WO2022220231A1 - Method for isolating fluorinated substance - Google Patents
Method for isolating fluorinated substance Download PDFInfo
- Publication number
- WO2022220231A1 WO2022220231A1 PCT/JP2022/017561 JP2022017561W WO2022220231A1 WO 2022220231 A1 WO2022220231 A1 WO 2022220231A1 JP 2022017561 W JP2022017561 W JP 2022017561W WO 2022220231 A1 WO2022220231 A1 WO 2022220231A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- sof
- group
- carbon atoms
- fluoride
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000000126 substance Substances 0.000 title claims abstract description 11
- -1 sulfinyl compound Chemical class 0.000 claims abstract description 165
- VRTQPEYVMHATOA-UHFFFAOYSA-N (4-tert-butyl-2,6-dimethylphenyl)-trifluoro-$l^{4}-sulfane Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1S(F)(F)F VRTQPEYVMHATOA-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000006227 byproduct Substances 0.000 claims abstract description 10
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims abstract description 9
- 125000001302 tertiary amino group Chemical group 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 36
- 239000011541 reaction mixture Substances 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 21
- 238000003682 fluorination reaction Methods 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 19
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 150000003335 secondary amines Chemical class 0.000 description 14
- 150000003512 tertiary amines Chemical group 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 150000002894 organic compounds Chemical class 0.000 description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000002222 fluorine compounds Chemical class 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- BSHXDCDKLVRNJH-UHFFFAOYSA-N CC(C)(C)C(C=C1C)=CC(C)=C1S(N1CCN(C)CC1)=O Chemical compound CC(C)(C)C(C=C1C)=CC(C)=C1S(N1CCN(C)CC1)=O BSHXDCDKLVRNJH-UHFFFAOYSA-N 0.000 description 3
- GSPSWSHLGVNGLJ-UHFFFAOYSA-N CC(C)(C)C(C=C1C)=CC(C)=C1S(OCCN(C)C)=O Chemical compound CC(C)(C)C(C=C1C)=CC(C)=C1S(OCCN(C)C)=O GSPSWSHLGVNGLJ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000012025 fluorinating agent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MFVFDTCSVFBOTL-UHFFFAOYSA-N 1,3-diazetidine Chemical compound C1NCN1 MFVFDTCSVFBOTL-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- PHQREJCPVUZOGR-UHFFFAOYSA-N 9,9-difluorofluorene Chemical compound C1=CC=C2C(F)(F)C3=CC=CC=C3C2=C1 PHQREJCPVUZOGR-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003759 ester based solvent Substances 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 229920002313 fluoropolymer Polymers 0.000 description 2
- 239000004811 fluoropolymer Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000005453 ketone based solvent Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ZBOWKDHBOFMERX-UHFFFAOYSA-N 1,3-diazepane Chemical compound C1CCNCNC1 ZBOWKDHBOFMERX-UHFFFAOYSA-N 0.000 description 1
- VPPMWVKTJWIMOY-UHFFFAOYSA-N 1,3-diazocane Chemical compound C1CCNCNCC1 VPPMWVKTJWIMOY-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- CXPUAWQOXQINEX-UHFFFAOYSA-N 1,4-diazocane Chemical compound C1CCNCCNC1 CXPUAWQOXQINEX-UHFFFAOYSA-N 0.000 description 1
- HTSQWLLKIZBMEO-UHFFFAOYSA-N 1,5-diazocane Chemical compound C1CNCCCNC1 HTSQWLLKIZBMEO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 239000012988 Dithioester Substances 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000002078 anthracen-1-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([*])=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000000748 anthracen-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C([H])=C([*])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000007323 disproportionation reaction Methods 0.000 description 1
- 125000005022 dithioester group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 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 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
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- 150000003564 thiocarbonyl compounds Chemical class 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000005323 thioketone group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/18—Preparation of halogenated hydrocarbons by replacement by halogens of oxygen atoms of carbonyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/38—Separation; Purification; Stabilisation; Use of additives
- C07C17/395—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to a chemical modification of at least one compound
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C23/00—Compounds containing at least one halogen atom bound to a ring other than a six-membered aromatic ring
- C07C23/18—Polycyclic halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/04—Sulfinic acids; Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/06—Sulfinamides
Definitions
- the present invention provides a fluorinated product obtained using 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, a byproduct produced from 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene It relates to a method of isolation from the product.
- 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is a fluorinating agent used in the fluorination reaction of organic compounds, and a commercially available product called Fluolead (registered trademark) is known.
- Fluolead® is a relatively stable and easy-to-handle fluorinating agent that fluorinates many types of organic compounds, including alcohols, carbonyl compounds, thiocarbonyl compounds, etc., in high yields (Patent Document 1 and Non-Patent Reference 1). These fluorinated compounds are useful in the development of various fields such as pharmaceuticals and agrochemicals and liquid crystal materials.
- Fluolead (registered trademark) is converted into a sulfinic acid fluoride compound (hereinafter also referred to as "SOF"), which is a by-product (see Scheme 1). It is not easy to separate SOF from the fluorinated product, which is the target of the reaction, and this poses a problem when using Fluolead (registered trademark) in industrial-scale fluorination reactions.
- SOF sulfinic acid fluoride compound
- the following three methods are mainly known as techniques for removing SOF from the fluorinated reaction target.
- Patent Document 2 Method using oxidation and hydrolysis treatment
- the method using chromatography has the problem that purification by column chromatography requires a great deal of cost on an industrial scale.
- the technique using the above-mentioned distillation has a problem that it cannot be applied when the target fluorinated compound is solid or has a high boiling point.
- the method using the oxidation and hydrolysis treatment has problems such as the need to go through three stages of chemical conversion and the use of an oxidizing agent with a risk of explosion. Another problem is that this method cannot be applied if the target fluoride compound has a structure that reacts during an oxidation reaction or a hydrolysis reaction.
- conventional approaches have problems with cost and the range of applicable fluorides.
- the object of the present invention is the production of fluorides with 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, in particular for the production of industrial scale quantities, by-products resulting from said production process.
- An object of the present invention is to provide a new technique capable of removing SOF, which is a product, in a more versatile and efficient manner and isolating a fluoride compound.
- the inventors of the present invention have conducted intensive studies to achieve the above object, and found that after converting SOF into a sulfinyl compound containing a secondary or tertiary amine skeleton, the sulfinyl compound can be easily converted from a fluoride. The inventors have found that they can be separated and removed, and completed the present invention.
- a fluorinated product obtained from a fluorination reaction with 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is isolated from a by-product represented by the following formula (1) (hereinafter also referred to as "SOF").
- SOF a by-product represented by the following formula (1)
- a method for (Step 1) A step of converting the SOF into a sulfinyl compound represented by the following formula (2) (hereinafter also referred to as “sulfinyl compound (2)”) in a reaction mixture containing the fluoride and the SOF.
- step 2 a step of removing the sulfinyl compound (2) obtained in step 1 by utilizing the difference in chemical properties from the fluoride compound.
- step 1 the reaction mixture containing the fluoride and the SOF is treated with an alcohol compound containing a secondary or tertiary amine skeleton represented by the following formula (3) to convert the SOF to the following formula ( The method according to the above [1], wherein the sulfinyl compound represented by 4) is converted.
- R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms.
- R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time.
- R 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms, and n 1 is an integer of 1 to 4.
- step 1 the reaction mixture containing the fluoride and the SOF is treated with a primary or secondary amine compound containing a secondary or tertiary amine skeleton represented by the following formula (5): , the method according to the above [1], wherein the SOF is converted into a sulfinyl compound represented by the following formula (6).
- R 3 and R 4 each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached;
- R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and
- n 2 is 1 to 8.
- R 3 and R 4 are not hydrogen atoms at the same time.
- the by-product SOF can be converted to a sulfinyl compound containing a secondary or tertiary amine skeleton by a one-step process.
- the sulfinyl compound can be separated and removed from the fluoride by a general post-treatment operation without column chromatography or distillation purification. Therefore, according to the present invention, SOF can be easily removed at a low cost, and an industrial scale amount of fluorinated compounds using 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene can be obtained. It can be produced with good purity.
- SOF can be separated from these fluorine compounds, whether they are solid or have a high boiling point.
- Example 1 is a chart comparing HPLC analysis results of an organic layer before addition of acetic acid and an organic layer after liquid separation operation in Example 1.
- FIG. 4 is a chart comparing the HPLC analysis results of the organic layer before addition of acetic acid and the organic layer after filtration in Example 2.
- FIG. 1 is a chart comparing HPLC analysis results of an organic layer before addition of acetic acid and an organic layer after liquid separation operation in Example 1.
- FIG. 4 is a chart comparing the HPLC analysis results of the organic layer before addition of acetic acid and the organic layer after filtration in Example 2.
- the reaction mixture containing the fluorinated compound and the SOF used in Step 1 of the present invention is prepared by adding an organic compound such as 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene (hereinafter also referred to as "fluorination reaction step"; see Scheme 4), without particular limitation, and any one can be used.
- the reaction mixture contains a fluorinated reaction target fluorinated from an organic compound or the like, and a by-product SOF generated from 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene. Additionally, the reaction mixture may also contain unreacted or excess 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene and/or unfluorinated compounds in the fluorination reaction.
- the fluorination reaction step can be performed with known reactions and conditions (see, for example, Non-Patent Document 1, which is incorporated by reference for all purposes).
- an organic compound to be fluorinated, 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, a solvent, and hydrogen fluoride may be mixed and reacted in a reactor.
- the organic compound to be fluorinated is not particularly limited as long as it contains a hydroxyl group, a carbonyl group, or a thiocarbonyl group, and any compound may be used.
- organic compounds are selected from the group consisting of alcohols, aldehydes, ketones, diketones, ketoesters, carboxylic acids, thioketones, thioesters, dithioesters, thiocarbonates and dithiocarbonates.
- Cyclic compounds having a carbonyl group in the ring such as 9-fluorenone can also be used.
- Preferred are compounds containing a hydroxyl group and a carbonyl group.
- the organic compound is preferably a fluorinated compound having chemical properties different from those of the sulfinyl compound (2) after fluorination,
- 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is not particularly limited, and for example, commercially available Fluolead (registered trademark) may be used.
- the above hydrogen fluoride may be used as a mixture with an organic solvent.
- organic solvents include ethers such as diethyl ether and tetrahydrofuran, and organic bases such as pyridine and triethylamine.
- organic bases are preferred, and pyridine is more preferred.
- the conditions for the fluorination reaction vary depending on the type of the organic compound to be fluorinated, but the reaction temperature is preferably in the range of about -20 to about 120°C from the viewpoint of obtaining a fluorinated compound in good yield. , more preferably from about 0 to about 60° C., and most preferably at room temperature.
- reaction time can be selected so that the fluorination is completed. It is preferably about 1 minute to 24 hours, more preferably about 5 minutes to 6 hours. It may take about 6 days depending on the type of organic compound to be fluorinated.
- Organic solvents such as dichloromethane, heptane, toluene, and chloroform can be used as solvents.
- an organic solvent capable of satisfactorily dissolving the target fluorinated compound is preferable because the target fluorinated compound can be easily taken out by liquid separation operation in the removal step described later.
- the above conversion reaction step is not particularly limited as long as the sulfinyl compound (2) can be obtained from SOF, and may be carried out by any method.
- the reaction mixture containing the fluorinated compound and the SOF is treated with an alcohol containing a secondary or tertiary amine skeleton represented by the following formula (3) (hereinafter also referred to as "alcohol compound (3)”).
- SOF may be converted into a sulfinyl compound represented by the following formula (4) (hereinafter also referred to as "sulfinyl compound (4)").
- R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms. or a hydrogen atom, or R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time.
- R 1 and R 2 are not hydrogen atoms at the same time.
- amine compound (5) a primary or secondary amine containing a secondary or tertiary amine skeleton represented by the following formula (5) (hereinafter referred to as "amine compound (5) ”) to convert the SOF to a sulfinyl compound represented by the following formula (6) (hereinafter also referred to as “sulfinyl compound (6)”).
- R 3 and R 4 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached; R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and n 2 is 1 to 8. However, R 3 and R 4 are not hydrogen atoms at the same time. ]
- the sulfinyl compounds (4) and (6) are included in the sulfinyl compound (2). That is, the group of the sulfinyl compound (4): —O—(CH 2 ) n1 —N(R 1 )R 2 is an alkoxy group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
- the group of sulfinyl compound (6): —N(R 5 )—(CH 2 ) n2 —N(R 3 )R 4 is such that R 3 and R 5 together with the nitrogen atom to which they are attached When it does not form a ring together, it corresponds to R which is a secondary or tertiary amino group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
- the group of sulfinyl compound (6): —N(R 5 )—(CH 2 ) n2 —N(R 3 )R 4 is such that R 3 and R 5 together with the nitrogen atom to which they are attached When they form a ring together, they correspond to R, which is a cyclic amino group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
- R 1 and R 2 in the above formulas (3) and (4) are each independently of each other, preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, still more preferably is a methyl group.
- n 1 in formulas (3) and (4) is preferably an integer of 1 to 4, more preferably 2.
- R 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms, and n 1 is an integer of 1 to 4. .
- Alcohol compound (3) is preferably 2-(dimethylamino)ethanol.
- the sulfinyl compound (4) preferably has the formula: It is a compound represented by or a salt thereof.
- R 3 , R 4 and R 5 in the above formulas (5) and (6) are each independently preferably an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group, It is an ethyl group or a hydrogen atom, more preferably a methyl group.
- R 3 and R 5 of formulas (5) and (6) above preferably together with the nitrogen atom to which they are attached form a ring, in particular piperazine, and R 4 is preferably It is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group, an ethyl group or a hydrogen atom, still more preferably a methyl group.
- n2 in formulas (5) and ( 6 ) is preferably an integer of 1-4.
- n 2 is preferably an integer of 1-2, more preferably 2.
- R 3 , R 4 and R 5 are each independently an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is 1 Integer from ⁇ 4.
- R 3 and R 5 preferably form a ring together with the nitrogen atom to which they are attached, and R 4 has 1 to 1 carbon atoms. 4 alkyl groups or hydrogen atoms, and n2 is an integer of 1-2 .
- Amine compound (5) is preferably N-methylpiperazine.
- the sulfinyl compound (6) preferably has the formula: It is a compound represented by or a salt thereof.
- Salts of the sulfinyl compounds (4) and (6) include organic acid salts such as acetate, propionate, butyrate, trifluoroacetate, methanesulfonate, and trifluoromethanesulfonate, and hydrochlorides, Examples include inorganic acid salts such as sulfates, nitrates, phosphates and hydrofluorides, preferably organic acid salts, more preferably acetates.
- the "alkyl group having 1 to 18 carbon atoms" is , which may be linear or branched, preferably an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl , a pentyl group, an isopentyl group, etc., more preferably an alkyl group having 1 to 4 carbon atoms, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group. etc., more preferably a methyl group or an ethyl group, particularly preferably a methyl group.
- the “aryl group having 6 to 30 carbon atoms” is a monocyclic or may be polycyclic such as bicyclic or tricyclic, preferably phenyl group, 1-naphthyl group, 2-naphthyl group, 1-anthryl group, 2-anthryl group, 9-anthryl group, 1-phenanthryl group, 2-phenanthryl group, 3-phenanthryl group, 4-phenanthryl group and 9-phenanthryl group, more preferably phenyl group, 1-naphthyl group and 2-naphthyl group, still more preferably phenyl group .
- the "aralkyl group having 7 to 30 carbon atoms" is, for example, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group and the like, more preferably , a benzyl group, a 1-phenylethyl group and a 2-phenylethyl group, and more preferably a benzyl group.
- the ring formed by R 1 and R 2 together with the nitrogen atom to which they are bonded is exemplified by piperidine, pyrrolidine, azetidine, aziridine, azepane, and azocane.
- piperidine, pyrrolidine and azetidine are preferred, piperidine and pyrrolidine are more preferred, and piperidine is even more preferred.
- the ring formed by R 3 and R 4 together with the nitrogen atom to which they are bonded is exemplified by piperidine, pyrrolidine, azetidine, aziridine, azepane, and azocane.
- piperidine, pyrrolidine and azetidine are preferred, piperidine and pyrrolidine are more preferred, and piperidine is even more preferred.
- piperazine, hexahydropyrimidine, imidazolidine, 1,3-diazetidine as a ring formed by R 3 and R 5 together with the nitrogen atom to which they are bonded 1,3-diazepane, 1,4-diazepane, 1,3-diazocane, 1,4-diazocane and 1,5-diazocane, preferably piperazine, hexahydropyrimidine, imidazolidine and 1,3-diazetidine.
- piperazine, hexahydropyrimidine and imidazolidine are more preferred, and piperazine is even more preferred.
- the reaction mixture containing the fluoride compound and the SOF is treated with the alcohol compound (3) or the amine compound (5) to convert the SOF to the sulfinyl compound (4) or (6).
- a preferred amount of alcohol compound (3) can be selected from the range of about 0.1 to about 30 moles per mole of SOF.
- About 1 to about 3 moles of alcohol compound (3) per mole of SOF is more preferred.
- a preferred amount of amine compound (5) can be selected from the range of about 0.1 to about 30 mol per 1 mol of SOF.
- amine compound (5) More preferably, about 1 to about 3 moles of amine compound (5) per mole of SOF.
- These alcohol compound (3) and amine compound (5) may be used as a solvent or one of the solvents in the conversion reaction step.
- the amount of SOF in the reaction mixture can be determined by the expected yield of fluorinated product produced in the fluorination reaction step (SOF is produced at least equimolar to the fluorinated product) or by objective detection methods such as NMR. , can be predicted.
- the amount of SOF can also be estimated from the amount of 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene used in the fluorination reaction step.
- the reaction temperature of the conversion reaction is preferably in the range of about -40 to about 120°C, more preferably about 0 to about 40°C, in order to achieve high conversion of SOF to sulfinyl compound (4), Room temperature is most preferred.
- the reaction temperature of the conversion reaction is preferably in the range of about -40 to about 120°C, more preferably about 0 to about 40°C, in order to achieve high conversion of SOF to sulfinyl compound (6). Yes, most preferably at room temperature.
- the reaction time can be chosen such that complete conversion of SOF to sulfinyl compound (4) occurs. It is preferably about 1 minute to about 24 hours, more preferably about 5 minutes to about 4 hours, particularly preferably about 10 minutes to about 1 hour. Also, the reaction time can be selected such that complete conversion of SOF to sulfinyl compound (6) occurs. It is preferably about 1 minute to about 24 hours, more preferably about 5 minutes to about 4 hours, particularly preferably about 10 minutes to about 1 hour.
- a base in order to neutralize the hydrogen fluoride present in the reactor.
- the base used for neutralizing hydrogen fluoride include organic bases such as tertiary amines, inorganic bases such as potassium carbonate, etc., preferably inorganic bases, and more preferably potassium carbonate. .
- Suitable solvents for use herein include, but are not limited to, hydrocarbon-based solvents, aromatic-based solvents, halogen-based solvents, ether-based solvents, ester-based solvents, ketone-based solvents, and mixtures thereof.
- hydrocarbon solvents are octane, heptane, hexane, pentane, and the like.
- aromatic solvents are toluene, xylene, benzene and the like.
- halogen-based solvents are dichloromethane, 1,2-dichloroethane, chloroform, trichlorethylene, tetrachloroethylene, and the like.
- ether solvents are diethyl ether, tetrahydrofuran, 2-methoxy-2-methylpropane and the like.
- ester solvents are ethyl acetate, isopropyl acetate, ethyl propionate and the like.
- ketone-based solvents are acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like.
- the alcohol compound (3) or amine compound (5) as a reaction substrate for the conversion reaction step can also be used as a solvent or one of the solvents.
- the solvent is used in the fluorination reaction step and is already present, so the addition of new solvent is often not required. That is, since the solvent already exists in the reaction mixture obtained from the fluorination reaction step, the alcohol compound (3) or the amine compound (5) is preferably newly added. However, even if the reaction mixture resulting from the fluorination reaction step contains solvent, fresh solvent can be added. However, for simplification of the process, it is preferable to omit the process of adding a new solvent.
- the sulfinyl compound (2) obtained from the conversion reaction step is separated from the fluorine compound by utilizing the difference in chemical properties from the fluoride compound, and removed from the reaction mixture of the present invention.
- a step of removing (hereinafter also referred to as “removing step”; see Scheme 6) is performed.
- the reaction mixture of the present invention contains a fluoride and SOF before the conversion reaction step as described above.
- the reaction mixture will contain the fluoride and the sulfinyl compound (2) (see scheme 5).
- the sulfinyl compound (2) is removed from the reaction mixture containing the fluorinated compound and the sulfinyl compound (2) by, for example, a general post-treatment operation, utilizing the fact that the sulfinyl compound (2) has different chemical properties from the fluorinated compound. It can be removed separately from the fluoride.
- a general post-treatment operation liquid-liquid separation or liquid-solid separation applicable on an industrial scale can be used. For example, by adding water to the reaction mixture containing the fluoride and the sulfinyl compound (2) and performing a liquid separation operation, an organic layer containing the fluoride and an aqueous layer containing the sulfinyl compound (2) are separated.
- the sulfinyl compound (2) can be easily removed simply by taking out the aqueous layer.
- an organic solvent such as n-heptane
- the sulfinyl compound (2) is precipitated and filtered off for easy removal. be able to.
- the sulfinyl compound (2) can be removed by standard and simple means that do not require special treatment using column chromatography, rectification purification, and other sophisticated techniques. , the fluoride can be isolated. This is a significant improvement in industrial application over the prior art techniques for isolating fluorides.
- the removal step includes treating the reaction mixture containing the fluoride obtained from the conversion reaction step and the sulfinyl compound (2) with an acid, It is preferable to remove the sulfinyl compound (2) by utilizing the difference in chemical properties from the fluorinated compound. That is, by adding an acid to the reaction mixture and then adding water to perform a liquid separation operation, the sulfinyl compound (2) can be more efficiently distributed to the aqueous layer, and as a result, the aqueous layer By removing the sulfinyl compound (2) can be easily removed.
- the sulfinyl compound (2) can be easily removed by precipitating the sulfinyl compound (2) by acid treatment and filtering the solid containing the sulfinyl compound (2).
- Acids that can be used are not particularly limited, but organic acids such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrofluoric acid. and the like, preferably an organic acid, more preferably acetic acid.
- the present invention by concentrating the organic layer containing the fluorine compound obtained in the removing step, a highly pure fluoride can be easily obtained.
- the fluorine compound can be dissolved in a larger amount in the organic layer by treating with an acid in the removal step described above, so that a higher purity fluoride can be obtained. It is advantageous to obtain Accordingly, the present invention is advantageously applied to the removal of by-products in the production of fluorides that do not form salts with acids.
- fluorinated compounds that do not form salts with acids include compounds that do not have a basic substituent such as an amino group or a pyridyl group.
- Example 1 A method for removing SOF from 9,9-difluorofluorene produced by fluorinating 9-fluorenone with Fluolead® using 2-(dimethylamino)ethanol
- Example 2 Method for removing SOF from 9,9-difluorofluorene produced by fluorinating 9-fluorenone with Fluolead® using N-methylpiperazine
- the present invention uses 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene as a fluorinating agent to produce a fluorinated product, particularly in industrial scale production, by removing SOF as a by-product. , can be used to isolate the desired fluorinated compound.
Abstract
The purpose of the present invention is to provide a novel technique which can be employed in the production of a fluorinated substance using 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, whereby it becomes possible to remove an SOF that is a by-product versatilely and efficiently to isolate the fluorinated substance. The present invention relates to a method for converting an SOF to a sulfinyl compound containing a secondary or tertiary amine backbone and then removing the sulfinyl compound.
Description
本発明は、２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンを用いて得られたフッ素化物を、２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンから生じた副生成物から単離する方法に関する。
The present invention provides a fluorinated product obtained using 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, a byproduct produced from 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene It relates to a method of isolation from the product.
２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンは有機化合物のフッ素化反応において使用されるフッ素化剤であり、Ｆｌｕｏｌｅａｄ（登録商標）という市販品が知られている。Ｆｌｕｏｌｅａｄ（登録商標）は比較的安定で取り扱いやすいフッ素化剤であり、アルコール、カルボニル化合物、チオカルボニル化合物等を含む多くの種類の有機化合物を高収率でフッ素化する（特許文献１及び非特許文献１）。これらのフッ素化物は医農薬品や液晶材料等の様々な分野の開発において有用である。しかしながら、Ｆｌｕｏｌｅａｄ（登録商標）はフッ素化反応後、副生成物であるスルフィン酸フルオリド化合物（以下「ＳＯＦ」ともいう）へと変換される（スキーム１参照）。ＳＯＦは反応目的物であるフッ素化物と分離することが容易ではなく、Ｆｌｕｏｌｅａｄ（登録商標）を工業スケールのフッ素化反応で利用するうえで問題となっている。
2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is a fluorinating agent used in the fluorination reaction of organic compounds, and a commercially available product called Fluolead (registered trademark) is known. Fluolead® is a relatively stable and easy-to-handle fluorinating agent that fluorinates many types of organic compounds, including alcohols, carbonyl compounds, thiocarbonyl compounds, etc., in high yields (Patent Document 1 and Non-Patent Reference 1). These fluorinated compounds are useful in the development of various fields such as pharmaceuticals and agrochemicals and liquid crystal materials. However, after the fluorination reaction, Fluolead (registered trademark) is converted into a sulfinic acid fluoride compound (hereinafter also referred to as "SOF"), which is a by-product (see Scheme 1). It is not easy to separate SOF from the fluorinated product, which is the target of the reaction, and this poses a problem when using Fluolead (registered trademark) in industrial-scale fluorination reactions.
ＳＯＦを反応目的物のフッ素化物から除去する手法としては、主に以下の３つの方法が知られている。
The following three methods are mainly known as techniques for removing SOF from the fluorinated reaction target.
(1) クロマトグラフィーを用いた手法
ＳＯＦは、アルカリ水溶液等で処理することによってスルフィン酸へと加水分解され、その後に不均化反応を起こして不均化物へと変換される（スキーム２参照）。この不均化物をカラムクロマトグラフィーによって除去することが可能である。 (1) Technique using chromatography SOF is hydrolyzed to sulfinic acid by treatment with an alkaline aqueous solution, etc., and then undergoes a disproportionation reaction to convert to a disproportionate (see Scheme 2). . This disproportionate can be removed by column chromatography.
ＳＯＦは、アルカリ水溶液等で処理することによってスルフィン酸へと加水分解され、その後に不均化反応を起こして不均化物へと変換される（スキーム２参照）。この不均化物をカラムクロマトグラフィーによって除去することが可能である。 (1) Technique using chromatography SOF is hydrolyzed to sulfinic acid by treatment with an alkaline aqueous solution, etc., and then undergoes a disproportionation reaction to convert to a disproportionate (see Scheme 2). . This disproportionate can be removed by column chromatography.
(2) 蒸留を用いた手法
目的とするフッ素化物が低沸点の場合、蒸留することによりフッ素化物と不均化物を分離することが可能である。 (2) Method Using Distillation When the target fluoride compound has a low boiling point, it is possible to separate the fluoride compound and the disproportionate compound by distillation.
目的とするフッ素化物が低沸点の場合、蒸留することによりフッ素化物と不均化物を分離することが可能である。 (2) Method Using Distillation When the target fluoride compound has a low boiling point, it is possible to separate the fluoride compound and the disproportionate compound by distillation.
(3) 酸化及び加水分解処理を用いた手法（特許文献２）
ＳＯＦをアルコールと反応させてスルフィン酸エステルへと変換し、これを酸化反応によってスルホン酸エステルに誘導、続く加水分解反応によってスルホン酸塩とし、これを分液除去する手法が報告されている（スキーム３参照）。 (3) Method using oxidation and hydrolysis treatment (Patent Document 2)
A method has been reported in which SOF is reacted with an alcohol to convert it to a sulfinate ester, which is then oxidized to yield a sulfonate ester, followed by a hydrolysis reaction to yield a sulfonate, which is removed by liquid separation (Scheme 3).
ＳＯＦをアルコールと反応させてスルフィン酸エステルへと変換し、これを酸化反応によってスルホン酸エステルに誘導、続く加水分解反応によってスルホン酸塩とし、これを分液除去する手法が報告されている（スキーム３参照）。 (3) Method using oxidation and hydrolysis treatment (Patent Document 2)
A method has been reported in which SOF is reacted with an alcohol to convert it to a sulfinate ester, which is then oxidized to yield a sulfonate ester, followed by a hydrolysis reaction to yield a sulfonate, which is removed by liquid separation (Scheme 3).
しかしながら、前記のクロマトグラフィーを用いた手法は、カラムクロマトグラフィーによる精製が工業スケールでは多大なコストがかかるという問題がある。また、前記の蒸留を用いた手法は、目的とするフッ素化物が固体又は高沸点の場合、適応できないという問題がある。また、前記の酸化及び加水分解処理を用いた手法は、三段階の化学変換を経る必要があり、また爆発の危険性がある酸化剤を使用する等の問題点がある。さらに目的とするフッ素化物が、酸化反応や加水分解反応時に反応する構造であれば本手法は適応できないことも問題である。
このように、従来の手法ではコスト及び適応可能なフッ素化物の範囲に問題があった。 However, the method using chromatography has the problem that purification by column chromatography requires a great deal of cost on an industrial scale. In addition, the technique using the above-mentioned distillation has a problem that it cannot be applied when the target fluorinated compound is solid or has a high boiling point. In addition, the method using the oxidation and hydrolysis treatment has problems such as the need to go through three stages of chemical conversion and the use of an oxidizing agent with a risk of explosion. Another problem is that this method cannot be applied if the target fluoride compound has a structure that reacts during an oxidation reaction or a hydrolysis reaction.
Thus, conventional approaches have problems with cost and the range of applicable fluorides.
このように、従来の手法ではコスト及び適応可能なフッ素化物の範囲に問題があった。 However, the method using chromatography has the problem that purification by column chromatography requires a great deal of cost on an industrial scale. In addition, the technique using the above-mentioned distillation has a problem that it cannot be applied when the target fluorinated compound is solid or has a high boiling point. In addition, the method using the oxidation and hydrolysis treatment has problems such as the need to go through three stages of chemical conversion and the use of an oxidizing agent with a risk of explosion. Another problem is that this method cannot be applied if the target fluoride compound has a structure that reacts during an oxidation reaction or a hydrolysis reaction.
Thus, conventional approaches have problems with cost and the range of applicable fluorides.
本発明の目的は、２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンを用いたフッ素化物の製造、特に工業的規模の量での製造のために、当該製造工程から生じた副生成物であるＳＯＦをより汎用的且つ効率的に除去して、フッ素化物を単離することができる新しい手法を提供することである。
The object of the present invention is the production of fluorides with 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, in particular for the production of industrial scale quantities, by-products resulting from said production process. An object of the present invention is to provide a new technique capable of removing SOF, which is a product, in a more versatile and efficient manner and isolating a fluoride compound.
本発明者らは、前記目的を達成するために鋭意研究を重ねた結果、ＳＯＦを第２級又は第３級アミン骨格を含むスルフィニル化合物に転化してから、当該スルフィニル化合物をフッ素化物から簡便に分離して除去し得ることを見出し、本発明を完成させた。
The inventors of the present invention have conducted intensive studies to achieve the above object, and found that after converting SOF into a sulfinyl compound containing a secondary or tertiary amine skeleton, the sulfinyl compound can be easily converted from a fluoride. The inventors have found that they can be separated and removed, and completed the present invention.
すなわち、本発明は以下のとおりである。
［１］
２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンによるフッ素化反応から得られたフッ素化物を下記式（１）で表される副生成物（以下「ＳＯＦ」ともいう）から単離する方法であって、
（工程１）前記フッ素化物と前記ＳＯＦとを含む反応混合物において、前記ＳＯＦを下記式（２）で表されるスルフィニル化合物（以下「スルフィニル化合物（２）」ともいう）に転化する工程
（式中、Ｒは、第２級若しくは第３級アミン骨格を含むアルコキシ基、第２級若しくは第３級アミン骨格を含む第２級若しくは第３級アミノ基、又は第２級若しくは第３級アミン骨格を含む環状アミノ基である）；及び
（工程２）工程１で得られた前記スルフィニル化合物（２）を、前記フッ素化物との化学的性質の違いを利用して除去する工程
を含む方法。
［２］
前記工程１において、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（３）で表される第２級又は第３級アミン骨格を含むアルコール化合物で処理して、前記ＳＯＦを下記式（４）で表されるスルフィニル化合物に転化する、前記［１］に記載の方法。
〔式（３）及び（４）中、Ｒ１及びＲ２は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ１及びＲ２は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ１は１～８の整数である。但し、Ｒ１及びＲ２は同時に水素原子ではない。〕
［３］
前記Ｒ１及びＲ２が、それぞれ互いに独立して、炭素数が１～４のアルキル基であり、ｎ１が１～４の整数である、前記［２］に記載の方法。
［４］
前記工程１において、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（５）で表される第２級又は第３級アミン骨格を含む第１級又は第２級アミン化合物で処理して、前記ＳＯＦを下記式（６）で表されるスルフィニル化合物に転化する、前記［１］に記載の方法。
〔式（５）及び（６）中、Ｒ３及びＲ４は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ３及びＲ４は、それらが結合している窒素原子と一緒になって環を形成していてもよく；Ｒ５は、炭素数が１～１８のアルキル基又は水素原子であるか、あるいは、Ｒ３及びＲ５は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ２は１～８である。但し、Ｒ３及びＲ４は同時に水素原子ではない。〕
［５］
前記Ｒ３、Ｒ４、及びＲ５が、それぞれ互いに独立して、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～４の整数である、前記［４］に記載の方法。
［６］
前記Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成し、Ｒ４が、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～２の整数である、前記［４］に記載の方法。
［７］
前記工程１から得られた前記フッ素化物と前記スルフィニル化合物（２）とを含む反応混合物を酸で処理してから、前記スルフィニル化合物（２）を除去する、前記［１］～［６］のいずれか一つに記載の方法。
［８］
前記フッ素化物が酸によって塩を形成しない、前記［７］に記載の方法。
［９］
下記式（４）で表される化合物又はその塩。
（式中、Ｒ１、Ｒ２、及びｎ１は、前記［２］に定義されたとおりである）
［１０］
下記式（６）で表される化合物又はその塩。
（式中、Ｒ３、Ｒ４、Ｒ５、及びｎ２は、前記［４］に定義されたとおりである） That is, the present invention is as follows.
[1]
A fluorinated product obtained from a fluorination reaction with 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is isolated from a by-product represented by the following formula (1) (hereinafter also referred to as "SOF"). a method for
(Step 1) A step of converting the SOF into a sulfinyl compound represented by the following formula (2) (hereinafter also referred to as “sulfinyl compound (2)”) in a reaction mixture containing the fluoride and the SOF.
(wherein R is an alkoxy group containing a secondary or tertiary amine skeleton, a secondary or tertiary amino group containing a secondary or tertiary amine skeleton, or a secondary or tertiary a cyclic amino group containing an amine skeleton); and (step 2) a step of removing the sulfinyl compound (2) obtained in step 1 by utilizing the difference in chemical properties from the fluoride compound. .
[2]
In step 1, the reaction mixture containing the fluoride and the SOF is treated with an alcohol compound containing a secondary or tertiary amine skeleton represented by the following formula (3) to convert the SOF to the following formula ( The method according to the above [1], wherein the sulfinyl compound represented by 4) is converted.
[In the formulas (3) and (4), R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms. or a hydrogen atom, or R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time. ]
[3]
The method according to [2] above, wherein R 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms, and n 1 is an integer of 1 to 4.
[4]
In step 1, the reaction mixture containing the fluoride and the SOF is treated with a primary or secondary amine compound containing a secondary or tertiary amine skeleton represented by the following formula (5): , the method according to the above [1], wherein the SOF is converted into a sulfinyl compound represented by the following formula (6).
[In the formulas (5) and (6), R 3 and R 4 each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached; R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and n 2 is 1 to 8. However, R 3 and R 4 are not hydrogen atoms at the same time. ]
[5]
The above [4], wherein R 3 , R 4 and R 5 are each independently an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is an integer of 1 to 4. the method of.
[6]
R 3 and R 5 form a ring together with the nitrogen atom to which they are attached, R 4 is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is 1 to The method according to [4] above, which is an integer of 2.
[7]
Any of the above [1] to [6], wherein the reaction mixture containing the fluorinated compound obtained from the step 1 and the sulfinyl compound (2) is treated with an acid, and then the sulfinyl compound (2) is removed. or the method described in one.
[8]
The method according to [7] above, wherein the fluoride does not form a salt with an acid.
[9]
A compound represented by the following formula (4) or a salt thereof.
(Wherein, R 1 , R 2 and n 1 are as defined in [2] above)
[10]
A compound represented by the following formula (6) or a salt thereof.
(Wherein, R 3 , R 4 , R 5 and n 2 are as defined in [4] above)
［１］
２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンによるフッ素化反応から得られたフッ素化物を下記式（１）で表される副生成物（以下「ＳＯＦ」ともいう）から単離する方法であって、
（工程１）前記フッ素化物と前記ＳＯＦとを含む反応混合物において、前記ＳＯＦを下記式（２）で表されるスルフィニル化合物（以下「スルフィニル化合物（２）」ともいう）に転化する工程
（式中、Ｒは、第２級若しくは第３級アミン骨格を含むアルコキシ基、第２級若しくは第３級アミン骨格を含む第２級若しくは第３級アミノ基、又は第２級若しくは第３級アミン骨格を含む環状アミノ基である）；及び
（工程２）工程１で得られた前記スルフィニル化合物（２）を、前記フッ素化物との化学的性質の違いを利用して除去する工程
を含む方法。
［２］
前記工程１において、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（３）で表される第２級又は第３級アミン骨格を含むアルコール化合物で処理して、前記ＳＯＦを下記式（４）で表されるスルフィニル化合物に転化する、前記［１］に記載の方法。
〔式（３）及び（４）中、Ｒ１及びＲ２は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ１及びＲ２は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ１は１～８の整数である。但し、Ｒ１及びＲ２は同時に水素原子ではない。〕
［３］
前記Ｒ１及びＲ２が、それぞれ互いに独立して、炭素数が１～４のアルキル基であり、ｎ１が１～４の整数である、前記［２］に記載の方法。
［４］
前記工程１において、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（５）で表される第２級又は第３級アミン骨格を含む第１級又は第２級アミン化合物で処理して、前記ＳＯＦを下記式（６）で表されるスルフィニル化合物に転化する、前記［１］に記載の方法。
〔式（５）及び（６）中、Ｒ３及びＲ４は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ３及びＲ４は、それらが結合している窒素原子と一緒になって環を形成していてもよく；Ｒ５は、炭素数が１～１８のアルキル基又は水素原子であるか、あるいは、Ｒ３及びＲ５は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ２は１～８である。但し、Ｒ３及びＲ４は同時に水素原子ではない。〕
［５］
前記Ｒ３、Ｒ４、及びＲ５が、それぞれ互いに独立して、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～４の整数である、前記［４］に記載の方法。
［６］
前記Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成し、Ｒ４が、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～２の整数である、前記［４］に記載の方法。
［７］
前記工程１から得られた前記フッ素化物と前記スルフィニル化合物（２）とを含む反応混合物を酸で処理してから、前記スルフィニル化合物（２）を除去する、前記［１］～［６］のいずれか一つに記載の方法。
［８］
前記フッ素化物が酸によって塩を形成しない、前記［７］に記載の方法。
［９］
下記式（４）で表される化合物又はその塩。
（式中、Ｒ１、Ｒ２、及びｎ１は、前記［２］に定義されたとおりである）
［１０］
下記式（６）で表される化合物又はその塩。
（式中、Ｒ３、Ｒ４、Ｒ５、及びｎ２は、前記［４］に定義されたとおりである） That is, the present invention is as follows.
[1]
A fluorinated product obtained from a fluorination reaction with 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is isolated from a by-product represented by the following formula (1) (hereinafter also referred to as "SOF"). a method for
(Step 1) A step of converting the SOF into a sulfinyl compound represented by the following formula (2) (hereinafter also referred to as “sulfinyl compound (2)”) in a reaction mixture containing the fluoride and the SOF.
(wherein R is an alkoxy group containing a secondary or tertiary amine skeleton, a secondary or tertiary amino group containing a secondary or tertiary amine skeleton, or a secondary or tertiary a cyclic amino group containing an amine skeleton); and (step 2) a step of removing the sulfinyl compound (2) obtained in step 1 by utilizing the difference in chemical properties from the fluoride compound. .
[2]
In step 1, the reaction mixture containing the fluoride and the SOF is treated with an alcohol compound containing a secondary or tertiary amine skeleton represented by the following formula (3) to convert the SOF to the following formula ( The method according to the above [1], wherein the sulfinyl compound represented by 4) is converted.
[In the formulas (3) and (4), R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms. or a hydrogen atom, or R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time. ]
[3]
The method according to [2] above, wherein R 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms, and n 1 is an integer of 1 to 4.
[4]
In step 1, the reaction mixture containing the fluoride and the SOF is treated with a primary or secondary amine compound containing a secondary or tertiary amine skeleton represented by the following formula (5): , the method according to the above [1], wherein the SOF is converted into a sulfinyl compound represented by the following formula (6).
[In the formulas (5) and (6), R 3 and R 4 each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached; R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and n 2 is 1 to 8. However, R 3 and R 4 are not hydrogen atoms at the same time. ]
[5]
The above [4], wherein R 3 , R 4 and R 5 are each independently an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is an integer of 1 to 4. the method of.
[6]
R 3 and R 5 form a ring together with the nitrogen atom to which they are attached, R 4 is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is 1 to The method according to [4] above, which is an integer of 2.
[7]
Any of the above [1] to [6], wherein the reaction mixture containing the fluorinated compound obtained from the step 1 and the sulfinyl compound (2) is treated with an acid, and then the sulfinyl compound (2) is removed. or the method described in one.
[8]
The method according to [7] above, wherein the fluoride does not form a salt with an acid.
[9]
A compound represented by the following formula (4) or a salt thereof.
(Wherein, R 1 , R 2 and n 1 are as defined in [2] above)
[10]
A compound represented by the following formula (6) or a salt thereof.
(Wherein, R 3 , R 4 , R 5 and n 2 are as defined in [4] above)
本発明によれば、副生成物であるＳＯＦを一段階の工程によって第２級又は第３級アミン骨格を含むスルフィニル化合物に転化することができる。また、当該スルフィニル化合物は、カラムクロマトグラフィーや蒸留精製を介さずに、一般的な後処理操作で、フッ素化物から分離して除去することができる。そのため、本発明によれば、ＳＯＦを簡便に低コストで除去することができるので、２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンを用いた工業的規模の量のフッ素化物を良好な純度で製造することができる。
加えて、本発明は、酸化反応や加水分解反応、蒸留の必要がないため、爆発の危険性がある酸化剤を使用しなくても済み、フッ素化物が酸化反応や加水分解反応時に反応する構造を有していても、また固体又は高沸点であっても、これらフッ素化合物からＳＯＦを分離することができ、汎用性に優れ、幅広いフッ素化合物の単離に適用することができる。 According to the present invention, the by-product SOF can be converted to a sulfinyl compound containing a secondary or tertiary amine skeleton by a one-step process. In addition, the sulfinyl compound can be separated and removed from the fluoride by a general post-treatment operation without column chromatography or distillation purification. Therefore, according to the present invention, SOF can be easily removed at a low cost, and an industrial scale amount of fluorinated compounds using 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene can be obtained. It can be produced with good purity.
In addition, since the present invention does not require oxidation reaction, hydrolysis reaction, or distillation, it is not necessary to use an oxidizing agent with a risk of explosion. SOF can be separated from these fluorine compounds, whether they are solid or have a high boiling point.
加えて、本発明は、酸化反応や加水分解反応、蒸留の必要がないため、爆発の危険性がある酸化剤を使用しなくても済み、フッ素化物が酸化反応や加水分解反応時に反応する構造を有していても、また固体又は高沸点であっても、これらフッ素化合物からＳＯＦを分離することができ、汎用性に優れ、幅広いフッ素化合物の単離に適用することができる。 According to the present invention, the by-product SOF can be converted to a sulfinyl compound containing a secondary or tertiary amine skeleton by a one-step process. In addition, the sulfinyl compound can be separated and removed from the fluoride by a general post-treatment operation without column chromatography or distillation purification. Therefore, according to the present invention, SOF can be easily removed at a low cost, and an industrial scale amount of fluorinated compounds using 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene can be obtained. It can be produced with good purity.
In addition, since the present invention does not require oxidation reaction, hydrolysis reaction, or distillation, it is not necessary to use an oxidizing agent with a risk of explosion. SOF can be separated from these fluorine compounds, whether they are solid or have a high boiling point.
(1) フッ素化反応工程
本発明の工程１において使用される、前記フッ素化物と前記ＳＯＦとを含む反応混合物は、有機化合物などを２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンによってフッ素化させる工程（以下「フッ素化反応工程」ともいう；スキーム４参照）から得られたものであれば、特に制限されず、任意のものが使用できる。当該反応混合物には、有機化合物などからフッ素化された反応目的物のフッ素化物、及び２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンから生じた副生成物のＳＯＦが含まれる。さらに、当該反応混合物は、フッ素化反応において未反応又は過剰である２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼン及び／又はフッ素化されていない化合物も含み得る。
(1) Fluorination Reaction Step The reaction mixture containing the fluorinated compound and the SOF used in Step 1 of the present invention is prepared by adding an organic compound such as 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene (hereinafter also referred to as "fluorination reaction step"; see Scheme 4), without particular limitation, and any one can be used. The reaction mixture contains a fluorinated reaction target fluorinated from an organic compound or the like, and a by-product SOF generated from 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene. Additionally, the reaction mixture may also contain unreacted or excess 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene and/or unfluorinated compounds in the fluorination reaction.
本発明の工程１において使用される、前記フッ素化物と前記ＳＯＦとを含む反応混合物は、有機化合物などを２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンによってフッ素化させる工程（以下「フッ素化反応工程」ともいう；スキーム４参照）から得られたものであれば、特に制限されず、任意のものが使用できる。当該反応混合物には、有機化合物などからフッ素化された反応目的物のフッ素化物、及び２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンから生じた副生成物のＳＯＦが含まれる。さらに、当該反応混合物は、フッ素化反応において未反応又は過剰である２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼン及び／又はフッ素化されていない化合物も含み得る。
フッ素化反応工程は、公知の反応及び条件で実施できる（例えば、あらゆる目的のための参照により包含される、非特許文献１を参照）。例えば、反応器中で、フッ素化の対象である有機化合物、２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼン、溶媒、及びフッ化水素を混合して反応させてもよい。
The fluorination reaction step can be performed with known reactions and conditions (see, for example, Non-Patent Document 1, which is incorporated by reference for all purposes). For example, an organic compound to be fluorinated, 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene, a solvent, and hydrogen fluoride may be mixed and reacted in a reactor.
フッ素化の対象である有機化合物としては、ヒドロキシル基、カルボニル基、又はチオカルボニル基を含有するものであれば、特に制限されず、任意のものを使用してもよい。通常、使用される有機化合物は、アルコール、アルデヒド、ケトン、ジケトン、ケトエステル、カルボン酸、チオケトン、チオエステル、ジチオエステル、チオカーボネート、及びジチオカーボネートからなる群から選択される。９－フルオレノンなどのカルボニル基を環内に有する環式化合物を使用することもできる。好ましくは、ヒドロキシル基及びカルボニル基を含む化合物である。また、フッ素化物とスルフィニル化合物（２）とを化学的性質を利用して分離するため、有機化合物としては、フッ素化後にスルフィニル化合物（２）と化学的性質が異なるフッ素化物になるものが好ましく、酸と塩を形成する塩基性基、例えば、アミノ基やピリジル基を持っていない化合物がより好ましく、アミノ基を持っていない化合物が更に好ましい。
The organic compound to be fluorinated is not particularly limited as long as it contains a hydroxyl group, a carbonyl group, or a thiocarbonyl group, and any compound may be used. Typically used organic compounds are selected from the group consisting of alcohols, aldehydes, ketones, diketones, ketoesters, carboxylic acids, thioketones, thioesters, dithioesters, thiocarbonates and dithiocarbonates. Cyclic compounds having a carbonyl group in the ring such as 9-fluorenone can also be used. Preferred are compounds containing a hydroxyl group and a carbonyl group. Further, in order to separate the fluorinated compound and the sulfinyl compound (2) by utilizing their chemical properties, the organic compound is preferably a fluorinated compound having chemical properties different from those of the sulfinyl compound (2) after fluorination, A compound that does not have a basic group that forms a salt with an acid, such as an amino group or a pyridyl group, is more preferred, and a compound that does not have an amino group is even more preferred.
２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンは、特に制限されず、例えば、商業的に入手可能なＦｌｕｏｌｅａｄ（登録商標）を使用してもよい。
2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is not particularly limited, and for example, commercially available Fluolead (registered trademark) may be used.
前記のフッ化水素は有機溶媒との混合物を使用してもよい。有機溶媒としては、ジエチルエーテル、テトラヒドロフランなどのエーテル類やピリジン、トリエチルアミンなどの有機塩基が挙げられ、好ましくは有機塩基であり、より好ましくはピリジンである。
The above hydrogen fluoride may be used as a mixture with an organic solvent. Examples of organic solvents include ethers such as diethyl ether and tetrahydrofuran, and organic bases such as pyridine and triethylamine. Organic bases are preferred, and pyridine is more preferred.
フッ素化反応の条件は、フッ素化される有機化合物などの種類によって異なるが、反応温度は、フッ素化物を良好な収率で得られる点から、好ましくは約－２０～約１２０℃の範囲であり、より好ましくは、約０～約６０℃であり、最も好ましくは室温である。
The conditions for the fluorination reaction vary depending on the type of the organic compound to be fluorinated, but the reaction temperature is preferably in the range of about -20 to about 120°C from the viewpoint of obtaining a fluorinated compound in good yield. , more preferably from about 0 to about 60° C., and most preferably at room temperature.
また、反応時間はフッ素化が完結するように選択できる。好ましくは約１分間～２４時間であり、より好ましくは約５分間～６時間である。フッ素化される有機化合物などの種類によっては６日間程度かかることもある。
Also, the reaction time can be selected so that the fluorination is completed. It is preferably about 1 minute to 24 hours, more preferably about 5 minutes to 6 hours. It may take about 6 days depending on the type of organic compound to be fluorinated.
溶媒は、有機溶媒、例えば、ジクロロメタン、ヘプタン、トルエン、クロロホルムが使用できる。特に、後述の除去工程での分液操作で容易に目的とするフッ素化物を取り出せる点から、目的とするフッ素化物を良好に溶解できる有機溶媒が好ましい。
Organic solvents such as dichloromethane, heptane, toluene, and chloroform can be used as solvents. In particular, an organic solvent capable of satisfactorily dissolving the target fluorinated compound is preferable because the target fluorinated compound can be easily taken out by liquid separation operation in the removal step described later.
(2) 転化反応工程
本発明では、前記のフッ素化工程で得られた前記フッ素化物と前記ＳＯＦとを含む反応混合物において、ＳＯＦを転化して下記式（２）で表されるスルフィニル化合物（以下「スルフィニル化合物（２）」）を得る工程（以下「転化反応工程」ともいう；スキーム５参照）を行う：
（式中、Ｒは、第２級若しくは第３級アミン骨格を含むアルコキシ基、第２級若しくは第３級アミン骨格を含む第２級若しくは第３級アミノ基、又は第２級若しくは第３級アミン骨格を含む環状アミノ基である）。
(2) Conversion reaction step In the present invention, in the reaction mixture containing the fluorinated compound obtained in the fluorination step and the SOF, the SOF is converted into a sulfinyl compound represented by the following formula (2) (hereinafter referred to as A step of obtaining “sulfinyl compound (2)”) (hereinafter also referred to as “conversion reaction step”; see Scheme 5) is carried out:
(wherein R is an alkoxy group containing a secondary or tertiary amine skeleton, a secondary or tertiary amino group containing a secondary or tertiary amine skeleton, or a secondary or tertiary is a cyclic amino group containing an amine skeleton).
本発明では、前記のフッ素化工程で得られた前記フッ素化物と前記ＳＯＦとを含む反応混合物において、ＳＯＦを転化して下記式（２）で表されるスルフィニル化合物（以下「スルフィニル化合物（２）」）を得る工程（以下「転化反応工程」ともいう；スキーム５参照）を行う：
（式中、Ｒは、第２級若しくは第３級アミン骨格を含むアルコキシ基、第２級若しくは第３級アミン骨格を含む第２級若しくは第３級アミノ基、又は第２級若しくは第３級アミン骨格を含む環状アミノ基である）。
(wherein R is an alkoxy group containing a secondary or tertiary amine skeleton, a secondary or tertiary amino group containing a secondary or tertiary amine skeleton, or a secondary or tertiary is a cyclic amino group containing an amine skeleton).
前記の転化反応工程は、ＳＯＦからスルフィニル化合物（２）を得ることができれば、特に制限されず、任意の方法で実施してもよい。
The above conversion reaction step is not particularly limited as long as the sulfinyl compound (2) can be obtained from SOF, and may be carried out by any method.
例えば、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（３）で表される第２級又は第３級アミン骨格を含むアルコール（以下「アルコール化合物（３）」ともいう）で処理して、ＳＯＦを下記式（４）で表されるスルフィニル化合物（以下「スルフィニル化合物（４）」ともいう）に転化してもよい。
〔式（３）及び（４）中、Ｒ１及びＲ２は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ１及びＲ２は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ１は１～８の整数である。但し、Ｒ１及びＲ２は同時に水素原子ではない。〕 For example, the reaction mixture containing the fluorinated compound and the SOF is treated with an alcohol containing a secondary or tertiary amine skeleton represented by the following formula (3) (hereinafter also referred to as "alcohol compound (3)"). SOF may be converted into a sulfinyl compound represented by the following formula (4) (hereinafter also referred to as "sulfinyl compound (4)").
[In the formulas (3) and (4), R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms. or a hydrogen atom, or R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time. ]
〔式（３）及び（４）中、Ｒ１及びＲ２は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ１及びＲ２は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ１は１～８の整数である。但し、Ｒ１及びＲ２は同時に水素原子ではない。〕 For example, the reaction mixture containing the fluorinated compound and the SOF is treated with an alcohol containing a secondary or tertiary amine skeleton represented by the following formula (3) (hereinafter also referred to as "alcohol compound (3)"). SOF may be converted into a sulfinyl compound represented by the following formula (4) (hereinafter also referred to as "sulfinyl compound (4)").
[In the formulas (3) and (4), R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms. or a hydrogen atom, or R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time. ]
あるいは、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（５）で表される第２級又は第３級アミン骨格を含む第１級又は第２級アミン（以下「アミン化合物（５）」ともいう）で処理して、ＳＯＦを下記式（６）で表されるスルフィニル化合物（以下「スルフィニル化合物（６）」ともいう）に転化してもよい。
〔式（５）及び（６）中、Ｒ３及びＲ４は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ３及びＲ４は、それらが結合している窒素原子と一緒になって環を形成していてもよく；Ｒ５は、炭素数が１～１８のアルキル基又は水素原子であるか、あるいは、Ｒ３及びＲ５は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ２は１～８である。但し、Ｒ３及びＲ４は同時に水素原子ではない。〕 Alternatively, a primary or secondary amine containing a secondary or tertiary amine skeleton represented by the following formula (5) (hereinafter referred to as "amine compound (5) ”) to convert the SOF to a sulfinyl compound represented by the following formula (6) (hereinafter also referred to as “sulfinyl compound (6)”).
[In formulas (5) and (6), R 3 and R 4 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached; R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and n 2 is 1 to 8. However, R 3 and R 4 are not hydrogen atoms at the same time. ]
〔式（５）及び（６）中、Ｒ３及びＲ４は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ３及びＲ４は、それらが結合している窒素原子と一緒になって環を形成していてもよく；Ｒ５は、炭素数が１～１８のアルキル基又は水素原子であるか、あるいは、Ｒ３及びＲ５は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ２は１～８である。但し、Ｒ３及びＲ４は同時に水素原子ではない。〕 Alternatively, a primary or secondary amine containing a secondary or tertiary amine skeleton represented by the following formula (5) (hereinafter referred to as "amine compound (5) ”) to convert the SOF to a sulfinyl compound represented by the following formula (6) (hereinafter also referred to as “sulfinyl compound (6)”).
[In formulas (5) and (6), R 3 and R 4 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached; R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and n 2 is 1 to 8. However, R 3 and R 4 are not hydrogen atoms at the same time. ]
なお、スルフィニル化合物（４）及び（６）はスルフィニル化合物（２）に包含される。
すなわち、スルフィニル化合物（４）の基：－Ｏ－（ＣＨ２）ｎ１－Ｎ（Ｒ１）Ｒ２は、スルフィニル化合物（２）の第２級又は第３級アミン骨格を含むアルコキシ基であるＲに対応する。
また、スルフィニル化合物（６）の基：－Ｎ（Ｒ５）－（ＣＨ２）ｎ２－Ｎ（Ｒ３）Ｒ４は、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成しない場合は、スルフィニル化合物（２）の第２級又は第３級アミン骨格を含む第２級又は第３級アミノ基であるＲに対応する。
さらに、スルフィニル化合物（６）の基：－Ｎ（Ｒ５）－（ＣＨ２）ｎ２－Ｎ（Ｒ３）Ｒ４は、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成する場合は、スルフィニル化合物（２）の第２級又は第３級アミン骨格を含む環状アミノ基であるＲに対応する。 The sulfinyl compounds (4) and (6) are included in the sulfinyl compound (2).
That is, the group of the sulfinyl compound (4): —O—(CH 2 ) n1 —N(R 1 )R 2 is an alkoxy group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2). corresponds to
Also, the group of sulfinyl compound (6): —N(R 5 )—(CH 2 ) n2 —N(R 3 )R 4 is such that R 3 and R 5 together with the nitrogen atom to which they are attached When it does not form a ring together, it corresponds to R which is a secondary or tertiary amino group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
Additionally, the group of sulfinyl compound (6): —N(R 5 )—(CH 2 ) n2 —N(R 3 )R 4 is such that R 3 and R 5 together with the nitrogen atom to which they are attached When they form a ring together, they correspond to R, which is a cyclic amino group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
すなわち、スルフィニル化合物（４）の基：－Ｏ－（ＣＨ２）ｎ１－Ｎ（Ｒ１）Ｒ２は、スルフィニル化合物（２）の第２級又は第３級アミン骨格を含むアルコキシ基であるＲに対応する。
また、スルフィニル化合物（６）の基：－Ｎ（Ｒ５）－（ＣＨ２）ｎ２－Ｎ（Ｒ３）Ｒ４は、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成しない場合は、スルフィニル化合物（２）の第２級又は第３級アミン骨格を含む第２級又は第３級アミノ基であるＲに対応する。
さらに、スルフィニル化合物（６）の基：－Ｎ（Ｒ５）－（ＣＨ２）ｎ２－Ｎ（Ｒ３）Ｒ４は、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成する場合は、スルフィニル化合物（２）の第２級又は第３級アミン骨格を含む環状アミノ基であるＲに対応する。 The sulfinyl compounds (4) and (6) are included in the sulfinyl compound (2).
That is, the group of the sulfinyl compound (4): —O—(CH 2 ) n1 —N(R 1 )R 2 is an alkoxy group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2). corresponds to
Also, the group of sulfinyl compound (6): —N(R 5 )—(CH 2 ) n2 —N(R 3 )R 4 is such that R 3 and R 5 together with the nitrogen atom to which they are attached When it does not form a ring together, it corresponds to R which is a secondary or tertiary amino group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
Additionally, the group of sulfinyl compound (6): —N(R 5 )—(CH 2 ) n2 —N(R 3 )R 4 is such that R 3 and R 5 together with the nitrogen atom to which they are attached When they form a ring together, they correspond to R, which is a cyclic amino group containing a secondary or tertiary amine skeleton of the sulfinyl compound (2).
前記式（３）及び（４）のＲ１及びＲ２は、それぞれ互いに独立して、好ましくは炭素数が１～４のアルキル基であり、より好ましくはメチル基又はエチル基であり、さらに好ましくはメチル基である。
R 1 and R 2 in the above formulas (3) and (4) are each independently of each other, preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, still more preferably is a methyl group.
前記式（３）及び（４）のｎ１は、好ましくは１～４の整数であり、より好ましくは２である。
n 1 in formulas (3) and (4) is preferably an integer of 1 to 4, more preferably 2.
前記式（３）及び（４）は、好ましくは、Ｒ１及びＲ２が、それぞれ互いに独立して、炭素数が１～４のアルキル基であり、ｎ１が、１～４の整数である。
In formulas (3) and (4), preferably R 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms, and n 1 is an integer of 1 to 4. .
アルコール化合物（３）は、好ましくは２－（ジメチルアミノ）エタノールである。
スルフィニル化合物（４）は、好ましくは下式：
で表される化合物又はその塩である。 Alcohol compound (3) is preferably 2-(dimethylamino)ethanol.
The sulfinyl compound (4) preferably has the formula:
It is a compound represented by or a salt thereof.
スルフィニル化合物（４）は、好ましくは下式：
で表される化合物又はその塩である。 Alcohol compound (3) is preferably 2-(dimethylamino)ethanol.
The sulfinyl compound (4) preferably has the formula:
It is a compound represented by or a salt thereof.
前記式（５）及び（６）のＲ３、Ｒ４、及びＲ５は、それぞれ互いに独立して、好ましくは炭素数が１～４のアルキル基又は水素原子であり、より好ましくはメチル基、エチル基、又は水素原子であり、さらに好ましくはメチル基である。
あるいは、前記式（５）及び（６）のＲ３及びＲ５は、好ましくは、それらが結合している窒素原子と一緒になって環を、特にピペラジンを形成し、Ｒ４は、好ましくは炭素数が１～４のアルキル基又は水素原子であり、より好ましくはメチル基、エチル基、又は水素原子であり、さらに好ましくはメチル基である。 R 3 , R 4 and R 5 in the above formulas (5) and (6) are each independently preferably an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group, It is an ethyl group or a hydrogen atom, more preferably a methyl group.
Alternatively, R 3 and R 5 of formulas (5) and (6) above preferably together with the nitrogen atom to which they are attached form a ring, in particular piperazine, and R 4 is preferably It is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group, an ethyl group or a hydrogen atom, still more preferably a methyl group.
あるいは、前記式（５）及び（６）のＲ３及びＲ５は、好ましくは、それらが結合している窒素原子と一緒になって環を、特にピペラジンを形成し、Ｒ４は、好ましくは炭素数が１～４のアルキル基又は水素原子であり、より好ましくはメチル基、エチル基、又は水素原子であり、さらに好ましくはメチル基である。 R 3 , R 4 and R 5 in the above formulas (5) and (6) are each independently preferably an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group, It is an ethyl group or a hydrogen atom, more preferably a methyl group.
Alternatively, R 3 and R 5 of formulas (5) and (6) above preferably together with the nitrogen atom to which they are attached form a ring, in particular piperazine, and R 4 is preferably It is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group, an ethyl group or a hydrogen atom, still more preferably a methyl group.
前記式（５）及び（６）のｎ２は、好ましくは１～４の整数である。
但し、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成する場合は、ｎ２は、好ましくは１～２の整数であり、より好ましくは２である。 n2 in formulas (5) and ( 6 ) is preferably an integer of 1-4.
However, when R 3 and R 5 together with the nitrogen atom to which they are attached form a ring, n 2 is preferably an integer of 1-2, more preferably 2.
但し、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成する場合は、ｎ２は、好ましくは１～２の整数であり、より好ましくは２である。 n2 in formulas (5) and ( 6 ) is preferably an integer of 1-4.
However, when R 3 and R 5 together with the nitrogen atom to which they are attached form a ring, n 2 is preferably an integer of 1-2, more preferably 2.
前記式（５）及び（６）は、好ましくは、Ｒ３、Ｒ４、及びＲ５が、それぞれ互いに独立して、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～４の整数である。
あるいは、前記式（５）及び（６）は、好ましくは、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成し、Ｒ４が、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～２の整数である。 In formulas (5) and (6), preferably R 3 , R 4 and R 5 are each independently an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is 1 Integer from ~4.
Alternatively, in formulas (5) and (6), R 3 and R 5 preferably form a ring together with the nitrogen atom to which they are attached, and R 4 has 1 to 1 carbon atoms. 4 alkyl groups or hydrogen atoms, and n2 is an integer of 1-2 .
あるいは、前記式（５）及び（６）は、好ましくは、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成し、Ｒ４が、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～２の整数である。 In formulas (5) and (6), preferably R 3 , R 4 and R 5 are each independently an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is 1 Integer from ~4.
Alternatively, in formulas (5) and (6), R 3 and R 5 preferably form a ring together with the nitrogen atom to which they are attached, and R 4 has 1 to 1 carbon atoms. 4 alkyl groups or hydrogen atoms, and n2 is an integer of 1-2 .
アミン化合物（５）は、好ましくはＮ－メチルピペラジンである。
スルフィニル化合物（６）は、好ましくは下式：
で表される化合物又はその塩である。 Amine compound (5) is preferably N-methylpiperazine.
The sulfinyl compound (6) preferably has the formula:
It is a compound represented by or a salt thereof.
スルフィニル化合物（６）は、好ましくは下式：
で表される化合物又はその塩である。 Amine compound (5) is preferably N-methylpiperazine.
The sulfinyl compound (6) preferably has the formula:
It is a compound represented by or a salt thereof.
スルフィニル化合物（４）及び（６）の塩としては、酢酸塩、プロピオン酸塩、酪酸塩、トリフルオロ酢酸塩、メタンスルホン酸塩、トリフルオロメタンスルホン酸塩等の有機酸塩、及び、塩酸塩、硫酸塩、硝酸塩、リン酸塩、フッ化水素酸塩等の無機酸塩が例示され、好ましくは、有機酸塩であり、より好ましくは、酢酸塩である。
Salts of the sulfinyl compounds (4) and (6) include organic acid salts such as acetate, propionate, butyrate, trifluoroacetate, methanesulfonate, and trifluoromethanesulfonate, and hydrochlorides, Examples include inorganic acid salts such as sulfates, nitrates, phosphates and hydrofluorides, preferably organic acid salts, more preferably acetates.
前記式（３）及び（４）のＲ１及びＲ２、ならびに前記式（５）及び（６）のＲ３、Ｒ４、及びＲ５において、「炭素数が１～１８のアルキル基」は、直鎖状又は分岐状でよく、好ましくは炭素数１～６のアルキル基、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基、ペンチル基、イソペンチル基などであり、より好ましくは炭素数が１～４のアルキル基、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔ－ブチル基などであり、さらに好ましくは、メチル基またはエチル基であり、特に好ましくは、メチル基である。
In R 1 and R 2 of the formulas (3) and (4), and R 3 , R 4 and R 5 of the formulas (5) and (6), the "alkyl group having 1 to 18 carbon atoms" is , which may be linear or branched, preferably an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl , a pentyl group, an isopentyl group, etc., more preferably an alkyl group having 1 to 4 carbon atoms, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group. etc., more preferably a methyl group or an ethyl group, particularly preferably a methyl group.
前記式（３）及び（４）のＲ１及びＲ２、ならびに前記式（５）及び（６）のＲ３及びＲ４において、「炭素数が６～３０のアリール基」は、単環式又は二環式若しくは三環式などの多環式でよく、好ましくは、フェニル基、１－ナフチル基、２－ナフチル基、１－アントリル基、２－アントリル基、９－アントリル基、１－フェナントリル基、２－フェナントリル基、３－フェナントリル基、４－フェナントリル基、９－フェナントリル基であり、より好ましくはフェニル基、１－ナフチル基、２－ナフチル基であり、さらに好ましくは、フェニル基である。
In R 1 and R 2 in the formulas (3) and (4), and R 3 and R 4 in the formulas (5) and (6), the “aryl group having 6 to 30 carbon atoms” is a monocyclic or may be polycyclic such as bicyclic or tricyclic, preferably phenyl group, 1-naphthyl group, 2-naphthyl group, 1-anthryl group, 2-anthryl group, 9-anthryl group, 1-phenanthryl group, 2-phenanthryl group, 3-phenanthryl group, 4-phenanthryl group and 9-phenanthryl group, more preferably phenyl group, 1-naphthyl group and 2-naphthyl group, still more preferably phenyl group .
前記式（３）及び（４）のＲ１及びＲ２、ならびに前記式（５）及び（６）のＲ３及びＲ４において、「炭素数が７～３０のアラルキル基」は、例えば、ベンジル基、１－フェニルエチル基、２－フェニルエチル基、１－フェニルプロピル基、２－フェニルプロピル基、３－フェニルプロピル基、１－ナフチルメチル基、２－ナフチルメチル基などであり、より好ましくは、ベンジル基、１－フェニルエチル基、２－フェニルエチル基であり、更に好ましくは、ベンジル基である。
In R 1 and R 2 in the formulas (3) and (4) and R 3 and R 4 in the formulas (5) and (6), the "aralkyl group having 7 to 30 carbon atoms" is, for example, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group and the like, more preferably , a benzyl group, a 1-phenylethyl group and a 2-phenylethyl group, and more preferably a benzyl group.
前記式（３）及び（４）において、Ｒ１及びＲ２が、それらが結合している窒素原子と一緒になって形成する環として、ピペリジン、ピロリジン、アゼチジン、アジリジン、アゼパン、アゾカンが例示され、ピペリジン、ピロリジン、アゼチジンが好ましく、ピペリジン、ピロリジンがより好ましく、ピペリジンがさらに好ましい。
In the above formulas (3) and (4), the ring formed by R 1 and R 2 together with the nitrogen atom to which they are bonded is exemplified by piperidine, pyrrolidine, azetidine, aziridine, azepane, and azocane. , piperidine, pyrrolidine and azetidine are preferred, piperidine and pyrrolidine are more preferred, and piperidine is even more preferred.
前記式（５）及び（６）において、Ｒ３及びＲ４が、それらが結合している窒素原子と一緒になって形成する環として、ピペリジン、ピロリジン、アゼチジン、アジリジン、アゼパン、アゾカンが例示され、ピペリジン、ピロリジン、アゼチジンが好ましく、ピペリジン、ピロリジンがより好ましく、ピペリジンがさらに好ましい。
In the above formulas (5) and (6), the ring formed by R 3 and R 4 together with the nitrogen atom to which they are bonded is exemplified by piperidine, pyrrolidine, azetidine, aziridine, azepane, and azocane. , piperidine, pyrrolidine and azetidine are preferred, piperidine and pyrrolidine are more preferred, and piperidine is even more preferred.
前記式（５）及び（６）において、Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって形成する環として、ピペラジン、ヘキサヒドロピリミジン、イミダゾリジン、１，３－ジアゼチジン、１，３－ジアゼパン、１，４－ジアゼパン、１，３－ジアゾカン、１，４－ジアゾカン、１，５－ジアゾカンが例示され、ピペラジン、ヘキサヒドロピリミジン、イミダゾリジン、１，３－ジアゼチジンが好ましく、ピペラジン、ヘキサヒドロピリミジン、イミダゾリジンがより好ましく、ピペラジンがさらに好ましい。
In the above formulas (5) and (6), piperazine, hexahydropyrimidine, imidazolidine, 1,3-diazetidine as a ring formed by R 3 and R 5 together with the nitrogen atom to which they are bonded , 1,3-diazepane, 1,4-diazepane, 1,3-diazocane, 1,4-diazocane and 1,5-diazocane, preferably piperazine, hexahydropyrimidine, imidazolidine and 1,3-diazetidine. , piperazine, hexahydropyrimidine and imidazolidine are more preferred, and piperazine is even more preferred.
転化反応工程では、前述のとおり、前記フッ素化物と前記ＳＯＦとを含む反応混合物をアルコール化合物（３）又はアミン化合物（５）で処理して、ＳＯＦをスルフィニル化合物（４）又は（６）に転化させる。
ＳＯＦのスルフィニル化合物（４）への高い転化を達成するため、好ましい量のアルコール化合物（３）は、１モルのＳＯＦに対して、約０．１～約３０モルの範囲から選択できる。１モルのＳＯＦに対して、約１～約３モルのアルコール化合物（３）がより好ましい。
また、ＳＯＦのスルフィニル化合物（６）への高い転化を達成するため、好ましい量のアミン化合物（５）は、１モルのＳＯＦに対して、約０．１～約３０モルの範囲から選択できる。１モルのＳＯＦに対して、約１～約３モルのアミン化合物（５）がより好ましい。
これらアルコール化合物（３）及びアミン化合物（５）は、転化反応工程における溶媒又は溶媒の一つとして使用してもよい。
上記反応混合物中のＳＯＦの量は、フッ素化反応工程で製造されるフッ素化物の予想される収率（ＳＯＦはフッ素化物と等モル以上で生成される）、又はＮＭＲ等の客観的検出法によって、予測することができる。ＳＯＦの量は、フッ素化反応工程で用いた２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンの量から見積もることもできる。 In the conversion reaction step, as described above, the reaction mixture containing the fluoride compound and the SOF is treated with the alcohol compound (3) or the amine compound (5) to convert the SOF to the sulfinyl compound (4) or (6). Let
To achieve high conversion of SOF to sulfinyl compound (4), a preferred amount of alcohol compound (3) can be selected from the range of about 0.1 to about 30 moles per mole of SOF. About 1 to about 3 moles of alcohol compound (3) per mole of SOF is more preferred.
Also, in order to achieve high conversion of SOF to sulfinyl compound (6), a preferred amount of amine compound (5) can be selected from the range of about 0.1 to about 30 mol per 1 mol of SOF. More preferably, about 1 to about 3 moles of amine compound (5) per mole of SOF.
These alcohol compound (3) and amine compound (5) may be used as a solvent or one of the solvents in the conversion reaction step.
The amount of SOF in the reaction mixture can be determined by the expected yield of fluorinated product produced in the fluorination reaction step (SOF is produced at least equimolar to the fluorinated product) or by objective detection methods such as NMR. , can be predicted. The amount of SOF can also be estimated from the amount of 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene used in the fluorination reaction step.
ＳＯＦのスルフィニル化合物（４）への高い転化を達成するため、好ましい量のアルコール化合物（３）は、１モルのＳＯＦに対して、約０．１～約３０モルの範囲から選択できる。１モルのＳＯＦに対して、約１～約３モルのアルコール化合物（３）がより好ましい。
また、ＳＯＦのスルフィニル化合物（６）への高い転化を達成するため、好ましい量のアミン化合物（５）は、１モルのＳＯＦに対して、約０．１～約３０モルの範囲から選択できる。１モルのＳＯＦに対して、約１～約３モルのアミン化合物（５）がより好ましい。
これらアルコール化合物（３）及びアミン化合物（５）は、転化反応工程における溶媒又は溶媒の一つとして使用してもよい。
上記反応混合物中のＳＯＦの量は、フッ素化反応工程で製造されるフッ素化物の予想される収率（ＳＯＦはフッ素化物と等モル以上で生成される）、又はＮＭＲ等の客観的検出法によって、予測することができる。ＳＯＦの量は、フッ素化反応工程で用いた２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンの量から見積もることもできる。 In the conversion reaction step, as described above, the reaction mixture containing the fluoride compound and the SOF is treated with the alcohol compound (3) or the amine compound (5) to convert the SOF to the sulfinyl compound (4) or (6). Let
To achieve high conversion of SOF to sulfinyl compound (4), a preferred amount of alcohol compound (3) can be selected from the range of about 0.1 to about 30 moles per mole of SOF. About 1 to about 3 moles of alcohol compound (3) per mole of SOF is more preferred.
Also, in order to achieve high conversion of SOF to sulfinyl compound (6), a preferred amount of amine compound (5) can be selected from the range of about 0.1 to about 30 mol per 1 mol of SOF. More preferably, about 1 to about 3 moles of amine compound (5) per mole of SOF.
These alcohol compound (3) and amine compound (5) may be used as a solvent or one of the solvents in the conversion reaction step.
The amount of SOF in the reaction mixture can be determined by the expected yield of fluorinated product produced in the fluorination reaction step (SOF is produced at least equimolar to the fluorinated product) or by objective detection methods such as NMR. , can be predicted. The amount of SOF can also be estimated from the amount of 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene used in the fluorination reaction step.
転化反応の反応温度は、ＳＯＦのスルフィニル化合物（４）への高い転化を達成するために、好ましくは約－４０～約１２０℃の範囲であり、より好ましくは約０～約４０℃であり、最も好ましくは室温である。
また、転化反応の反応温度は、ＳＯＦのスルフィニル化合物（６）への高い転化を達成するために、好ましくは約－４０～約１２０℃の範囲であり、より好ましくは約０～約４０℃であり、最も好ましくは室温である。 The reaction temperature of the conversion reaction is preferably in the range of about -40 to about 120°C, more preferably about 0 to about 40°C, in order to achieve high conversion of SOF to sulfinyl compound (4), Room temperature is most preferred.
In addition, the reaction temperature of the conversion reaction is preferably in the range of about -40 to about 120°C, more preferably about 0 to about 40°C, in order to achieve high conversion of SOF to sulfinyl compound (6). Yes, most preferably at room temperature.
また、転化反応の反応温度は、ＳＯＦのスルフィニル化合物（６）への高い転化を達成するために、好ましくは約－４０～約１２０℃の範囲であり、より好ましくは約０～約４０℃であり、最も好ましくは室温である。 The reaction temperature of the conversion reaction is preferably in the range of about -40 to about 120°C, more preferably about 0 to about 40°C, in order to achieve high conversion of SOF to sulfinyl compound (4), Room temperature is most preferred.
In addition, the reaction temperature of the conversion reaction is preferably in the range of about -40 to about 120°C, more preferably about 0 to about 40°C, in order to achieve high conversion of SOF to sulfinyl compound (6). Yes, most preferably at room temperature.
反応時間は、ＳＯＦのスルフィニル化合物（４）への転化が完全に起こるように選択できる。好ましくは約１分間～約２４時間であり、より好ましくは約５分間～約４時間であり、特に好ましくは約１０分間～約１時間である。
また、反応時間は、ＳＯＦのスルフィニル化合物（６）への転化が完全に起こるように選択できる。好ましくは約１分間～約２４時間であり、より好ましくは約５分間～約４時間であり、特に好ましくは約１０分間～約１時間である。 The reaction time can be chosen such that complete conversion of SOF to sulfinyl compound (4) occurs. It is preferably about 1 minute to about 24 hours, more preferably about 5 minutes to about 4 hours, particularly preferably about 10 minutes to about 1 hour.
Also, the reaction time can be selected such that complete conversion of SOF to sulfinyl compound (6) occurs. It is preferably about 1 minute to about 24 hours, more preferably about 5 minutes to about 4 hours, particularly preferably about 10 minutes to about 1 hour.
また、反応時間は、ＳＯＦのスルフィニル化合物（６）への転化が完全に起こるように選択できる。好ましくは約１分間～約２４時間であり、より好ましくは約５分間～約４時間であり、特に好ましくは約１０分間～約１時間である。 The reaction time can be chosen such that complete conversion of SOF to sulfinyl compound (4) occurs. It is preferably about 1 minute to about 24 hours, more preferably about 5 minutes to about 4 hours, particularly preferably about 10 minutes to about 1 hour.
Also, the reaction time can be selected such that complete conversion of SOF to sulfinyl compound (6) occurs. It is preferably about 1 minute to about 24 hours, more preferably about 5 minutes to about 4 hours, particularly preferably about 10 minutes to about 1 hour.
フッ素化反応終了後、又は転化反応終了後に、反応器内に存在するフッ化水素を中和するために、塩基を加えるのが好ましい。フッ化水素を中和するために使用される塩基は、例えば、３級アミン等の有機塩基、炭酸カリウム等の無機塩基等が挙げられ、好ましくは無機塩基であり、より好ましくは炭酸カリウムである。
After the fluorination reaction or the conversion reaction is completed, it is preferable to add a base in order to neutralize the hydrogen fluoride present in the reactor. Examples of the base used for neutralizing hydrogen fluoride include organic bases such as tertiary amines, inorganic bases such as potassium carbonate, etc., preferably inorganic bases, and more preferably potassium carbonate. .
転化反応は、新たに溶媒を用いて行うか又は用いないで行われる。ここで使用する好適な溶媒としては、限定されないが、炭化水素系溶媒、芳香族系溶媒、ハロゲン系溶媒、エーテル系溶媒、エステル系溶媒、ケトン系溶媒、ならびにこれらの混合物が挙げられる。炭化水素系溶媒の例は、オクタン、ヘプタン、ヘキサン、ペンタン等である。芳香族系溶媒の例は、トルエン、キシレン、ベンゼン等である。ハロゲン系溶媒の例は、ジクロロメタン、１，２－ジクロロエタン、クロロホルム、トリクロロエチレン、テトラクロロエチレン等である。エーテル系溶媒の例は、ジエチルエーテル、テトラヒドロフラン、２－メトキシ－２－メチルプロパン等である。エステル系溶媒の例は、酢酸エチル、酢酸イソプロピル、プロピオン酸エチル等である。ケトン系溶媒の例は、アセトン、メチルイソブチルケトン、メチルエチルケトン等である。
前述したように、転化反応工程の反応基質としてのアルコール化合物（３）又はアミン化合物（５）は、溶媒又は溶媒の１つとしても使用することができる。 The conversion reaction may be carried out fresh with or without solvent. Suitable solvents for use herein include, but are not limited to, hydrocarbon-based solvents, aromatic-based solvents, halogen-based solvents, ether-based solvents, ester-based solvents, ketone-based solvents, and mixtures thereof. Examples of hydrocarbon solvents are octane, heptane, hexane, pentane, and the like. Examples of aromatic solvents are toluene, xylene, benzene and the like. Examples of halogen-based solvents are dichloromethane, 1,2-dichloroethane, chloroform, trichlorethylene, tetrachloroethylene, and the like. Examples of ether solvents are diethyl ether, tetrahydrofuran, 2-methoxy-2-methylpropane and the like. Examples of ester solvents are ethyl acetate, isopropyl acetate, ethyl propionate and the like. Examples of ketone-based solvents are acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like.
As described above, the alcohol compound (3) or amine compound (5) as a reaction substrate for the conversion reaction step can also be used as a solvent or one of the solvents.
前述したように、転化反応工程の反応基質としてのアルコール化合物（３）又はアミン化合物（５）は、溶媒又は溶媒の１つとしても使用することができる。 The conversion reaction may be carried out fresh with or without solvent. Suitable solvents for use herein include, but are not limited to, hydrocarbon-based solvents, aromatic-based solvents, halogen-based solvents, ether-based solvents, ester-based solvents, ketone-based solvents, and mixtures thereof. Examples of hydrocarbon solvents are octane, heptane, hexane, pentane, and the like. Examples of aromatic solvents are toluene, xylene, benzene and the like. Examples of halogen-based solvents are dichloromethane, 1,2-dichloroethane, chloroform, trichlorethylene, tetrachloroethylene, and the like. Examples of ether solvents are diethyl ether, tetrahydrofuran, 2-methoxy-2-methylpropane and the like. Examples of ester solvents are ethyl acetate, isopropyl acetate, ethyl propionate and the like. Examples of ketone-based solvents are acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like.
As described above, the alcohol compound (3) or amine compound (5) as a reaction substrate for the conversion reaction step can also be used as a solvent or one of the solvents.
多くの場合、溶媒はフッ素化反応工程で使用され、既に存在するので、新たな溶媒の追加はしばしば必要とされない。すなわち、フッ素化反応工程から得られた反応混合物には溶媒が既に存在しているので、新たに追加するものはアルコール化合物（３）又はアミン化合物（５）であることが好ましい。しかしながら、フッ素化反応工程から得られた反応混合が溶媒を含んでいる場合でも、新たに溶媒を添加することはできる。もっとも、工程の簡素化のため、新たな溶媒を添加する工程を省くのが好ましい。
In many cases the solvent is used in the fluorination reaction step and is already present, so the addition of new solvent is often not required. That is, since the solvent already exists in the reaction mixture obtained from the fluorination reaction step, the alcohol compound (3) or the amine compound (5) is preferably newly added. However, even if the reaction mixture resulting from the fluorination reaction step contains solvent, fresh solvent can be added. However, for simplification of the process, it is preferable to omit the process of adding a new solvent.
(3) 除去工程
本発明では、転化反応工程から得られたスルフィニル化合物（２）を、フッ素化物との化学的性質の違いを利用して、フッ素化合物と分離して、本発明の反応混合物から除去する工程（以下「除去工程」ともいう；スキーム６参照）を行う。
(3) Removal step In the present invention, the sulfinyl compound (2) obtained from the conversion reaction step is separated from the fluorine compound by utilizing the difference in chemical properties from the fluoride compound, and removed from the reaction mixture of the present invention. A step of removing (hereinafter also referred to as “removing step”; see Scheme 6) is performed.
本発明では、転化反応工程から得られたスルフィニル化合物（２）を、フッ素化物との化学的性質の違いを利用して、フッ素化合物と分離して、本発明の反応混合物から除去する工程（以下「除去工程」ともいう；スキーム６参照）を行う。
本発明の反応混合物は、転化反応工程前では、前述のとおりフッ素化物及びＳＯＦを含むが、転化反応工程では反応混合物中のＳＯＦがスルフィニル化合物（２）に転化されるので、転化反応工程を経た反応混合物はフッ素化物及びスルフィニル化合物（２）を含むことになる（スキーム５参照）。
The reaction mixture of the present invention contains a fluoride and SOF before the conversion reaction step as described above. The reaction mixture will contain the fluoride and the sulfinyl compound (2) (see scheme 5).
除去工程では、このフッ素化物とスルフィニル化合物（２）とを含む反応混合物から、スルフィニル化合物（２）を、フッ素化物と化学的性質が違うことを利用して、例えば、一般的な後処理操作によってフッ素化物から分離して除去することができる。
一般的な後処理操作として、工業的スケールにおいて応用可能な液－液分離又は液－固分離などが利用できる。例えば、フッ素化物とスルフィニル化合物（２）とを含む反応混合物に水を添加して、分液操作を行うことで、フッ素化物を含む有機層とスルフィニル化合物（２）を含む水層とを分離することができるので、水層を取り出すだけで、スルフィニル化合物（２）を簡便に除去することができる。あるいは、反応混合物にｎ－ヘプタンなどの有機溶媒を添加して、スルフィニル化合物（２）の溶解性を低下させることによって、スルフィニル化合物（２）を析出させて濾別することでも、簡便に除去することができる。
このように、本発明によれば、カラムクロマトグラフィー、精留精製、及び他の高度な技術を用いる特殊な処理を必要としない、標準的で単純な手段でスルフィニル化合物（２）を除去して、フッ素化物を単離することができる。このことは、フッ素化物を単離する従来技術に対する、工業的応用における重大な改善である。 In the removal step, the sulfinyl compound (2) is removed from the reaction mixture containing the fluorinated compound and the sulfinyl compound (2) by, for example, a general post-treatment operation, utilizing the fact that the sulfinyl compound (2) has different chemical properties from the fluorinated compound. It can be removed separately from the fluoride.
As a general post-treatment operation, liquid-liquid separation or liquid-solid separation applicable on an industrial scale can be used. For example, by adding water to the reaction mixture containing the fluoride and the sulfinyl compound (2) and performing a liquid separation operation, an organic layer containing the fluoride and an aqueous layer containing the sulfinyl compound (2) are separated. Therefore, the sulfinyl compound (2) can be easily removed simply by taking out the aqueous layer. Alternatively, by adding an organic solvent such as n-heptane to the reaction mixture to reduce the solubility of the sulfinyl compound (2), the sulfinyl compound (2) is precipitated and filtered off for easy removal. be able to.
Thus, according to the present invention, the sulfinyl compound (2) can be removed by standard and simple means that do not require special treatment using column chromatography, rectification purification, and other sophisticated techniques. , the fluoride can be isolated. This is a significant improvement in industrial application over the prior art techniques for isolating fluorides.
一般的な後処理操作として、工業的スケールにおいて応用可能な液－液分離又は液－固分離などが利用できる。例えば、フッ素化物とスルフィニル化合物（２）とを含む反応混合物に水を添加して、分液操作を行うことで、フッ素化物を含む有機層とスルフィニル化合物（２）を含む水層とを分離することができるので、水層を取り出すだけで、スルフィニル化合物（２）を簡便に除去することができる。あるいは、反応混合物にｎ－ヘプタンなどの有機溶媒を添加して、スルフィニル化合物（２）の溶解性を低下させることによって、スルフィニル化合物（２）を析出させて濾別することでも、簡便に除去することができる。
このように、本発明によれば、カラムクロマトグラフィー、精留精製、及び他の高度な技術を用いる特殊な処理を必要としない、標準的で単純な手段でスルフィニル化合物（２）を除去して、フッ素化物を単離することができる。このことは、フッ素化物を単離する従来技術に対する、工業的応用における重大な改善である。 In the removal step, the sulfinyl compound (2) is removed from the reaction mixture containing the fluorinated compound and the sulfinyl compound (2) by, for example, a general post-treatment operation, utilizing the fact that the sulfinyl compound (2) has different chemical properties from the fluorinated compound. It can be removed separately from the fluoride.
As a general post-treatment operation, liquid-liquid separation or liquid-solid separation applicable on an industrial scale can be used. For example, by adding water to the reaction mixture containing the fluoride and the sulfinyl compound (2) and performing a liquid separation operation, an organic layer containing the fluoride and an aqueous layer containing the sulfinyl compound (2) are separated. Therefore, the sulfinyl compound (2) can be easily removed simply by taking out the aqueous layer. Alternatively, by adding an organic solvent such as n-heptane to the reaction mixture to reduce the solubility of the sulfinyl compound (2), the sulfinyl compound (2) is precipitated and filtered off for easy removal. be able to.
Thus, according to the present invention, the sulfinyl compound (2) can be removed by standard and simple means that do not require special treatment using column chromatography, rectification purification, and other sophisticated techniques. , the fluoride can be isolated. This is a significant improvement in industrial application over the prior art techniques for isolating fluorides.
スルフィニル化合物（２）をより効率的に除去することができる点から、除去工程は、転化反応工程から得られたフッ素化物とスルフィニル化合物（２）とを含む反応混合物を酸で処理してから、当該スルフィニル化合物（２）を、フッ素化物との化学的性質の違いを利用して除去するのが好ましい。
すなわち、当該反応混合物に酸を加えてから、水を添加して、分液操作を行うことにより、スルフィニル化合物（２）を水層へより効率的に分配させることができ、その結果、水層を取り除くことで、簡便にスルフィニル化合物（２）を除去することができる。あるいは、酸処理によりスルフィニル化合物（２）を析出させ、当該スルフィニル化合物（２）を含む固体をろ別することにより、簡便に除去することができる。
使用できる酸としては、特に制限されないが、酢酸、プロピオン酸、酪酸、トリフルオロ酢酸、メタンスルホン酸、トリフルオロメタンスルホン酸等の有機酸、及び、塩酸、硫酸、硝酸、リン酸、フッ化水素酸等の無機酸が挙げられ、好ましくは、有機酸であり、更に好ましくは、酢酸である。 Since the sulfinyl compound (2) can be removed more efficiently, the removal step includes treating the reaction mixture containing the fluoride obtained from the conversion reaction step and the sulfinyl compound (2) with an acid, It is preferable to remove the sulfinyl compound (2) by utilizing the difference in chemical properties from the fluorinated compound.
That is, by adding an acid to the reaction mixture and then adding water to perform a liquid separation operation, the sulfinyl compound (2) can be more efficiently distributed to the aqueous layer, and as a result, the aqueous layer By removing the sulfinyl compound (2) can be easily removed. Alternatively, the sulfinyl compound (2) can be easily removed by precipitating the sulfinyl compound (2) by acid treatment and filtering the solid containing the sulfinyl compound (2).
Acids that can be used are not particularly limited, but organic acids such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrofluoric acid. and the like, preferably an organic acid, more preferably acetic acid.
すなわち、当該反応混合物に酸を加えてから、水を添加して、分液操作を行うことにより、スルフィニル化合物（２）を水層へより効率的に分配させることができ、その結果、水層を取り除くことで、簡便にスルフィニル化合物（２）を除去することができる。あるいは、酸処理によりスルフィニル化合物（２）を析出させ、当該スルフィニル化合物（２）を含む固体をろ別することにより、簡便に除去することができる。
使用できる酸としては、特に制限されないが、酢酸、プロピオン酸、酪酸、トリフルオロ酢酸、メタンスルホン酸、トリフルオロメタンスルホン酸等の有機酸、及び、塩酸、硫酸、硝酸、リン酸、フッ化水素酸等の無機酸が挙げられ、好ましくは、有機酸であり、更に好ましくは、酢酸である。 Since the sulfinyl compound (2) can be removed more efficiently, the removal step includes treating the reaction mixture containing the fluoride obtained from the conversion reaction step and the sulfinyl compound (2) with an acid, It is preferable to remove the sulfinyl compound (2) by utilizing the difference in chemical properties from the fluorinated compound.
That is, by adding an acid to the reaction mixture and then adding water to perform a liquid separation operation, the sulfinyl compound (2) can be more efficiently distributed to the aqueous layer, and as a result, the aqueous layer By removing the sulfinyl compound (2) can be easily removed. Alternatively, the sulfinyl compound (2) can be easily removed by precipitating the sulfinyl compound (2) by acid treatment and filtering the solid containing the sulfinyl compound (2).
Acids that can be used are not particularly limited, but organic acids such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid, and hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrofluoric acid. and the like, preferably an organic acid, more preferably acetic acid.
本発明では、除去工程で得られたフッ素化合物を含む有機層を濃縮することによって、高い純度のフッ素化物を簡便に得ることができる。
また、得られたフッ素化物が酸によって塩を形成するものでない場合は、前述の除去工程において酸で処理すると、当該フッ素化合物は有機層により多量に溶解し得るため、より高純度のフッ素化物が得られ有利である。したがって、本発明は、酸によって塩を形成しないフッ素化物の製造における副生成物の除去に適用するのが都合がよい。
酸によって塩を形成しないフッ素化物として、アミノ基やピリジル基等の塩基性置換基を有しない化合物が例示される。 In the present invention, by concentrating the organic layer containing the fluorine compound obtained in the removing step, a highly pure fluoride can be easily obtained.
In addition, if the obtained fluoride does not form a salt with an acid, the fluorine compound can be dissolved in a larger amount in the organic layer by treating with an acid in the removal step described above, so that a higher purity fluoride can be obtained. It is advantageous to obtain Accordingly, the present invention is advantageously applied to the removal of by-products in the production of fluorides that do not form salts with acids.
Examples of fluorinated compounds that do not form salts with acids include compounds that do not have a basic substituent such as an amino group or a pyridyl group.
また、得られたフッ素化物が酸によって塩を形成するものでない場合は、前述の除去工程において酸で処理すると、当該フッ素化合物は有機層により多量に溶解し得るため、より高純度のフッ素化物が得られ有利である。したがって、本発明は、酸によって塩を形成しないフッ素化物の製造における副生成物の除去に適用するのが都合がよい。
酸によって塩を形成しないフッ素化物として、アミノ基やピリジル基等の塩基性置換基を有しない化合物が例示される。 In the present invention, by concentrating the organic layer containing the fluorine compound obtained in the removing step, a highly pure fluoride can be easily obtained.
In addition, if the obtained fluoride does not form a salt with an acid, the fluorine compound can be dissolved in a larger amount in the organic layer by treating with an acid in the removal step described above, so that a higher purity fluoride can be obtained. It is advantageous to obtain Accordingly, the present invention is advantageously applied to the removal of by-products in the production of fluorides that do not form salts with acids.
Examples of fluorinated compounds that do not form salts with acids include compounds that do not have a basic substituent such as an amino group or a pyridyl group.
次に、実施例を挙げて本発明を具体的に説明するが、本発明はこれら実施例に制限されるものではない。
Next, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these Examples.
［実施例１］
９－フルオレノンをＦｌｕｏｌｅａｄ（登録商標）でフッ素化して生成された９，９－ジフルオロフルオレンから、２－（ジメチルアミノ）エタノールを用いてＳＯＦを除去する方法
[Example 1]
A method for removing SOF from 9,9-difluorofluorene produced by fluorinating 9-fluorenone with Fluolead® using 2-(dimethylamino)ethanol
９－フルオレノンをＦｌｕｏｌｅａｄ（登録商標）でフッ素化して生成された９，９－ジフルオロフルオレンから、２－（ジメチルアミノ）エタノールを用いてＳＯＦを除去する方法
A method for removing SOF from 9,9-difluorofluorene produced by fluorinating 9-fluorenone with Fluolead® using 2-(dimethylamino)ethanol
セプタム部を備えたフッ素ポリマー（ＰＦＡ）の反応器に、２．０ｇ（１１．１ｍｍｏｌ）の９－フルオレノン、５．５６ｇ（２２．２ｍｍｏｌ）のＦｌｕｏｌｅａｄ（登録商標）、３．８ｍＬのジクロロメタン、２．０４ｇ（７．７７ｍｍｏｌ）のフッ化水素とピリジンの７：３（重量比）混合物を仕込んだ。反応器をセプタムで閉じて室温にて１４４時間撹拌した。
氷浴にて冷却した後、２．９７ｇ（３．３３ｍｍｏｌ）の２－（ジメチルアミノ）エタノールを反応混合物に加えた。氷浴を取り除き反応混合物を１時間撹拌し、その後、６．１４ｇ（４．４４ｍｍｏｌ）の炭酸カリウムと１７．５ｍＬのｎ－ヘプタンからなる懸濁液中に反応混合物を注いだ。
これをろ過した後、ろ液に３．３４ｇ（５．５６ｍｍｏｌ）の酢酸を加え、室温で３０分間攪拌した。６ｍＬの水を加えて分液した後、得られた有機層を水洗し、水洗後の有機層をＨＰＬＣによって分析した。 In a fluoropolymer (PFA) reactor equipped with a septum, 2.0 g (11.1 mmol) 9-fluorenone, 5.56 g (22.2 mmol) Fluolead®, 3.8 mL dichloromethane, 2 04 g (7.77 mmol) of a 7:3 (weight ratio) mixture of hydrogen fluoride and pyridine was charged. The reactor was closed with a septum and stirred at room temperature for 144 hours.
After cooling in an ice bath, 2.97 g (3.33 mmol) of 2-(dimethylamino)ethanol was added to the reaction mixture. The ice bath was removed and the reaction mixture was stirred for 1 hour, after which the reaction mixture was poured into a suspension consisting of 6.14 g (4.44 mmol) of potassium carbonate and 17.5 mL of n-heptane.
After filtering this, 3.34 g (5.56 mmol) of acetic acid was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. After adding 6 mL of water and liquid-separating, the obtained organic layer was washed with water, and the organic layer after washing was analyzed by HPLC.
氷浴にて冷却した後、２．９７ｇ（３．３３ｍｍｏｌ）の２－（ジメチルアミノ）エタノールを反応混合物に加えた。氷浴を取り除き反応混合物を１時間撹拌し、その後、６．１４ｇ（４．４４ｍｍｏｌ）の炭酸カリウムと１７．５ｍＬのｎ－ヘプタンからなる懸濁液中に反応混合物を注いだ。
これをろ過した後、ろ液に３．３４ｇ（５．５６ｍｍｏｌ）の酢酸を加え、室温で３０分間攪拌した。６ｍＬの水を加えて分液した後、得られた有機層を水洗し、水洗後の有機層をＨＰＬＣによって分析した。 In a fluoropolymer (PFA) reactor equipped with a septum, 2.0 g (11.1 mmol) 9-fluorenone, 5.56 g (22.2 mmol) Fluolead®, 3.8 mL dichloromethane, 2 04 g (7.77 mmol) of a 7:3 (weight ratio) mixture of hydrogen fluoride and pyridine was charged. The reactor was closed with a septum and stirred at room temperature for 144 hours.
After cooling in an ice bath, 2.97 g (3.33 mmol) of 2-(dimethylamino)ethanol was added to the reaction mixture. The ice bath was removed and the reaction mixture was stirred for 1 hour, after which the reaction mixture was poured into a suspension consisting of 6.14 g (4.44 mmol) of potassium carbonate and 17.5 mL of n-heptane.
After filtering this, 3.34 g (5.56 mmol) of acetic acid was added to the filtrate, and the mixture was stirred at room temperature for 30 minutes. After adding 6 mL of water and liquid-separating, the obtained organic layer was washed with water, and the organic layer after washing was analyzed by HPLC.
ＳＯＦは、Ｎ，Ｎ－ジメチルアミノエタノールによって４－ｔｅｒｔ－ブチル－２，６－ジメチルフェニルスルフィン酸２－（ジメチルアミノ）エチルに転化され、酢酸を加え水洗することにより有機層から除去された。これは酢酸を加える前のろ液のＨＰＬＣ分析結果と比較して、４－ｔｅｒｔ－ブチル－２，６－ジメチルフェニルスルフィン酸２－（ジメチルアミノ）エチルのピークが消失していることから確認した（図１）。４－ｔｅｒｔ－ブチル－２，６－ジメチルフェニルスルフィン酸２－（ジメチルアミノ）エチルは、以下に示したＮＭＲとＭＳにより構造を確認した。
SOF was converted to 2-(dimethylamino)ethyl 4-tert-butyl-2,6-dimethylphenylsulfinate with N,N-dimethylaminoethanol and removed from the organic layer by adding acetic acid and washing with water. This was confirmed by the disappearance of the peak of 2-(dimethylamino)ethyl 4-tert-butyl-2,6-dimethylphenylsulfinate compared with the HPLC analysis results of the filtrate before the addition of acetic acid. (Fig. 1). The structure of 2-(dimethylamino)ethyl 4-tert-butyl-2,6-dimethylphenylsulfinate was confirmed by NMR and MS shown below.
１Ｈ ＮＭＲ （ＣＤＣｌ３） δ７．０２（ｓ、２Ｈ）、４．１４（ｍ、２Ｈ）、２．６４（ｍ、２Ｈ）、２．６２（ｓ、６Ｈ）２．２６（ｓ、６Ｈ）、１．２８（ｓ、９Ｈ）；ＣＩ－ＭＳ ２９８（Ｍ＋Ｈ）
1H NMR (CDCl3) δ 7.02 (s, 2H), 4.14 (m, 2H), 2.64 (m, 2H), 2.62 (s, 6H) 2.26 (s, 6H), 1 .28 (s, 9H); CI-MS 298 (M+H)
［実施例２］
９－フルオレノンをＦｌｕｏｌｅａｄ（登録商標）でフッ素化して生成された９，９－ジフルオロフルオレンから、Ｎ－メチルピペラジンを用いてＳＯＦを除去する方法
[Example 2]
Method for removing SOF from 9,9-difluorofluorene produced by fluorinating 9-fluorenone with Fluolead® using N-methylpiperazine
９－フルオレノンをＦｌｕｏｌｅａｄ（登録商標）でフッ素化して生成された９，９－ジフルオロフルオレンから、Ｎ－メチルピペラジンを用いてＳＯＦを除去する方法
Method for removing SOF from 9,9-difluorofluorene produced by fluorinating 9-fluorenone with Fluolead® using N-methylpiperazine
セプタム部を備えたフッ素ポリマー（ＰＦＡ）の反応器に、１．０ｇ（５．５５ｍｍｏｌ）の９－フルオレノン、２．７８ｇ（１１．１ｍｍｏｌ）のＦｌｕｏｌｅａｄ（登録商標）、１．９ｍＬのジクロロメタン、１．０２ｇ（３．８８ｍｍｏｌ）のフッ化水素とピリジンの７：３（重量比）混合物を仕込んだ。反応器をセプタムで閉じて室温にて１４４時間撹拌した。
氷浴にて冷却した後、１．６７ｇ（１６．７ｍｍｏｌ）のＮ－メチルピペラジンを反応混合物に加えた。氷浴を取り除き反応混合物を１時間撹拌し、その後、３．０７ｇ（２２．２ｍｍｏｌ）の炭酸カリウムと８．８ｍＬのｎ－ヘプタンからなる懸濁液中に反応混合物を注いだ。
ろ過した後、ろ液に１．６７ｇ（２７．８ｍｍｏｌ）の酢酸を加え、室温で１５分間攪拌した。３ｍＬの水を加えて３０分攪拌した後、析出した結晶をろ過した。ろ液を分液して得られた有機層を水洗し、水洗後の有機層をＨＰＬＣによって分析した。 In a fluoropolymer (PFA) reactor equipped with a septum, 1.0 g (5.55 mmol) 9-fluorenone, 2.78 g (11.1 mmol) Fluolead®, 1.9 mL dichloromethane, 1 0.02 g (3.88 mmol) of a 7:3 (weight ratio) mixture of hydrogen fluoride and pyridine was charged. The reactor was closed with a septum and stirred at room temperature for 144 hours.
After cooling in an ice bath, 1.67 g (16.7 mmol) of N-methylpiperazine was added to the reaction mixture. The ice bath was removed and the reaction mixture was stirred for 1 hour, after which the reaction mixture was poured into a suspension consisting of 3.07 g (22.2 mmol) of potassium carbonate and 8.8 mL of n-heptane.
After filtration, 1.67 g (27.8 mmol) of acetic acid was added to the filtrate and stirred at room temperature for 15 minutes. After adding 3 mL of water and stirring for 30 minutes, precipitated crystals were filtered. The organic layer obtained by separating the filtrate was washed with water, and the organic layer after washing was analyzed by HPLC.
氷浴にて冷却した後、１．６７ｇ（１６．７ｍｍｏｌ）のＮ－メチルピペラジンを反応混合物に加えた。氷浴を取り除き反応混合物を１時間撹拌し、その後、３．０７ｇ（２２．２ｍｍｏｌ）の炭酸カリウムと８．８ｍＬのｎ－ヘプタンからなる懸濁液中に反応混合物を注いだ。
ろ過した後、ろ液に１．６７ｇ（２７．８ｍｍｏｌ）の酢酸を加え、室温で１５分間攪拌した。３ｍＬの水を加えて３０分攪拌した後、析出した結晶をろ過した。ろ液を分液して得られた有機層を水洗し、水洗後の有機層をＨＰＬＣによって分析した。 In a fluoropolymer (PFA) reactor equipped with a septum, 1.0 g (5.55 mmol) 9-fluorenone, 2.78 g (11.1 mmol) Fluolead®, 1.9 mL dichloromethane, 1 0.02 g (3.88 mmol) of a 7:3 (weight ratio) mixture of hydrogen fluoride and pyridine was charged. The reactor was closed with a septum and stirred at room temperature for 144 hours.
After cooling in an ice bath, 1.67 g (16.7 mmol) of N-methylpiperazine was added to the reaction mixture. The ice bath was removed and the reaction mixture was stirred for 1 hour, after which the reaction mixture was poured into a suspension consisting of 3.07 g (22.2 mmol) of potassium carbonate and 8.8 mL of n-heptane.
After filtration, 1.67 g (27.8 mmol) of acetic acid was added to the filtrate and stirred at room temperature for 15 minutes. After adding 3 mL of water and stirring for 30 minutes, precipitated crystals were filtered. The organic layer obtained by separating the filtrate was washed with water, and the organic layer after washing was analyzed by HPLC.
ＳＯＦは、Ｎ－メチルピペラジンによって１－（（４－ｔｅｒｔ－ブチル－２，６－ジメチルフェニル）スルフィニル）－４－メチルピペラジンに転化され、酢酸を加えてろ過し、ろ液を水洗することにより有機層から除去された。これは酢酸を加える前のろ液のＨＰＬＣ分析結果と比較して、１－（（４－ｔｅｒｔ－ブチル－２，６－ジメチルフェニル）スルフィニル）－４－メチルピペラジンのピークが消失していることから確認した（図２）。１－（（４－ｔｅｒｔ－ブチル－２，６－ジメチルフェニル）スルフィニル）－４－メチルピペラジンは、以下のＭＳにより構造を確認した。
SOF is converted to 1-((4-tert-butyl-2,6-dimethylphenyl)sulfinyl)-4-methylpiperazine by N-methylpiperazine, added with acetic acid, filtered, and washed with water. Removed from the organic layer. This is because the peak of 1-((4-tert-butyl-2,6-dimethylphenyl)sulfinyl)-4-methylpiperazine has disappeared compared to the HPLC analysis result of the filtrate before adding acetic acid. (Fig. 2). The structure of 1-((4-tert-butyl-2,6-dimethylphenyl)sulfinyl)-4-methylpiperazine was confirmed by the following MS.
ＣＩ－ＭＳ ３０９（Ｍ＋Ｈ）
CI-MS 309 (M+H)
本発明は、フッ素化剤として２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンを用いたフッ素化物の製造、特に工業的規模での製造において、副生成物のＳＯＦを除去して、目的とするフッ素化物を単離することに利用できる。
The present invention uses 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene as a fluorinating agent to produce a fluorinated product, particularly in industrial scale production, by removing SOF as a by-product. , can be used to isolate the desired fluorinated compound.
Claims (10)
- ２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンによるフッ素化反応から得られたフッ素化物を下記式（１）で表される副生成物（以下「ＳＯＦ」ともいう）から単離する方法であって、
（工程１）前記フッ素化物と前記ＳＯＦとを含む反応混合物において、前記ＳＯＦを下記式（２）で表されるスルフィニル化合物（以下「スルフィニル化合物（２）」ともいう）に転化する工程
（式中、Ｒは、第２級若しくは第３級アミン骨格を含むアルコキシ基、第２級若しくは第３級アミン骨格を含む第２級若しくは第３級アミノ基、又は第２級若しくは第３級アミン骨格を含む環状アミノ基である）；及び
（工程２）工程１で得られた前記スルフィニル化合物（２）を、前記フッ素化物との化学的性質の違いを利用して除去する工程
を含む方法。 A fluorinated product obtained from a fluorination reaction with 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene is isolated from a by-product represented by the following formula (1) (hereinafter also referred to as "SOF"). a method for
(Step 1) A step of converting the SOF into a sulfinyl compound represented by the following formula (2) (hereinafter also referred to as “sulfinyl compound (2)”) in a reaction mixture containing the fluoride and the SOF.
(wherein R is an alkoxy group containing a secondary or tertiary amine skeleton, a secondary or tertiary amino group containing a secondary or tertiary amine skeleton, or a secondary or tertiary a cyclic amino group containing an amine skeleton); and (step 2) a step of removing the sulfinyl compound (2) obtained in step 1 by utilizing the difference in chemical properties from the fluoride compound. . - 前記工程１において、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（３）で表される第２級又は第３級アミン骨格を含むアルコール化合物で処理して、前記ＳＯＦを下記式（４）で表されるスルフィニル化合物に転化する、請求項１に記載の方法。
〔式（３）及び（４）中、Ｒ１及びＲ２は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ１及びＲ２は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ１は１～８の整数である。但し、Ｒ１及びＲ２は同時に水素原子ではない。〕 In step 1, the reaction mixture containing the fluoride and the SOF is treated with an alcohol compound containing a secondary or tertiary amine skeleton represented by the following formula (3) to convert the SOF to the following formula ( The method according to claim 1, wherein the sulfinyl compound represented by 4) is converted.
[In the formulas (3) and (4), R 1 and R 2 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or an aryl group having 7 to 30 carbon atoms. or a hydrogen atom, or R 1 and R 2 may form a ring together with the nitrogen atom to which they are attached; and n 1 is 1-8 is an integer of However, R 1 and R 2 are not hydrogen atoms at the same time. ] - 前記Ｒ１及びＲ２が、それぞれ互いに独立して、炭素数が１～４のアルキル基であり、ｎ１が１～４の整数である、請求項２に記載の方法。 3. The method according to claim 2, wherein R 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms and n 1 is an integer of 1 to 4.
- 前記工程１において、前記フッ素化物と前記ＳＯＦとを含む反応混合物を下記式（５）で表される第２級又は第３級アミン骨格を含む第１級又は第２級アミン化合物で処理して、前記ＳＯＦを下記式（６）で表されるスルフィニル化合物に転化する、請求項１に記載の方法。
〔式（５）及び（６）中、Ｒ３及びＲ４は、それぞれ互いに独立して、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が７～３０のアラルキル基、又は水素原子であるか、あるいは、Ｒ３及びＲ４は、それらが結合している窒素原子と一緒になって環を形成していてもよく；Ｒ５は、炭素数が１～１８のアルキル基又は水素原子であるか、あるいは、Ｒ３及びＲ５は、それらが結合している窒素原子と一緒になって環を形成していてもよく；そして、ｎ２は１～８である。但し、Ｒ３及びＲ４は同時に水素原子ではない。〕 In the step 1, the reaction mixture containing the fluoride and the SOF is treated with a primary or secondary amine compound containing a secondary or tertiary amine skeleton represented by the following formula (5): , wherein the SOF is converted into a sulfinyl compound represented by the following formula (6).
[In formulas (5) and (6), R 3 and R 4 are each independently an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, or or a hydrogen atom, or R 3 and R 4 may form a ring together with the nitrogen atom to which they are attached; R 5 has 1 carbon atom 18 alkyl groups or hydrogen atoms, or R 3 and R 5 may together form a ring with the nitrogen atom to which they are attached; and n 2 is 1 to 8. However, R 3 and R 4 are not hydrogen atoms at the same time. ] - 前記Ｒ３、Ｒ４、及びＲ５が、それぞれ互いに独立して、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～４の整数である、請求項４に記載の方法。 5. The method according to claim 4, wherein R 3 , R 4 and R 5 are each independently an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is an integer of 1 to 4. Method.
- 前記Ｒ３及びＲ５が、それらが結合している窒素原子と一緒になって環を形成し、Ｒ４が、炭素数が１～４のアルキル基又は水素原子であり、ｎ２が１～２の整数である、請求項４に記載の方法。 R 3 and R 5 form a ring together with the nitrogen atom to which they are attached, R 4 is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, and n 2 is 1 to 5. The method of claim 4, which is an integer of two.
- 前記工程１から得られた前記フッ素化物と前記スルフィニル化合物（２）とを含む反応混合物を酸で処理してから、前記スルフィニル化合物（２）を除去する、請求項１～６のいずれか一項に記載の方法。 7. Any one of claims 1 to 6, wherein the reaction mixture containing the fluoride obtained from step 1 and the sulfinyl compound (2) is treated with an acid before the sulfinyl compound (2) is removed. The method described in .
- 前記フッ素化物が酸によって塩を形成しない、請求項７に記載の方法。 The method according to claim 7, wherein the fluoride does not form salts with acids.
- 下記式（４）で表される化合物又はその塩。
（式中、Ｒ１、Ｒ２、及びｎ１は、請求項２に定義されたとおりである） A compound represented by the following formula (4) or a salt thereof.
(wherein R 1 , R 2 and n 1 are as defined in claim 2) - 下記式（６）で表される化合物又はその塩。
（式中、Ｒ３、Ｒ４、Ｒ５、及びｎ２は、請求項４に定義されたとおりである） A compound represented by the following formula (6) or a salt thereof.
(wherein R 3 , R 4 , R 5 and n 2 are as defined in claim 4)
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