Chemical compound [Fe+2].[I-].[I-] BQZGVMWPHXIKEQ-UHFFFAOYSA-L 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- MQBZEOSAUAGEAU-UHFFFAOYSA-N oxoazaniumylideneiron Chemical compound O=[N+]=[Fe] MQBZEOSAUAGEAU-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000003151 propanoic acid esters Chemical class 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明の目的は、入手容易かつ安価な試薬を用いて、(2,2,2−トリフルオロエチル)ケトンを製造する方法を提供することにある。
すなわち本発明は、
(i)一般式(1)
(ii)酸が、塩酸、酢酸または塩酸と酢酸の混合物である(i)に記載の製造方法;
(iii)3−オキソ−2−(トリフルオロメチル)プロパン酸エステル(1)と酸のモル比が、1:10から1:500の範囲から選ばれたモル比である(i)または(ii)のいずれかに記載の製造方法;
(iv)以下の工程Aから工程Cを含む工程からなることを特徴とする(2,2,2−トリフルオロエチルケトン)の製造方法;
工程A:鉄化合物、過酸化水素水および一般式(4)R8−S(=O)−R8(4)(式中、R8は炭素数1〜4のアルキル基またはフェニル基を示す。)で表されるスルホキシドの存在下、一般式(5)
工程B:3−アミノ−2−トリフルオロメチル−2−プロペン酸エステル(6)と酸を反応させることを特徴とする一般式(1)
工程C:3−オキソ−2−(トリフルオロメチル)プロパン酸エステル(1)を酸と反応させることを特徴とする一般式(3)
(v)工程AのR8が、メチル基である(iv)に記載の製造方法;
(vi)工程Aの鉄化合物が、硫酸鉄(II)またはフェロセンである(iv)または(v)のいずれかに記載の製造方法;に関するものである。以下に本発明を詳細に説明する。
工程C
工程A
工程B
反応時間は反応温度にもよるが、0.5時間以上行うことで、目的物を収率良く得ることができる。
1H−NMR(重ジメチルスルホキシド):δ1.09(3H,t,J=7.1Hz),4.17(2H,q,J=7.1Hz),6.31(1H,q,JHF=8.5Hz),7.58−7.63(2H,m),7.72−7.77(1H,m),8.05−8.09(2H,m).
19F−NMR(重ジメチルスルホキシド):δ−63.4(d,JFH=8.5Hz).
1H−NMR(重クロロホルム):δ3.80(2H,q,JHF=10.0Hz),7.48−7.56(2H,m),7.61−7.67(1H,m),7.92−7.97(2H,m).
19F−NMR(重クロロホルム):δ−62.0(t,JFH=10.0Hz).
1H−NMR(重ジメチルスルホキシド):δ1.22(3H,t,J=7.1Hz),4.17(2H,q,J=7.1Hz),7.31−7.37(2H,m),7.41−7.50(3H,m),8.10(1H,brs),9.13(1H,brs).
19F−NMR(重ジメチルスルホキシド):δ−47.6.
1H−NMR(重ジメチルスルホキシド):δ1.21(3H,t,J=7.1Hz),2.31(3H,s),4.23(2H,q,J=7.1Hz),5.34(1H,q,JHF=9.0Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.8(d,JFH=9.0Hz).
反応容器にフェロセン0.112g(0.6mmol)を量り取り、容器内をアルゴン置換した。さらに、ジメチルスルホキシド8.0mL、ヨウ化トリフルオロメチルの3.0mol/Lジメチルスルホキシド溶液2.0mL(ヨウ化トリフルオロメチル6.0mmol)、3−アミノ−2−ブテン酸エチル0.258g(2.0mmol)を加えた。得られた混合物に30%過酸化水素水0.4mL(過酸化水素4.0mmol)を毎分0.04mLの速度で滴下した後、室温で1時間攪拌した。得られた3−アミノ−2−トリフルオロメチル−2−ブテン酸エチルを含む粗生成物に、濃塩酸2.0mLを加え、さらに室温で2時間攪拌した。反応溶液に2,2,2−トリフルオロエタノールを加え、19F−NMRにより、3−オキソ−2−(トリフルオロメチル)ブタン酸エチルが生成率41%で生成していることを確認した。
1H−NMR(重ジメチルスルホキシド):δ2.16(3H,s),3.74(2H,q,JHF=11.2Hz).
19F−NMR(重ジメチルスルホキシド):δ−61.7(t,JFH=11.2Hz).
1H−NMR(重ジメチルスルホキシド):δ0.84(3H,t,J=7.2Hz),1.20(3H,t,J=7.1Hz),1.51(2H,sextet,J=7.2Hz),2.64(2H,t,J=7.2Hz),4.21(2H,q,JHF=7.1Hz),5.35(1H,q,J=9.0Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.4(d,JFH=9.0Hz).
1H−NMR(重ジメチルスルホキシド):δ0.84(3H,t,J=7.3Hz),1.49(2H,sextet,J=7.3Hz),2.47(2H,t,J=7.3Hz),3.69(2H,q,JHF=11.2Hz).
19F−NMR(重ジメチルスルホキシド):δ−61.7(t,JFH=11.2Hz).
1H−NMR(重ジメチルスルホキシド):δ1.06(6H,d,J=6.8Hz),1.19(3H,t,J=7.1Hz),2.86(1H,septet,J=6.8Hz),4.20(2H,q,J=7.1Hz),5.59(2H,q,JHF=8.8Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.7(d,JFH=8.8Hz).
1H−NMR(重クロロホルム):δ1.15(6H,d,J=6.9Hz),2.68(1H,septet,J=6.9Hz),3.28(2H,q,JHF=10.3Hz).
19F−NMR(重クロロホルム):δ−62.5(t,JFH=10.3Hz).
1H−NMR(重ジメチルスルホキシド):δ0.84(3H,t,J=7.3Hz),1.20(3H,t,J=7.1Hz),1.26(2H,sextet,J=7.3Hz),1.48(2H,quintet,J=7.3Hz),2.62−2.69(2H,m),4.21(2H,q,J=7.1Hz),5.36(1H,q,JHF=9.0Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.4(d,JFH=9.0Hz).
1H−NMR(重クロロホルム):δ0.92(3H,t,J=7.3Hz),1.31(2H,sextet,J=7.3Hz),1.59(2H,quintet,J=7.3Hz),2.53(2H,t,J=7.3Hz),3.22(1H,q,JHF=10.5Hz).
19F−NMR(重クロロホルム):δ−62.8(t,JFH=10.5Hz).
1H−NMR(重ジメチルスルホキシド):δ1.09(3H,t,J=7.1Hz),2.40(3H,s),4.16(2H,q,J=7.1Hz),6.27(1H,q,JHF=8.5Hz),7.41(2H,d,J=8.2Hz),7.97(2H,d,J=8.2Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.4(d,JFH=8.5Hz).
1H−NMR(重クロロホルム):δ2.44(3H,s),3.76(2H,q,JHF=10.1Hz),7.30(2H,d,J=8.2Hz),7.83(2H,d,J=8.2Hz).
19F−NMR(重クロロホルム):δ−62.0(t,JFH=10.1Hz).
1H−NMR(重ジメチルスルホキシド):δ1.09(3H,t,J=7.1Hz),4.17(2H,q,J=7.1Hz),6.34(1H,q,JHF=8.4Hz),7.70(2H,d,J=8.5Hz),8.08(2H,d,J=8.5Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.3(d,JFH=8.4Hz).
1H−NMR(重クロロホルム):δ3.77(2H,q,JHF=9.9Hz),7.49(2H,d,J=8.7Hz),7.88(2H,d,J=8.7Hz).
19F−NMR(重クロロホルム):δ−62.0(t,JFH=9.9Hz).
1H−NMR(重ジメチルスルホキシド):δ1.07(3H,t,J=7.1Hz),4.12−4.22(2H,m),6.50(1H,q,JHF=8.4Hz),7.83−7.90(1H,m),8.11−8.16(1H,m),8.31−8.37(1H,m),8.38−8.43(1H,m).
19F−NMR(重ジメチルスルホキシド):δ−61.4(3F,s),−63.1(3F,d,JFH=8.4Hz).
1H−NMR(重ジメチルスルホキシド):δ4.53(2H,q,JHF=10.8Hz),7.78−7.85(1H,m),8.04−8.10(1H,m),8.24−8.30(2H,m).
19F−NMR(重ジメチルスルホキシド):δ−61.1(3F,t,JFH=10.8Hz),−61.2(3F,s).
1H−NMR(重ジメチルスルホキシド):δ1.09(3H,t,J=7.1Hz),3.83(3H,s),4.17(2H,q,J=7.1Hz),6.33(1H,q,JHF=8.6Hz),7.29−7.34(1H,m),7.48−7.58(2H,m),7.64−7.69(1H,m).
19F−NMR(重ジメチルスルホキシド):δ−63.1(d,JFH=8.6Hz).
1H−NMR(重クロロホルム):δ3.78(2H,q,JHF=9.9Hz),3.87(3H,s),7.15−7.20(1H,m),7.38−7.44(1H,m),7.45−7.50(2H,m).
19F−NMR(重クロロホルム):δ−62.1(t,JFH=10.3Hz).
1H−NMR(重ジメチルスルホキシド):δ1.13(3H,t,J=7.1Hz),3.86(3H,s),4.13−4.23(2H,m),5.66(1H,q,JHF=8.9Hz),7.06−7.12(1H,m),7.20−7.25(1H,m),7.62−7.68(1H,m),7.73−7.77(1H,m).
19F−NMR(重ジメチルスルホキシド):δ−62.8(d,JFH=8.9Hz).
1H−NMR(重クロロホルム):δ3.88(2H,q,JHF=10.3Hz),3.95(3H,s),6.97−7.01(1H,m),7.02−7.07(1H,m),7.50−7.56(1H,m),7.79−7.84(1H,m).
19F−NMR(重クロロホルム):δ−62.5(t,J=10.3Hz).
1H−NMR(重ジメチルスルホキシド):δ1.08(3H,t,J=7.1Hz),4.14−4.21(2H,m),6.46(1H,q,JHF=8.4Hz),8.29(2H,d,J=9.0Hz),8.41(2H,d,J=9.0Hz).
19F−NMR(重ジメチルスルホキシド):δ−63.0(d,JFH=8.4Hz).
1H−NMR(重クロロホルム):δ3.85(2H,q,JHF=9.7Hz),8.11(2H,d,J=9.0Hz),8.37(2H,d,J=9.0Hz).
19F−NMR(重クロロホルム):δ−61.9(t,J=9.7Hz).
1H−NMR(重ジメチルスルホキシド):δ1.21(3H,t,J=7.1Hz),4.21(2H,q,J=7.1Hz),9.06(2H,brs).
19F−NMR(重ジメチルスルホキシド):δ−52.3(3F,q,J=15.4Hz),−64.3(3F,q,J=15.4Hz).
1H−NMR(重ジメチルスルホキシド):δ2.69(2H,q,J=11.0Hz),7.38(2H,s).
19F−NMR(重ジメチルスルホキシド):δ−59.0(3F,m),−84.4(3F,q,J=3.4Hz).
1H−NMR(重ジメチルスルホキシド):δ1.19(3H,t,J=7.1Hz),3.85(1H,q,JHF=8.7Hz),4.11−4.20(2H,m),7.79(2H,brs).
19F−NMR(重ジメチルスルホキシド):δ−61.0(3F,m),−82.5(3F,q,J=4.1Hz).
3−オキソ−3−フェニル−2−(トリフルオロメチル)プロパン酸エチル0.130g(0.5mmol)を反応容器にとり、アルゴン置換した。メタノール6.0mL、水酸化ナトリウムの2.0mol/L水溶液3.0mL(水酸化ナトリウム6.0mmol)加え、室温で2時間撹拌した。反応液を一部取り19F−NMRで分析したところ、原料である3−オキソ−3−フェニル−2−(トリフルオロメチル)プロパン酸エチルは消失したが、3,3,3−トリフルオロ−1−フェニル−1−プロパノンに対応するシグナルの出現は確認されず、また他の含フッ素も一切検出されなかった。
Claims (6)
- 酸が、塩酸、酢酸または塩酸と酢酸の混合物である請求項1に記載の製造方法。
- 3−オキソ−2−(トリフルオロメチル)プロパン酸エステル(1)と酸のモル比が、1:10から1:500の範囲から選ばれたモル比である請求項1または2のいずれかに記載の製造方法。
- 以下の工程Aから工程Cを含む工程からなることを特徴とする(2,2,2−トリフルオロエチルケトン)の製造方法。
工程A:鉄化合物、過酸化水素および一般式(4)R8−S(=O)−R8(4)(式中、R8は炭素数1〜4のアルキル基またはフェニル基を示す。)で表されるスルホキシドの存在下、一般式(5)
工程B:3−アミノ−2−トリフルオロメチル−2−プロペン酸エステル(6)と酸を反応させることを特徴とする一般式(1)
工程C:3−オキソ−2−(トリフルオロメチル)プロパン酸エステル(1)を酸と反応させることを特徴とする一般式(3)
- 工程AのR8が、メチル基である請求項4に記載の製造方法。
- 工程Aの鉄化合物が、硫酸鉄(II)またはフェロセンである請求項4または5のいずれかに記載の製造方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015023856A JP6435207B2 (ja) | 2015-02-10 | 2015-02-10 | (2,2,2−トリフルオロエチル)ケトンの製造方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015023856A JP6435207B2 (ja) | 2015-02-10 | 2015-02-10 | (2,2,2−トリフルオロエチル)ケトンの製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016147812A true JP2016147812A (ja) | 2016-08-18 |
JP6435207B2 JP6435207B2 (ja) | 2018-12-05 |
Family
ID=56687685
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015023856A Active JP6435207B2 (ja) | 2015-02-10 | 2015-02-10 | (2,2,2−トリフルオロエチル)ケトンの製造方法 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP6435207B2 (ja) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB753304A (en) * | 1952-09-03 | 1956-07-25 | Robert Neville Haszeldine | Polyfluorinated polyethers |
JPH06234665A (ja) * | 1990-05-23 | 1994-08-23 | Rhone Poulenc Chim | 酸化性媒質中でペルフルオロアルカンスルフィン酸ナトリウムにより求核性物質をペルフルオロアルキル化する反応剤および方法 |
JP2013043831A (ja) * | 2011-08-22 | 2013-03-04 | Nagoya Institute Of Technology | 第三級α‐トリフルオロメチルケトン誘導体及びその製造法 |
WO2014083936A1 (ja) * | 2012-11-27 | 2014-06-05 | 株式会社クレハ | カルボニル化合物の製造方法 |
-
2015
- 2015-02-10 JP JP2015023856A patent/JP6435207B2/ja active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB753304A (en) * | 1952-09-03 | 1956-07-25 | Robert Neville Haszeldine | Polyfluorinated polyethers |
JPH06234665A (ja) * | 1990-05-23 | 1994-08-23 | Rhone Poulenc Chim | 酸化性媒質中でペルフルオロアルカンスルフィン酸ナトリウムにより求核性物質をペルフルオロアルキル化する反応剤および方法 |
JP2013043831A (ja) * | 2011-08-22 | 2013-03-04 | Nagoya Institute Of Technology | 第三級α‐トリフルオロメチルケトン誘導体及びその製造法 |
WO2014083936A1 (ja) * | 2012-11-27 | 2014-06-05 | 株式会社クレハ | カルボニル化合物の製造方法 |
Non-Patent Citations (2)
Title |
---|
JOURNAL OF FLUORINE CHEMISTRY, vol. 26, JPN6018040916, 1984, pages 183 - 210 * |
ZHURNAL ORGANICHESKOI KHIMII, vol. 22(2), JPN6018040915, 1986, pages 441 - 442 * |
Also Published As
Publication number | Publication date |
---|---|
JP6435207B2 (ja) | 2018-12-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5587307B2 (ja) | アルケノンの製造方法 | |
EP3452437B1 (en) | Method for aromatic fluorination | |
JP3533134B2 (ja) | フッ素化剤及びその製法と使用 | |
JP6029090B2 (ja) | フッ素化物の単離方法 | |
WO2009122834A1 (ja) | 4-パーフルオロイソプロピルアニリン類の製造方法 | |
WO2021157590A1 (ja) | ジフルオロメチル置換芳香族複素環化合物の製造方法 | |
JP6435207B2 (ja) | (2,2,2−トリフルオロエチル)ケトンの製造方法 | |
KR20110025182A (ko) | 3-메틸-2-티오펜카르복실산의 제조 방법 | |
JP6723817B2 (ja) | (トリフルオロメチル)マロン酸エステルの製造方法 | |
JP5853771B2 (ja) | α,α−ジフルオロ芳香族化合物の製造方法 | |
JP2008280250A (ja) | パーフルオロアルキル基を有するα,β−不飽和カルボニル化合物およびその製造方法 | |
WO2016132805A1 (ja) | 含フッ素α-ケトカルボン酸エステル類の実用的な製造方法 | |
JP5067780B2 (ja) | パーフルオロアルキル基を有するキノリン類の製造方法 | |
JP5238172B2 (ja) | パーフルオロアルキル基を有する含窒素六員環化合物およびその製造方法 | |
JP5090711B2 (ja) | 2,6−ジアミノ−8,8−ビス(パーフルオロアルキル)−8h−プリン類の製造方法 | |
EP1352898B1 (en) | Process for producing beta-ketonitrile compound | |
JP4165110B2 (ja) | 4−オキシピリミジン誘導体の製法 | |
JP4273271B2 (ja) | ピラゾール化合物及びその製造法 | |
JP5915004B2 (ja) | ピラゾール化合物の製造方法 | |
JP5205971B2 (ja) | テトラヒドロピラン化合物の製造方法 | |
US10472312B2 (en) | Method for producing phenoxyethanol derivative | |
JP2008231040A (ja) | アミド化合物およびその製造方法 | |
JP2006312644A (ja) | β−ケトニトリル類の製法 | |
WO2005014514A1 (ja) | 4-ヒドロキシジフェニルエーテルの製造方法 | |
JP4371416B2 (ja) | 高純度2,4−ジクロロ−3−アルキル−6−tert−ブチルフェノール類およびその製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20171213 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A712 Effective date: 20180111 |
|
TRDD | Decision of grant or rejection written | ||
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20181012 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20181106 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20181112 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6435207 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |