JP3823385B2 - Process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof - Google Patents
Process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof Download PDFInfo
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- JP3823385B2 JP3823385B2 JP22284696A JP22284696A JP3823385B2 JP 3823385 B2 JP3823385 B2 JP 3823385B2 JP 22284696 A JP22284696 A JP 22284696A JP 22284696 A JP22284696 A JP 22284696A JP 3823385 B2 JP3823385 B2 JP 3823385B2
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- YSVCSGNEHJLYDH-UHFFFAOYSA-N 2,4,5-trifluoro-3-iodobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(I)=C1F YSVCSGNEHJLYDH-UHFFFAOYSA-N 0.000 title claims description 19
- 238000000034 method Methods 0.000 title claims description 6
- 150000002148 esters Chemical class 0.000 title description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 19
- AKAMNXFLKYKFOJ-UHFFFAOYSA-N 2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1F AKAMNXFLKYKFOJ-UHFFFAOYSA-N 0.000 claims description 17
- 239000011541 reaction mixture Substances 0.000 claims description 15
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- 238000005886 esterification reaction Methods 0.000 description 16
- 238000006192 iodination reaction Methods 0.000 description 13
- 239000008079 hexane Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- MVLZYHDOLNPPNJ-UHFFFAOYSA-N ethyl 2,4,5-trifluoro-3-iodobenzoate Chemical compound CCOC(=O)C1=CC(F)=C(F)C(I)=C1F MVLZYHDOLNPPNJ-UHFFFAOYSA-N 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- -1 quinolone carboxylic acid compounds Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- DLKNOGQOOZFICZ-UHFFFAOYSA-N 2,4,5-trifluorobenzonitrile Chemical compound FC1=CC(F)=C(C#N)C=C1F DLKNOGQOOZFICZ-UHFFFAOYSA-N 0.000 description 3
- NVWVZPFPZJYLNK-UHFFFAOYSA-N 3-amino-2,4,5-trifluorobenzoic acid Chemical compound NC1=C(F)C(F)=CC(C(O)=O)=C1F NVWVZPFPZJYLNK-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- JQFIRFIXZUFKJC-UHFFFAOYSA-N ethyl 2,4,5-trifluoro-3-(trifluoromethyl)benzoate Chemical compound CCOC(=O)C1=CC(F)=C(F)C(C(F)(F)F)=C1F JQFIRFIXZUFKJC-UHFFFAOYSA-N 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SUUYTEUAWNNSEE-UHFFFAOYSA-N 2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(C(F)(F)F)=C1F SUUYTEUAWNNSEE-UHFFFAOYSA-N 0.000 description 2
- YSVCSGNEHJLYDH-UHFFFAOYSA-M 2,4,5-trifluoro-3-iodobenzoate Chemical class [O-]C(=O)C1=CC(F)=C(F)C(I)=C1F YSVCSGNEHJLYDH-UHFFFAOYSA-M 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- OOCCDEMITAIZTP-QPJJXVBHSA-N Cinnamyl alcohol Natural products OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M Copper(I) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000005591 charge neutralization Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940035429 isobutyl alcohol Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical class FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- MWKFXSUHUHTGQN-UHFFFAOYSA-N 1-Decanol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 1
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-Heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 1
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N 1-Hexanol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 1
- ZWRUINPWMLAQRD-UHFFFAOYSA-N 1-Nonanol Chemical compound CCCCCCCCCO ZWRUINPWMLAQRD-UHFFFAOYSA-N 0.000 description 1
- GQRSVZXIGIYKTF-UHFFFAOYSA-N 1-bromo-2,4,5-trifluoro-3-iodobenzene Chemical compound FC1=CC(Br)=C(F)C(I)=C1F GQRSVZXIGIYKTF-UHFFFAOYSA-N 0.000 description 1
- OVKYJTHDMZIEGN-UHFFFAOYSA-N 2,4-dichloro-5-fluoro-3-iodobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(Cl)C(I)=C1Cl OVKYJTHDMZIEGN-UHFFFAOYSA-N 0.000 description 1
- UUWRGHXQVQUWHR-UHFFFAOYSA-N 3-amino-2,4-dichloro-5-fluorobenzoic acid Chemical compound NC1=C(Cl)C(F)=CC(C(O)=O)=C1Cl UUWRGHXQVQUWHR-UHFFFAOYSA-N 0.000 description 1
- KVBWBCRPWVKFQT-UHFFFAOYSA-M 3-iodobenzoate Chemical compound [O-]C(=O)C1=CC=CC(I)=C1 KVBWBCRPWVKFQT-UHFFFAOYSA-M 0.000 description 1
- KVBWBCRPWVKFQT-UHFFFAOYSA-N 3-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC(I)=C1 KVBWBCRPWVKFQT-UHFFFAOYSA-N 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N Allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- WCASXYBKJHWFMY-NSCUHMNNSA-N Crotyl alcohol Chemical compound C\C=C\CO WCASXYBKJHWFMY-NSCUHMNNSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N Cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N Cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N Isoamyl alcohol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N Propargyl alcohol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N Succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- RYPWQHONZWFXBN-UHFFFAOYSA-N dichloromethyl(methylidene)-$l^{3}-chlorane Chemical compound ClC(Cl)Cl=C RYPWQHONZWFXBN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GQJCAQADCPTHKN-UHFFFAOYSA-N methyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound COC(=O)C(F)(F)S(F)(=O)=O GQJCAQADCPTHKN-UHFFFAOYSA-N 0.000 description 1
- CHJMFYSWOSMQQK-UHFFFAOYSA-N methyl 2,4,5-trifluoro-3-iodobenzoate Chemical compound COC(=O)C1=CC(F)=C(F)C(I)=C1F CHJMFYSWOSMQQK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Description
【0001】
【発明の属する技術分野】
本発明は、2,4,5−トリフルオロ−3−ヨ−ド安息香酸およびそのエステル類の製造方法に関する。
前述の2,4,5−トリフルオロ−3−ヨ−ド安息香酸およびそのエステル類は、例えば、抗菌剤、抗ウィルス剤として有用なキノロンカルボン酸系化合物の出発原料として有用である2,4,5−トリフルオロ−3−トリフルオロメチル安息香酸類の原料となる。(特開昭64−66180号公報、WO96/02512号公報参照)。
【0002】
【従来の技術】
従来の2,4,5−トリフルオロ−3−ヨ−ド安息香酸類およびそのエステル類を製造する方法としては、例えば3−アミノ−2,4,5−トリフルオロ安息香酸類のザンドマイヤー反応を用いる以下に示す方法がある。
(1)特開平3−95179号公報には、3−アミノ−2,4,5−トリフルオロ安息香酸とヨウ化第一銅、亜硝酸第三級ブチルを使用して2,4,5−トリフルオロ−3−ヨ−ド安息香酸を製造する方法が開示されている。
【0003】
(2)特開昭63−88157号公報および特開平6−25125号公報には、3−アミノ−2,4−ジクロロ−5−フルオロ安息香酸から塩酸、亜硝酸ナトリウム、ヨウ化カリウムと反応させて2,4−ジクロロ−5−フルオロ−3−ヨ−ド安息香酸を製造する方法が開示されている。
しかし、前述の方法(1)、(2)はいずれもその収率は低く、かつ3−アミノ−2,4,5−トリフルオロ安息香酸、そのエステル類を得るために多段階の工程を必要とするという点で工業的に満足する方法ではなかった。
【0004】
従って、公知の製法(1)、(2)のいずれもが2,4,5−トリフルオロ−3−ヨード安息香酸、そのエステル類を得る方法としては、不満があった。
【0005】
芳香族化合物をトリフルオロメタンスルホン酸存在下、N−ヨ−ドスクシイミドと反応させヨ−ド化合物を得る方法は公知である(J.Org.Chem.,1993年 58巻,3194頁、J.Chem.Res.,Synop.,1977年 215頁参照)。
しかし芳香族置換基としてカルボキシル基を有する化合物については報告がない。またこれらの芳香族誘導体を反応させる際、反応する場所、すなわち位置選択性および逐次反応選択性が問題であり、反応させる芳香族誘導体によりその選択性は大きく変化する。
【0006】
本発明者らは1,3,4−トリフルオロベンゼン誘導体について本反応の適用性について鋭意検討した結果、2,4,5−トリフルオロ安息香酸誘導体が3位にヨウ素を選択的に導入できる化合物であることを見出し本発明に到達した。
また本発明では、前記反応後のエステル化反応にアルコールを使用することにより簡便にエステル化反応が進行し、単離精製に都合がよいことも見出した。
【0007】
【発明が解決しようとする課題】
本発明は、工業的な製造法として容易に、高収率に、2,4,5−トリフルオロ−3−ヨード安息香酸およびそのエステル類を製造する方法を提供することを目的とする。
【0008】
【課題を解決するための手段】
本発明の第一は、
2,4,5−トリフルオロ安息香酸とN−ヨ−ドスクシイミドとを、トリフルオロメタンスルホン酸存在下、反応させること特徴とする2,4,5−トリフルオロ−3−ヨ−ド安息香酸の製造方法に関し、
本発明の第二は、
2,4,5−トリフルオロ安息香酸とN−ヨ−ドスクシイミドとを、トリフルオロメタンスルホン酸存在下、反応させ、ついで反応混合物と、
一般式(I)
【0009】
【化3】
【0010】
(式中、Rはアルキル基、シクロアルキル基またはアラルキル基を示す)で表わされるアルコ−ル類とを反応させることを特徴とする、
一般式(II)
【0011】
【化4】
【0012】
(式中、Rは前記と同じ意味を示す)で表わされる2,4,5−トリフルオロ−3−ヨード安息香酸エステル類の製造方法に関し、
【0013】
本発明の第三は、
前記アルコ−ル類が炭素数1〜4のアルキルアルコールである前記に記載の製造方法に関する。
【0014】
【発明の実施の形態】
本発明は、例えば以下に示すような、
反応式(1)
【0015】
【化5】
【0016】
で表わされるヨウ素化反応、および
反応式(2)
【0017】
【化6】
【0018】
で表わされるエステル化反応で表すことができる。
【0019】
本発明のヨウ素化反応は、2,4,5−トリフルオロ安息香酸とN−ヨ−ドスクシイミドとを、トリフルオロメタンスルホン酸の存在下、反応させて2,4,5−トリフルオロ−3−ヨ−ド安息香酸を得る工程である。
【0020】
本発明のヨウ素化反応において使用する2,4,5−トリフルオロ安息香酸、トリフルオロメタンスルホン酸、N−ヨ−ドスクシイミドは市販されている。
【0021】
本発明のヨウ素化反応において使用するトリフルオロメタンスルホン酸のモル比率は、2,4,5−トリフルオロ安息香酸1モルに対して、通常1〜20モルの範囲、好ましくは2〜10モルである。
【0022】
本発明のヨウ素化反応において使用するN−ヨ−ドスクシイミドのモル比率は、2,4,5−トリフルオロ安息香酸1モルに対して、通常1〜5モルの範囲、好ましくは1〜2モルである。
【0023】
本発明のヨウ素化反応においてはトリフルオロメタンスルホン酸以外の溶媒は使用しない。
本反応は他の溶媒で希釈すると反応は進行しないか著しく遅くなる。
【0024】
本発明のヨウ素化反応においては反応温度は、通常0℃〜200℃の範囲で実施でき、好適には室温から100℃の範囲である。
本発明のヨウ素化反応においては反応時間は、反応温度にも大きく依存するが、0.5〜20時間の範囲である。
本発明のエステル化反応の反応圧力は、通常大気圧下で行われるが、減圧下、加圧下でも反応を行うことができる。
【0025】
本発明のヨウ素化反応は、特に水分の混入に注意して実施する以外は、通常の有機反応と同様の手順で実施される。
【0026】
本発明のヨウ素化反応によって得られた、2,4,5−トリフルオロ−3−ヨ−ド安息香酸を含む反応混合物(1)は、2,4,5−トリフルオロ−3−ヨード安息香酸を分離することなく、以下のエステル化反応に用いることができるが、通常の反応と同様に中和、濃縮、抽出等の後処理操作の後、再結晶、カラム精製等の方法で分離しても用いることができる。
【0027】
本発明のエステル化反応は、前記ヨウ素化反応で得られた2,4,5−トリフルオロ−3−ヨ−ド安息香酸とアルコ−ルとを反応させて2,4,5−トリフルオロ−3−ヨ−ド安息香酸エステルを得る工程である。
【0028】
本発明のエステル化反応は、通常は前記ヨウ素化反応によって得られた、2,4,5−トリフルオロ−3−ヨ−ド安息香酸を含む反応混合物(1)を直接使用するが、2,4,5−トリフルオロ−3−ヨ−ド安息香酸を、分離した後に使用してもよい。
【0029】
本発明のエステル化反応では、通常トリフルオロメタンスルホン酸溶液にアルコ−ル類を注入すると発熱するので、反応混合物(1)を希釈溶媒で希釈した希釈溶液をアルコ−ル中に滴下する方法が推奨される。
このような希釈溶媒としては、通常塩化メチレン、クロロホルム、ジクロロエタン等の有機塩素系溶媒、ベンゼン、トルエン、キシレン等の芳香族系溶媒が好適である。
【0030】
このような希釈溶媒の使用量は、前記ヨウ素化反応で使用したトリフルオロメタンスルホン酸1容量に対して0.2〜10容量倍が良い。
【0031】
本発明のエステル化反応で使用するアルコ−ルの示すRとしては、例えば炭素数1〜10の直鎖状または分枝状の飽和アルキル基、炭素数2〜10の直鎖状または分枝状の不飽和アルキル基、炭素数3〜10のシクロアルキル基、炭素数7〜10のアラルキル基を挙げることができ、好ましくは炭素数1〜10の直鎖状または分枝状のアルキル基、炭素数3〜4の直鎖状または分枝状の不飽和アルキル基、炭素数5〜6のシクロアルキル基、ベンジル基、シンナミル基、であり、さらに好ましくはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチルである。
【0032】
このようなRを置換基として持つアルコ−ルの具体例としては、メチルアルコ−ル、エチルアルコ−ル、プロピルアルコ−ル、イソプロピルアルコ−ル、ブチルアルコ−ル、イソブチルアルコ−ル、sec−ブチルアルコ−ル、tert−ブチルアルコ−ル、n−アミルアルコ−ル、イソアミルアルコ−ル、ヘキシルアルコ−ル、ヘプチルアルコ−ル、オクチルアルコ−ル、カプリルアルコ−ル、ノニルアルコ−ル、デシルアルコ−ル等の炭素数1〜10の直鎖又は分枝状の飽和アルキルアルコ−ル類、アリルアルコ−ル、クロチルアルコ−ル、プロパルギルアルコ−ルなどの不飽和アルキルアルコ−ル類、シクロペンチルアルコ−ル、シクロヘキシルアルコ−ルなどの脂環式アルコ−ル類、ベンジルアルコ−ル、シンナミルアルコ−ルなどの芳香族アルコ−ル類が好ましく、炭素数1〜10の直鎖又は分枝状の飽和アルキルアルコ−ルがさらに好ましく、メチルアルコ−ル、エチルアルコ−ル、プロピルアルコ−ル、イソプロピルアルコ−ル、ブチルアルコ−ル、イソブチルアルコ−ル、sec−ブチルアルコ−ル、tert−ブチルアルコ−ルが特に好ましい。
【0033】
本発明のエステル化反応で使用するアルコ−ルのモル比率は、反応させた2,4,5−トリフルオロ安息香酸1モルに対して、通常1〜100モルの範囲、好ましくは5〜50モルの範囲である。
【0034】
本発明のエステル化反応の反応温度は、通常−40℃から使用するアルコールの沸点までが実施可能である。トリフルオロメタンスルホン酸をアルコール類に加えると通常かなり発熱するので、最初は0℃以下に冷却して加え、その後室温ないし使用するアルコールの沸点付近に加熱することがさらに好ましい。
本発明のエステル化反応の反応時間は反応温度、トリフルオロメタンスルホン酸量、アルコールの量により変化するが、通常0.5時間から20時間の範囲で終了する。
【0035】
本発明のエステル化反応の反応圧力は、通常大気圧下で行われるが、減圧下、加圧下でも反応を行うことができる。
【0036】
本発明のエステル化反応によって得られた、反応混合物(2)からの生成物の単離は、通常の反応と同様に中和、濃縮、抽出等の後処理操作の後、蒸留、カラム精製等の方法で十分に純度の高い目的物が得られる。
【0037】
なお、エステル化反応中にヨウ素が遊離することがあるので、前記後処理操作中に、チオ硫酸ナトリウム等でヨウ素を反応系から除去することが好ましい。
【0038】
このようにして得られる2,4,5−トリフルオロ−3−ヨ−ド安息香酸エステル類としては、例えば2,4,5−トリフルオロ−3−ヨ−ド安息香酸メチル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸エチル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸−n−プロピル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸−i−プロピル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸−n−ブチル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸−i−ブチル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸−s−ブチル、2,4,5−トリフルオロ−3−ヨ−ド安息香酸−t−ブチル等の2,4,5−トリフルオロ−3−ヨ−ド安息香酸の炭素数1〜4のアルキルエステルが挙げられる。
【0039】
【発明の効果】
本発明によれば、2,4,5−トリフルオロ安息香酸とN−ヨ−ドスクシイミドとを、トリフルオロメタンスルホン酸存在下、反応させることにより、2,4,5−トリフルオロ−3−ヨ−ド安息香酸を高収率で、簡便に得ることができ、また2,4,5−トリフルオロ−3−ヨ−ド安息香酸とアルコ−ルとを反応させることによりエステル化反応が進行し、単離精製に好適である2,4,5−トリフルオロ−3−ヨ−ド安息香酸エステル類を得ることができる。
【0040】
【実施例】
以下に実施例を示して本発明をさらに詳しく説明するが、本発明の範囲はこれらに限定されるものではない。実施例、参考例および比較例における、液体クロマトグラフ(以下HPLCと略記する)、ガスクロマトグラフ(以下GCと略記する)の分析条件は以下の通りである。
【0041】
【0042】
【0043】
実施例1
トリフルオロメタンスルホン酸56.14g(0.375mol)と2,4,5−トリフルオロ安息香酸9.41g(0.053mol)との混合物(1)を−5℃に冷却し、N−ヨ−ドスクシイミド20.44g(0.91mol)を加えて混合物(2)を得た。得られた混合物(2)を室温で一時間撹拌後、さらに40〜45℃で6時間撹拌して反応させた。
【0044】
反応終了後、得られた反応混合物(1)に塩化メチレン20ミリリットルを加え、この溶液を0℃に冷却したエタノール45ミリリットル中に滴下した。その後45℃で4時間撹拌して反応させた。
得られた反応混合物(2)にヘキサン100ミリリットル、30%水酸化ナトリウム水溶液38ミリリットルを加えpHを7付近にした。ついで飽和チオ硫酸ナトリウム水溶液80ミリリットルを加えた。ヘキサン層を分液し、飽和炭酸水素ナトリウム水溶液50ミリリットルで洗浄後、無水硫酸マグネシウム乾燥、濾過、濃縮した。濃縮残査を減圧蒸留し沸点104℃/133Paの留分として2,4,5−トリフルオロ−3−ヨ−ド安息香酸エチル11.07g得た〔純度97.5%(HPLC分析)、0.0357mol〕。(2,4,5−トリフルオロ安息香酸に対する収率67%)。
【0045】
実施例2
トリフルオロメタンスルホン酸1552g(7.23mol)と2,4,5−トリフルオロ安息香酸252g(1.43mol)との混合物(1)を−5℃に冷却し、N−ヨ−ドスクシイミド483g(2.15mol)を加えて混合物(2)を得た。得られた混合物(2)を室温で2時間撹拌後、さらに45〜47℃で3時間撹拌して反応させた。
【0046】
反応終了後、得られた反応混合物(1)に塩化メチレン543ミリリットルを加え、この溶液を0℃に冷却したエタノ−ル1215ミリリットル中に滴下した。その後55〜56℃で4.5時間撹拌して反応させた。
得られた反応混合物(2)にヘキサン1930ミリリットルと30%水酸化ナトリウム水溶液960ミリリットルとを加えpHを6.5とした。ついで飽和チオ硫酸ナトリウム水溶液2002ミリリットルを加えた。ヘキサン層を分液し、水層をヘキサン1700ミリリットルで抽出した。合わせたヘキサン層を飽和炭酸水素ナトリウム水溶液1140ミリリットルで洗浄後、無水硫酸マグネシウム乾燥、濾過、濃縮した。以上の操作を三回行い合わせた濃縮残査を減圧蒸留し沸点105〜108℃/187〜200Paの留分として2,4,5−トリフルオロ−3−ヨ−ド安息香酸エチルを1087g得た〔純度97.6%(HPLC分析)、3.215mol〕。(2,4,5−トリフルオロ安息香酸に対する収率74.94%)。
【0047】
実施例3
トリフルオロメタンスルホン酸1.64g(10.9mmol)と2,4,5−トリフルオロ安息香酸383.8mg(2.18mmol)との混合物(1)を0〜−5℃に冷却し、N−ヨ−ドスクシイミド490.4mg(2.18mmol)を加えて混合物(2)を得た。得られた混合物(2)を室温で6時間撹拌して反応させた。
【0048】
反応終了後、得られた反応混合物に水5ミリリットル、酢酸エチル8ミリリットルを加えた後、30%NaOH水溶液でpHを5.0にした。酢酸エチル層を分液し無水硫酸マグネシウム乾燥、濾過、濃縮した。濃縮残査にヘキサン5mlを加え、析出した無色結晶(コハク酸イミド)を濾過し、濾液を濃縮し、固体246mgを得た。この固体をHPLCで分析すると、原料の2,4,5−トリフルオロ安息香酸が24%、2,4,5−トリフルオロ−3−ヨ−ド安息香酸が76%含まれていた。
【0049】
参考例1;2,4,5−トリフルオロ−3−トリフルオロメチル安息香酸エチルの製造
ヨウ化第一銅12.28g(65mmol)とジメチルホルムアミド2860mlとの混合物(1)にフルオロスルホニルジフルオロ酢酸メチル500g(2.6mol)と2,4,5−トリフルオロ−3−ヨ−ド安息香酸エチル441.4g(純度97.3%、1.3mol)とを加え、80〜86℃に加熱し、7時間撹拌して反応させた。
【0050】
反応終了後、得られた反応混合物をヘキサン3250ミリリットルと飽和炭酸水素ナトリウム水3250ミリリットルとの混合物(2)に滴下した。ヘキサン層を分液し無水硫酸マグネシウムで乾燥した。ヘキサンを減圧濃縮した残査642gには目的物の2,4,5−トリフルオロ−3−トリフルオロメチル安息香酸エチルが278.4g(1.02mol)含まれていることがGC分析で判明した。
【0051】
同様の操作を二回行い、合わせた濃縮物を30cmウットマー精留器を付けて減圧蒸留した。沸点74〜79℃/0.39kPa付近の留分を集めた。取得量567g、純度92.2%、1.927mol、(2,4,5−トリフルオロ−3−ヨ−ド安息香酸エチルに対する取得収率74.1%)。
【0052】
参考例2;2,4,5−トリフルオロ−3−トリフルオロメチル安息香酸の製造
上記実施例2で得られた2,4,5−トリフルオロ−3−トリフルオロメチル安息香酸エチル567g(純度92.2%、1.927mol)、酢酸1580ミリリットル、水316ミリリットルとp−トルエンスルホン酸一水和物733gとの混合物(1)を8時間、加熱還流撹拌して反応させた。この間反応系から250mlの溶媒留去、反応系への酢酸280ミリリットルと水42ミリリットルとの混合物(2)の追加を各々二回行った。
【0053】
反応終了後、得られた反応混合物に水1930ミリリットルを加え冷却し、トルエン3.85リットルを加えた。分液し、水層をさらにトルエン1.93リットルで三回抽出した。合わせたトルエン層を無水硫酸マグネシウムで乾燥し、濾過、濃縮後、濃縮残査にヘキサン1.9リットルを加えて加熱した。得られた均一溶液を0〜−6.5℃に冷却し結晶を析出させた。得られた結晶を濾過、ヘキサン洗浄、風乾して、2,4,5−トリフルオロ−3−トリフルオロメチル安息香酸401g、(1.64mol,純度99.8%)を得た。
【0054】
比較例1;2,4,5−トリフルオロブロムベンゼンの反応
トリフルオロメタンスルホン酸1.54g(10.24mmol)と2,4,5−トリフルオロブロムベンゼン432.2mg(2.05mmol)との混合物(1)を0〜−5℃に冷却し、N−ヨ−ドスクシイミド460.9mg(2.05mol)を加えて混合物(2)を得た。得られた混合物(2)を室温で6時間撹拌して反応させた。
【0055】
反応終了後、得られた反応混合物を、HPLCで分析すると、原料の2,4,5−トリフルオロブロムベンゼンが15%、3−ブロム−2,5,6−トリフルオロヨ−ドベンゼンが20%、2−ブロム−3,5,6−トリフルオロ−1,4−ジヨ−ドベンゼンが61%生成しており、モノブロム化の選択性はなかった。
【0056】
比較例2;2,4,5−トリフルオロベンゾニトリルの反応
トリフルオロメタンスルホン酸3.812g(25.4mmol)と2,4,5−トリフルオロベンゾニトリル798.1mg(5.08mmol)との混合物(1)を0〜−5℃に冷却し、N−ヨ−ドスクシイミド1143mg(5.08mol)を加えて混合物(2)を得た。得られた混合物(2)を室温で4時間撹拌して反応させた。
【0057】
反応終了後、得られた反応混合物を、HPLCで分析すると、原料の2,4,5−トリフルオロベンゾニトリルは反応していなかった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof.
The aforementioned 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof are useful as starting materials for quinolone carboxylic acid compounds useful as antibacterial agents and antiviral agents, for example. , 5-trifluoro-3-trifluoromethylbenzoic acid. (Refer to Unexamined-Japanese-Patent No. 64-66180, WO96 / 02512).
[0002]
[Prior art]
As a conventional method for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof, for example, the Sandmeyer reaction of 3-amino-2,4,5-trifluorobenzoic acid is used. There are the following methods.
(1) In Japanese Patent Laid-Open No. 3-95179, 3-amino-2,4,5-trifluorobenzoic acid, cuprous iodide, and tertiary butyl nitrite are used. A method for producing trifluoro-3-iodobenzoic acid is disclosed.
[0003]
(2) In JP-A-63-88157 and JP-A-6-25125, 3-amino-2,4-dichloro-5-fluorobenzoic acid is reacted with hydrochloric acid, sodium nitrite and potassium iodide. A process for producing 2,4-dichloro-5-fluoro-3-iodobenzoic acid.
However, the above-mentioned methods (1) and (2) are both low in yield and require a multi-step process to obtain 3-amino-2,4,5-trifluorobenzoic acid and its esters. It was not an industrially satisfactory method.
[0004]
Therefore, both of the known production methods (1) and (2) were unsatisfactory as a method for obtaining 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof.
[0005]
A method for obtaining an iodine compound by reacting an aromatic compound with N-iodosuccinimide in the presence of trifluoromethanesulfonic acid is known (J. Org. Chem., 1993, 58, 3194, J. Chem. Res., Synop., 1977, page 215).
However, there is no report on a compound having a carboxyl group as an aromatic substituent. Further, when these aromatic derivatives are reacted, the place of reaction, that is, regioselectivity and sequential reaction selectivity are problems, and the selectivity varies greatly depending on the aromatic derivative to be reacted.
[0006]
As a result of intensive studies on the applicability of this reaction for the 1,3,4-trifluorobenzene derivative, the present inventors have found that the 2,4,5-trifluorobenzoic acid derivative can selectively introduce iodine into the 3-position. The present invention has been found.
In the present invention, it has also been found that the use of alcohol for the esterification reaction after the reaction facilitates the esterification reaction, which is convenient for isolation and purification.
[0007]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof easily and in high yield as an industrial production method.
[0008]
[Means for Solving the Problems]
The first of the present invention is
Production of 2,4,5-trifluoro-3-iodobenzoic acid characterized by reacting 2,4,5-trifluorobenzoic acid and N-iodosuccinimide in the presence of trifluoromethanesulfonic acid Regarding the method,
The second of the present invention is
2,4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid, and then the reaction mixture;
Formula (I)
[0009]
[Chemical 3]
[0010]
(Wherein R represents an alkyl group, a cycloalkyl group or an aralkyl group), and is reacted with an alcohol represented by:
Formula (II)
[0011]
[Formula 4]
[0012]
(Wherein R represents the same meaning as described above), 2,4,5-trifluoro-3-iodobenzoic acid esters,
[0013]
The third aspect of the present invention is
The said alcohol is related with the manufacturing method as described above which is a C1-C4 alkyl alcohol.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
The present invention is, for example, as shown below:
Reaction formula (1)
[0015]
[Chemical formula 5]
[0016]
And the reaction formula (2)
[0017]
[Chemical 6]
[0018]
It can represent with the esterification reaction represented by these.
[0019]
In the iodination reaction of the present invention, 2,4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid to produce 2,4,5-trifluoro-3-iodine. -A step of obtaining dobenzoic acid.
[0020]
2,4,5-trifluorobenzoic acid, trifluoromethanesulfonic acid and N-iodosuccinimide used in the iodination reaction of the present invention are commercially available.
[0021]
The molar ratio of the trifluoromethanesulfonic acid used in the iodination reaction of the present invention is usually in the range of 1 to 20 mol, preferably 2 to 10 mol, relative to 1 mol of 2,4,5-trifluorobenzoic acid. .
[0022]
The molar ratio of N-iodosuccinimide used in the iodination reaction of the present invention is usually in the range of 1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of 2,4,5-trifluorobenzoic acid. is there.
[0023]
In the iodination reaction of the present invention, no solvent other than trifluoromethanesulfonic acid is used.
When this reaction is diluted with another solvent, the reaction does not proceed or becomes extremely slow.
[0024]
In the iodination reaction of the present invention, the reaction temperature can usually be carried out in the range of 0 ° C. to 200 ° C., and preferably in the range of room temperature to 100 ° C.
In the iodination reaction of the present invention, the reaction time greatly depends on the reaction temperature, but is in the range of 0.5 to 20 hours.
The reaction pressure of the esterification reaction of the present invention is usually carried out under atmospheric pressure, but the reaction can be carried out under reduced pressure or under pressure.
[0025]
The iodination reaction of the present invention is carried out in the same procedure as a normal organic reaction except that the iodination reaction is carried out with particular attention to water contamination.
[0026]
The reaction mixture (1) containing 2,4,5-trifluoro-3-iodobenzoic acid obtained by the iodination reaction of the present invention is 2,4,5-trifluoro-3-iodobenzoic acid. Can be used for the following esterification reactions without separation, but after post-treatment operations such as neutralization, concentration, extraction, etc., in the same manner as normal reactions, separation by recrystallization, column purification, etc. Can also be used.
[0027]
In the esterification reaction of the present invention, 2,4,5-trifluoro-3-iodobenzoic acid obtained by the iodination reaction and alcohol are reacted to produce 2,4,5-trifluoro- In this step, 3-iodobenzoate is obtained.
[0028]
The esterification reaction of the present invention directly uses a reaction mixture (1) containing 2,4,5-trifluoro-3-iodobenzoic acid, usually obtained by the iodination reaction. 4,5-trifluoro-3-iodobenzoic acid may be used after separation.
[0029]
In the esterification reaction of the present invention, when alcohols are usually injected into a trifluoromethanesulfonic acid solution, heat is generated. Therefore, a method in which a diluted solution obtained by diluting the reaction mixture (1) with a diluting solvent is dropped into the alcohol is recommended. Is done.
As such a diluting solvent, organic chlorine solvents such as methylene chloride, chloroform and dichloroethane, and aromatic solvents such as benzene, toluene and xylene are usually suitable.
[0030]
The amount of such a dilution solvent used is preferably 0.2 to 10 times the volume of 1 volume of trifluoromethanesulfonic acid used in the iodination reaction.
[0031]
Examples of R shown in the alcohol used in the esterification reaction of the present invention include, for example, a linear or branched saturated alkyl group having 1 to 10 carbon atoms, and a linear or branched structure having 2 to 10 carbon atoms. An unsaturated alkyl group, a cycloalkyl group having 3 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms, preferably a linear or branched alkyl group having 1 to 10 carbon atoms, carbon A linear or branched unsaturated alkyl group having 3 to 4 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, a benzyl group or a cinnamyl group, and more preferably methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl.
[0032]
Specific examples of the alcohol having R as a substituent include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol. Carbon number such as benzene, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, capryl alcohol, nonyl alcohol, decyl alcohol 1-10 linear or branched saturated alkyl alcohols, unsaturated alkyl alcohols such as allyl alcohol, crotyl alcohol, propargyl alcohol, cyclopentyl alcohol, cyclohexyl alcohol, etc. Alicyclic alcohols, benzyl alcohol, cinnamyl alcohol, etc. Aromatic alcohols are preferred, linear or branched saturated alkyl alcohols having 1 to 10 carbon atoms are more preferred, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, Butyl alcohol, isobutyl alcohol, sec-butyl alcohol, and tert-butyl alcohol are particularly preferred.
[0033]
The molar ratio of the alcohol used in the esterification reaction of the present invention is usually in the range of 1 to 100 mol, preferably 5 to 50 mol, relative to 1 mol of 2,4,5-trifluorobenzoic acid reacted. Range.
[0034]
The reaction temperature of the esterification reaction of the present invention can be usually carried out from -40 ° C to the boiling point of the alcohol used. When trifluoromethanesulfonic acid is added to alcohols, it usually generates a considerable amount of heat. Therefore, it is more preferable to first add it after cooling to 0 ° C. or lower, and then heat it to room temperature or near the boiling point of the alcohol used.
The reaction time of the esterification reaction of the present invention varies depending on the reaction temperature, the amount of trifluoromethanesulfonic acid, and the amount of alcohol, but is usually completed in the range of 0.5 to 20 hours.
[0035]
The reaction pressure of the esterification reaction of the present invention is usually carried out under atmospheric pressure, but the reaction can be carried out under reduced pressure or under pressure.
[0036]
Isolation of the product from the reaction mixture (2) obtained by the esterification reaction of the present invention is carried out by post-treatment operations such as neutralization, concentration, extraction, etc., and distillation, column purification, etc. A sufficiently pure target product can be obtained by this method.
[0037]
In addition, since iodine may be liberated during the esterification reaction, it is preferable to remove iodine from the reaction system with sodium thiosulfate or the like during the post-treatment operation.
[0038]
Examples of the 2,4,5-trifluoro-3-iodobenzoates thus obtained include methyl 2,4,5-trifluoro-3-iodobenzoate, 2,4,5- Ethyl 5-trifluoro-3-iodobenzoate, 2,4,5-trifluoro-3-iodobenzoate-n-propyl, 2,4,5-trifluoro-3-iodobenzoate Acid-i-propyl, 2,4,5-trifluoro-3-iodobenzoic acid-n-butyl, 2,4,5-trifluoro-3-iodobenzoic acid-i-butyl, 2, 2,4,5-trifluoro- such as 4,5-trifluoro-3-iodobenzoic acid-s-butyl, 2,4,5-trifluoro-3-iodobenzoic acid-t-butyl C1-C4 alkylester of 3-iodobenzoic acid is mentioned.
[0039]
【The invention's effect】
According to the present invention, 2,4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid to produce 2,4,5-trifluoro-3-iodo. Debenzoic acid can be easily obtained in a high yield, and the esterification reaction proceeds by reacting 2,4,5-trifluoro-3-iodobenzoic acid with alcohol, 2,4,5-trifluoro-3-iodobenzoic acid esters suitable for isolation and purification can be obtained.
[0040]
【Example】
The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples. The analysis conditions of the liquid chromatograph (hereinafter abbreviated as HPLC) and gas chromatograph (hereinafter abbreviated as GC) in the Examples, Reference Examples and Comparative Examples are as follows.
[0041]
[0042]
[0043]
Example 1
A mixture (1) of 56.14 g (0.375 mol) of trifluoromethanesulfonic acid and 9.41 g (0.053 mol) of 2,4,5-trifluorobenzoic acid was cooled to −5 ° C., and N-iodosuccinimide was obtained. 20.44 g (0.91 mol) was added to obtain a mixture (2). The obtained mixture (2) was stirred at room temperature for 1 hour, and further stirred at 40 to 45 ° C. for 6 hours to be reacted.
[0044]
After completion of the reaction, 20 ml of methylene chloride was added to the resulting reaction mixture (1), and this solution was dropped into 45 ml of ethanol cooled to 0 ° C. Thereafter, the reaction was allowed to stir at 45 ° C. for 4 hours.
To the obtained reaction mixture (2), 100 ml of hexane and 38 ml of 30% aqueous sodium hydroxide solution were added to adjust the pH to around 7. Then 80 ml of saturated aqueous sodium thiosulfate solution was added. The hexane layer was separated, washed with 50 ml of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under reduced pressure to obtain 11.07 g of ethyl 2,4,5-trifluoro-3-iodobenzoate as a fraction having a boiling point of 104 ° C./133 Pa (purity 97.5% (HPLC analysis), 0 0.0357 mol]. (Yield 67% based on 2,4,5-trifluorobenzoic acid).
[0045]
Example 2
A mixture (1) of 1552 g (7.23 mol) of trifluoromethanesulfonic acid and 252 g (1.43 mol) of 2,4,5-trifluorobenzoic acid was cooled to −5 ° C., and 483 g of N-iodosuccinimide (2. 15 mol) was added to obtain a mixture (2). The obtained mixture (2) was stirred at room temperature for 2 hours, and further stirred at 45 to 47 ° C. for 3 hours to be reacted.
[0046]
After completion of the reaction, 543 ml of methylene chloride was added to the resulting reaction mixture (1), and this solution was dropped into 1215 ml of ethanol cooled to 0 ° C. Thereafter, the reaction was carried out by stirring at 55 to 56 ° C. for 4.5 hours.
To the obtained reaction mixture (2), 1930 ml of hexane and 960 ml of 30% aqueous sodium hydroxide solution were added to adjust the pH to 6.5. Then, 2002 ml of saturated aqueous sodium thiosulfate solution was added. The hexane layer was separated, and the aqueous layer was extracted with 1700 ml of hexane. The combined hexane layers were washed with 1140 ml of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue obtained by performing the above operations three times was distilled under reduced pressure to obtain 1087 g of ethyl 2,4,5-trifluoro-3-iodobenzoate as a fraction having a boiling point of 105 to 108 ° C./187 to 200 Pa. [Purity 97.6% (HPLC analysis), 3.215 mol]. (Yield 74.94% based on 2,4,5-trifluorobenzoic acid).
[0047]
Example 3
A mixture (1) of 1.64 g (10.9 mmol) of trifluoromethanesulfonic acid and 383.8 mg (2.18 mmol) of 2,4,5-trifluorobenzoic acid was cooled to 0 to −5 ° C. -490.4 mg (2.18 mmol) of dosuccinimide was added to obtain a mixture (2). The resulting mixture (2) was reacted by stirring at room temperature for 6 hours.
[0048]
After completion of the reaction, 5 ml of water and 8 ml of ethyl acetate were added to the resulting reaction mixture, and the pH was adjusted to 5.0 with a 30% aqueous NaOH solution. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated. 5 ml of hexane was added to the concentrated residue, the precipitated colorless crystals (succinimide) were filtered, and the filtrate was concentrated to obtain 246 mg of a solid. When this solid was analyzed by HPLC, it contained 24% of the raw material 2,4,5-trifluorobenzoic acid and 76% of 2,4,5-trifluoro-3-iodobenzoic acid.
[0049]
Reference Example 1: Preparation of ethyl 2,4,5-trifluoro-3-trifluoromethylbenzoate To a mixture (1) of cuprous iodide (12.28 g, 65 mmol) and dimethylformamide (2860 ml), methyl fluorosulfonyldifluoroacetate 500 g (2.6 mol) and 441.4 g of ethyl 2,4,5-trifluoro-3-iodobenzoate (purity 97.3%, 1.3 mol) were added and heated to 80-86 ° C., The reaction was stirred for 7 hours.
[0050]
After completion of the reaction, the obtained reaction mixture was added dropwise to a mixture (2) of 3250 ml of hexane and 3250 ml of saturated aqueous sodium hydrogen carbonate. The hexane layer was separated and dried over anhydrous magnesium sulfate. GC analysis revealed that 642 g of the residue obtained by concentrating hexane under reduced pressure contained 278.4 g (1.02 mol) of the desired product, ethyl 2,4,5-trifluoro-3-trifluoromethylbenzoate. .
[0051]
The same operation was performed twice, and the combined concentrate was distilled under reduced pressure with a 30 cm Utmer rectifier. A fraction having a boiling point of 74 to 79 ° C./0.39 kPa was collected. Acquisition amount 567 g, purity 92.2%, 1.927 mol, (acquisition yield 74.1% based on ethyl 2,4,5-trifluoro-3-iodobenzoate).
[0052]
Reference Example 2: Production of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid 567 g of ethyl 2,4,5-trifluoro-3-trifluoromethylbenzoate obtained in Example 2 above (purity) 92.2%, 1.927 mol), a mixture (1) of 1580 ml of acetic acid, 316 ml of water and 733 g of p-toluenesulfonic acid monohydrate was reacted with stirring under heating and refluxing for 8 hours. During this period, 250 ml of the solvent was distilled off from the reaction system, and a mixture (2) of 280 ml of acetic acid and 42 ml of water was added to the reaction system twice.
[0053]
After completion of the reaction, the resulting reaction mixture was cooled by adding 1930 ml of water, and 3.85 liters of toluene was added. Liquid separation was performed, and the aqueous layer was further extracted three times with 1.93 liters of toluene. The combined toluene layers were dried over anhydrous magnesium sulfate, filtered and concentrated, and 1.9 liters of hexane was added to the concentrated residue and heated. The obtained homogeneous solution was cooled to 0 to −6.5 ° C. to precipitate crystals. The obtained crystals were filtered, washed with hexane, and air-dried to obtain 401 g of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid (1.64 mol, purity 99.8%).
[0054]
Comparative Example 1: Reaction of 2,4,5-trifluorobromobenzene Mixture of 1.54 g (10.24 mmol) of trifluoromethanesulfonic acid and 432.2 mg (2.05 mmol) of 2,4,5-trifluorobromobenzene (1) was cooled to 0 to -5 ° C, and 460.9 mg (2.05 mol) of N-iodosuccinimide was added to obtain a mixture (2). The resulting mixture (2) was reacted by stirring at room temperature for 6 hours.
[0055]
When the reaction mixture obtained after the reaction was analyzed by HPLC, the raw material 2,4,5-trifluorobromobenzene was 15%, 3-bromo-2,5,6-trifluoroiodobenzene was 20%, -61% of bromo-3,5,6-trifluoro-1,4-diiodobenzene was produced, and there was no selectivity for monobromination.
[0056]
Comparative Example 2: Reaction of 2,4,5-trifluorobenzonitrile A mixture of 3.812 g (25.4 mmol) of trifluoromethanesulfonic acid and 798.1 mg (5.08 mmol) of 2,4,5-trifluorobenzonitrile (1) was cooled to 0 to -5 ° C, and 1143 mg (5.08 mol) of N-iodosuccinimide was added to obtain a mixture (2). The resulting mixture (2) was reacted by stirring at room temperature for 4 hours.
[0057]
After completion of the reaction, the resulting reaction mixture was analyzed by HPLC. The raw material 2,4,5-trifluorobenzonitrile was not reacted.
Claims (3)
で表わされるアルコ−ル類とを反応させることを特徴とする、
一般式(II)
Characterized by reacting with an alcohol represented by:
Formula (II)
【0001】The method according to claim 2, wherein the alcohol is an alkyl alcohol having 1 to 4 carbon atoms.
[0001]
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