JP4937442B2 - Process for producing 5-fluorooxindole - Google Patents
Process for producing 5-fluorooxindole Download PDFInfo
- Publication number
- JP4937442B2 JP4937442B2 JP2000327345A JP2000327345A JP4937442B2 JP 4937442 B2 JP4937442 B2 JP 4937442B2 JP 2000327345 A JP2000327345 A JP 2000327345A JP 2000327345 A JP2000327345 A JP 2000327345A JP 4937442 B2 JP4937442 B2 JP 4937442B2
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- Prior art keywords
- group
- fluorooxindole
- fluoro
- formula
- nitrophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title description 16
- DDIIYGHHUMKDGI-UHFFFAOYSA-N 5-fluoro-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1 DDIIYGHHUMKDGI-UHFFFAOYSA-N 0.000 title description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 21
- -1 2- (5-fluoro-2-nitrophenyl) Malonic acid diester Chemical class 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- MEEMYHUBCLXWKU-UHFFFAOYSA-N 5-fluorooxy-1h-indole-3-carboxylic acid Chemical compound C1=C(OF)C=C2C(C(=O)O)=CNC2=C1 MEEMYHUBCLXWKU-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- SNQMQACBIRALMA-UHFFFAOYSA-N 5-fluoro-2-oxo-1,3-dihydroindole-3-carboxylic acid Chemical compound C1=C(F)C=C2C(C(=O)O)C(=O)NC2=C1 SNQMQACBIRALMA-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 230000000911 decarboxylating effect Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RVBYBJXSZRCIEL-UHFFFAOYSA-N (5-fluoro-1H-indol-3-yl) methyl carbonate Chemical compound C1=C(F)C=C2C(OC(=O)OC)=CNC2=C1 RVBYBJXSZRCIEL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- BFQLFVFACPPWDX-UHFFFAOYSA-N dimethyl 2-(5-fluoro-2-nitrophenyl)propanedioate Chemical compound COC(=O)C(C(=O)OC)C1=CC(F)=CC=C1[N+]([O-])=O BFQLFVFACPPWDX-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 3
- 150000002085 enols Chemical class 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229930194542 Keto Natural products 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-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
- 238000013019 agitation Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QCVCBPLJSYIIBX-UHFFFAOYSA-N 1h-indol-5-yl hypofluorite Chemical compound FOC1=CC=C2NC=CC2=C1 QCVCBPLJSYIIBX-UHFFFAOYSA-N 0.000 description 1
- RJXOVESYJFXCGI-UHFFFAOYSA-N 2,4-difluoro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1F RJXOVESYJFXCGI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 238000007664 blowing Methods 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
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- XHMOXAJGAJFKKU-UHFFFAOYSA-N ethanol;methyl acetate Chemical compound CCO.COC(C)=O XHMOXAJGAJFKKU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002483 hydrogen compounds Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- ABJDBYCUWNTRFB-UHFFFAOYSA-N methyl 2-(5-fluoro-2-nitrophenyl)acetate Chemical compound COC(=O)CC1=CC(F)=CC=C1[N+]([O-])=O ABJDBYCUWNTRFB-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- JRTYPQGPARWINR-UHFFFAOYSA-N palladium platinum Chemical compound [Pd].[Pt] JRTYPQGPARWINR-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルから5-フルオロオキシインドールを製造する方法に関する。5-フルオロオキシインドールは、抗癌剤や消炎鎮痛剤等の医薬品の合成中間体として有用な化合物である。
【０００２】
【従来の技術】
従来、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルから5-フルオロオキシインドールを製造する方法としては、Synthesis,1993,51に、水とジメチルスルホキシドの混合溶媒中で、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチルに塩化リチウムを作用させて、一旦5-フルオロ-2-ニトロフェニル酢酸メチルを生成させた後、次いで、鉄の存在下、酢酸中で脱炭酸させて5-フルオロオキシインドールを製造する方法が記載されている。しかしながら、この方法では、反応系が複雑な上に、目的物の合計収率が49％と低いという問題があった。
【０００３】
【発明が解決しようとする課題】
本発明の課題は、即ち、上記問題点を解決し、簡便な方法にて、入手が容易な2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルから5-フルオロオキシインドールを高収率で得る、工業的に好適な5-フルオロオキシインドールの製造法を提供するものである。
【０００４】
【課題を解決するための手段】
本発明の課題は、
（Ａ）一般式（１）
【０００５】
【化５】
（式中、Ｒ1及びＲ2は、同一又は異なっていても良く、反応に関与しない基を示す。）
で示される2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルを還元条件下で環化させて、一般式（２）
【０００７】
【化６】
（式中、Ｒ1は、前記と同義である。）
で示される5-フルオロオキシインドール-3-カルボン酸エステルを生成させる第一工程、
（Ｂ）次いで、5-フルオロオキシインドール-3-カルボン酸エステルを脱炭酸させる第二工程、
を含んでなることを特徴とする、式（３）
【０００９】
【化７】
で示される5-フルオロオキシインドールの製造法によって解決される。
【００１１】
【発明の実施の形態】
本発明は、
（Ａ）一般式（１）で示される2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルを還元条件下で環化させて、一般式（２）で示される5-フルオロオキシインドール-3-カルボン酸エステルを生成させる第一工程、
（Ｂ）次いで、5-フルオロオキシインドール-3-カルボン酸エステルを脱炭酸させる第二工程、
を含んでなる二つの工程によって5-フルオロオキシインドールを反応生成物として得るものである。
【００１２】
引き続き、前記の二つの工程を順次説明する。
（Ａ）第一工程
本発明の第一工程は、一般式（１）で示される2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルを還元条件下で環化させて、一般式（２）で示される5-フルオロオキシインドール-3-カルボン酸エステルを得る工程である。
【００１３】
本発明の第一工程において使用する2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルは、前記の一般式（１）で示される。その一般式（１）において、Ｒ1及びＲ2は、同一又は異なっていて良く、反応に関与しない基であり、具体的には、例えば、アルキル基、シクロアルキル基、アラルキル基又はアリール基を示す。
【００１４】
前記アルキル基としては、特に炭素数１〜１０のアルキル基が好ましく、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等が挙げられる。これらの基は、各種異性体も含む。
【００１５】
前記シクロアルキル基としては、特に炭素数３〜７のシクロアルキル基が好ましく、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基、シクロヘプチル基等が挙げられる。これらの基は、各種異性体も含む。
【００１６】
前記アラルキル基としては、特に炭素数７〜１０のアラルキル基が好ましく、例えば、ベンジル基、フェネチル基、フェニルプロピル基、フェニルブチル基が挙げられる。これらの基は、各種異性体も含む。
【００１７】
前記アリール基としては、特に炭素数６〜１４のアリール基が好ましく、例えば、フェニル基、トリル基、ナフチル基、アントラニル基等が挙げられる。これらの基は、各種異性体も含む。
【００１８】
本発明の第一工程は、一般的に行われる還元方法であれば特に限定されないが、触媒の存在下、水素雰囲気で行うのが好ましい。
【００１９】
前記触媒としては、パラジウム、白金、ニッケルからなる群から選ばれる少なくとも一つの金属原子を含むものであり、具体的には、例えば、パラジウム/炭素、パラジウム/硫酸バリウム、水酸化パラジウム/炭素、白金/炭素、パラジウム-白金/炭素、酸化白金、ラネ−ニッケル等が挙げられるが、好ましくはパラジウム/炭素が使用される。
【００２０】
前記触媒の使用量は、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルに対して、金属原子換算で、好ましくは0.01〜1.0重量％、更に好ましくは0.05〜0.5重量％である。なお、これらの触媒は、単独又は二種以上を混合して使用しても良い。
【００２１】
本発明の第一工程は、溶媒の存在中で反応させるのが好ましく、使用する溶媒としては、反応を阻害しないものならば特に限定されず、水；メタノール、エタノール等のアルコール類；酢酸メチル、酢酸エチル等のエステル類；ベンゼン、トルエン等の芳香族短か水素類；テトラヒドロフラン、ジオキサン等のエーテル類が挙げられるが、好ましくは水、アルコール類、エステル類、更に好ましくは水、メタノール、エタノール、酢酸エチルが使用される。
【００２２】
前記溶媒の使用量は、溶液の均一性や攪拌性により適宜調節するが、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルに対して、好ましくは3〜50重量倍、更に好ましくは5〜30重量倍である。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００２３】
本発明の第一工程は、例えば、水素雰囲気にて、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステル、触媒及び溶媒を混合して、攪拌する等の方法によって行われる。その際の反応圧力は、好ましくは0.1〜5MPa、更に好ましくは0.1〜2MPaであり、反応温度は、好ましくは20〜80℃、更に好ましくは30〜60℃である。
【００２４】
本発明の第一工程では、主な生成物として5-フルオロオキシインドール-3-カルボン酸エステルを含んだ溶液が得られるが、本発明においては、通常、必要ならば触媒を分離後、該溶液をそのまま又は濃縮した後に次の工程を行う。しかし、場合によっては、生成した5-フルオロオキシインドール-3-カルボン酸エステルを、例えば、再結晶、蒸留、カラムクロマトグラフィー等による一般的な方法によって一旦単離した後に、次の工程を行っても良い。
【００２５】
また、本発明の第一工程で得られる、一般式（２）
【００２６】
【化８】
（式中、Ｒ1は、前記と同義である。）
で示される5-フルオロオキシインドール-3-カルボン酸エステル（ケト型）は、5-フルオロオキシインドールの中間体として有用な新規化合物である。なお、溶液中では、一般式（４）
【００２８】
【化９】
（式中、Ｒ1は、前記と同義である。）
で示されるエノール型との平衡になる場合がある。
【００３０】
（Ｂ）第二工程
本発明の第二工程は、第一工程で得られた一般式（２）で示される5-フルオロオキシインドール-3-カルボン酸エステルを脱炭酸させて、5-フルオロオキシインドールを得る工程である。
【００３１】
本発明の第二工程は、一般的に行われる脱炭酸方法であれば特に限定されないが、酸の存在下で行うのが好ましい。
【００３２】
前記酸としては、塩酸、硫酸、硝酸、メタンスルホン酸、酢酸等が挙げられるが、好ましくは塩酸、硫酸が使用される。
【００３３】
前記酸の使用量は、5-フルオロオキシインドール-3-カルボン酸エステルに対して、好ましくは1〜10倍モル、更に好ましくは2〜5倍モルである。なお、これらの酸は、単独又は二種以上を混合して使用しても良い。
【００３４】
本発明の第二工程は、溶媒の存在中で反応させるのが好ましく、使用する溶媒としては、反応を阻害しないものならば特に限定されず、水；メタノール、エタノール、n-ブチルアルコール、t-ブチルアルコール等のアルコール類、テトラヒドロフラン、ジオキサン等のエーテル類；シクロヘキサン、トルエン等の炭化水素類が挙げられるが、好ましくは水、アルコール類、エーテル類、更に好ましくは水、メタノール、エタノールが使用される。
【００３５】
前記溶媒の使用量は、溶液の均一性や攪拌性により適宜調節するが、5-フルオロオキシインドール-3-カルボン酸エステルに対して、好ましくは2〜20重量倍、更に好ましくは4〜10重量倍である。なお、これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００３６】
本発明の第二工程は、例えば、不活性ガス雰囲気にて、第一工程で得られた5-フルオロオキシインドール-3-カルボン酸エステル又はこれを含む反応液、酸及び溶媒を混合して、攪拌する等の方法によって行われる。その際の反応温度は、好ましくは20〜110℃、更に好ましくは50〜90℃であり、反応圧力は特に限定されない。
【００３７】
本発明の第二工程で得られた5-フルオロオキシインドールは、例えば、再結晶、蒸留、カラムクロマトグラフィー等による一般的な方法によって分離・精製される。
【００３８】
【実施例】
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
【００３９】
参考例１（2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチルの合成）
攪拌装置、温度計、蒸留装置及び滴下漏斗を備えた内容積200mlのガラス製フラスコに、アルゴン雰囲気下、ナトリウムメトキシド3.40g(62.9mmol)及びジメチルスルホキシド30mlを加え、次いで、室温で攪拌しながら、純度98％のマロン酸ジメチル8.48g(62.9mmol)を5分間かけてゆるやかに滴下した。更に、シクロヘキサン10mlを加え、100〜105℃まで昇温後、生成するメタノールをシクロヘキサンと共に共沸蒸留（留去）した。この操作（メタノールの留去）を２回繰り返した後、70℃まで冷却し、純度98％の2,4-ジフルオロニトロベンゼン5.10g(31.4mmol)を10分間かけてゆるやかに滴下し、70〜80℃にて1時間反応させた。反応終了後、室温まで冷却した後、トルエン100mlを加え、攪拌しながら6mol/l塩酸5.25ml(31.4mmol)をゆるやかに滴下した。次いで、有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄し、無水硫酸マグネシウムを加えて乾燥した。濾過後、減圧下で濃縮し、得られた濃縮液をシリカゲルカラムクロマトグラフィー（充填剤：Daisogel 1002W、展開溶媒：ヘキサン:酢酸エチル=9:1(容量比)）で精製し、白色結晶として、純度98％（高速液体クロマトグラフィーの面積百分率）の2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチル5.60gを得た(単離収率64％)。
2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチルの物性値は以下の通りであった。
【００４０】
EI-MS(m/e)；225(M-NO2)、CI-MS(m/e)；272(M+1)
1H-NMR(CDCl3,δ(ppm))；3.82(6H,s)、5.40(1H,s)、7.20〜7.35(2H,m)、8.1〜8.2(1H,m)
【００４１】
実施例１
攪拌装置、温度計及びガス導入管を備えた内容積100mlのガラス製フラスコに、アルゴン雰囲気下、参考例１に準じて合成した純度98％の2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチル3.93g(14.2mmol)、5重量％パラジウム/炭素(49％含水品)0.5g(パラジウム原子として0.12mmol)及び酢酸エチル50mlを加えた。次いで、系内を水素で置換し、0.15MPaの水素圧力下、20℃で2時間反応させた。反応終了後、反応液を濾過して触媒を除いた後、濾液を減圧下で濃縮し、得られた濃縮液をシリカゲルカラムクロマトグラフィー（充填剤：Daisogel 1002W、展開溶媒：クロロホルム）で精製し、白色結晶として、純度99％（高速液体クロマトグラフィーの面積百分率）の5-フルオロ-3-メトキシカルボニルオキシインドール2.76gを得た(単離収率92％)。
5-フルオロ-3-メトキシカルボニルオキシインドールは、以下の物性値を有する新規な化合物である。なお、1H-NMRの積分値より、重クロロホルム中では、ケト型とエノール型が1：2.2の割合で存在していた。
【００４２】
融点；142〜143℃
EI-MS(m/e)；209(M+)、CI-MS(m/e)；210(M+1)
FT-IR(KBr法、cm-1)；3300〜2600、1647、1569、1481、1204、1160、1108
1H-NMR(CDCl3,δ(ppm))；
ケト型：3.82(3H,s)、4.48(1H,s)、6.81〜6.88(1H,m)、6.99(1H,ddd,J=2.7,8.5,8.5Hz)、7.08〜7.13(1H,m)、8.18(1H,s)
エノール型：3.97(3H,s)、6.81〜6.88(1H,m)、6.96〜7.02(1H,m)、7.39(1H,dd,J=2.3,9.4Hz)、8.24(1H,s)
【００４３】
実施例２
攪拌装置、温度計、還流冷却器及びガス導入管を備えた内容積500mlのガラス製フラスコに、アルゴン雰囲気下、参考例１に準じて合成した純度98％の2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチル60.0g(0.22mol)及びメタノール228gを加えた。攪拌下、液温を40〜45℃に維持しながら、5重量％パラジウム/炭素(49％含水品)3.0g(パラジウム原子として0.72mmol)を加えた。次いで、常圧で水素を123ml/min.の流速で吹き込みながら、同温度で3時間反応させた。反応終了後、反応液を濾過して触媒を除いた後、濾液を減圧下で濃縮し、得られた濃縮液にメタノール80ml及び水240mlを加えて10℃に冷却した。次いで、析出した結晶を濾過後、乾燥させて、白色の粗結晶として純度80％（高速液体クロマトグラフィーによる分析値）の5-フルオロ-3-メトキシカルボニルオキシインドール54.5gを得た(単離収率94％)。
【００４４】
実施例３
攪拌装置、温度計、滴下漏斗及び還流冷却器を備えた内容積500mlのガラス製フラスコに、実施例２で合成した純度80％（高速液体クロマトグラフィーによる分析値）の5-フルオロ-3-メトキシカルボニルオキシインドールの粗結晶26.5g(0.10mol)、メタノール66.9g及び6mol/l塩酸52.0ml(0.31mol)を加え、70〜80℃で2時間反応させた。反応終了後、室温まで冷却し、8mol/l水酸化ナトリウム水溶液55.0ml(0.44mol)を加えた後、40℃で30分間攪拌した。次いで、12mol/l塩酸8.3ml(0.10mol)を加えた。減圧下でメタノールを留去した後、反応液を0〜5℃まで冷却すると固体が析出してきたので濾別した。得られた固体をイソプロピルアルコール/水で再結晶し、白色結晶として純度99％（高速液体クロマトグラフィーの面積百分率）の5-フルオロオキシインドール12.6gを得た(単離収率80％)。
5-フルオロオキシインドールの物性値は以下の通りであった。
【００４５】
融点；141〜142℃
EI-MS(m/e)；151(M+)、CI-MS(m/e)；152(M+1)
元素分析；炭素63.56％、水素4.02％、窒素9.29％
（理論値(C8H6NOF)；炭素63.57％、水素4.00％、窒素9.27％）
FT-IR(KBr法、cm-1)；3400〜2500、1700、1633、1485、1317、1195、745、673、591
1H-NMR(CDCl3,δ(ppm))；3.56(2H,s)、6.75〜6.85(1H,m)、6.85〜7.00(2H,m)、9.03(1H,brs)
【００４６】
【発明の効果】
本発明により、簡便な方法にて、入手が容易な2-(5-フルオロ-2-ニトロフェニル)マロン酸ジエステルから5-フルオロオキシインドールを高収率で得る、工業的に好適な5-フルオロオキシインドールの製造法を提供することが出来る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing 5-fluorooxindole from 2- (5-fluoro-2-nitrophenyl) malonic acid diester. 5-fluorooxindole is a useful compound as a synthetic intermediate for pharmaceuticals such as anticancer agents and anti-inflammatory analgesics.
[0002]
[Prior art]
Conventionally, as a method for producing 5-fluorooxindole from 2- (5-fluoro-2-nitrophenyl) malonic acid diester, Synthesis, 1993 , 51, in a mixed solvent of water and dimethyl sulfoxide, 2- ( Lithium chloride is allowed to act on dimethyl 5-fluoro-2-nitrophenyl) malonate to form methyl 5-fluoro-2-nitrophenylacetate, and then decarboxylated in acetic acid in the presence of iron. Describes a process for producing 5-fluorooxindole. However, this method has a problem that the reaction system is complicated and the total yield of the target product is as low as 49%.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to solve the above-mentioned problems and to produce 5-fluorooxindole in high yield from 2- (5-fluoro-2-nitrophenyl) malonic acid diester which is easily available by a simple method. An industrially suitable process for producing 5-fluorooxindole obtained in (1) is provided.
[0004]
[Means for Solving the Problems]
The subject of the present invention is
(A) General formula (1)
[0005]
[Chemical formula 5]
(In the formula, R 1 and R 2 may be the same or different and each represents a group not involved in the reaction.)
2- (5-Fluoro-2-nitrophenyl) malonic acid diester represented by the general formula (2)
[0007]
[Chemical 6]
(In the formula, R 1 has the same meaning as described above.)
A first step of producing a 5-fluorooxyindole-3-carboxylic acid ester represented by:
(B) Then, a second step of decarboxylating 5-fluorooxindole-3-carboxylic acid ester,
(3) characterized by comprising
[0009]
[Chemical 7]
It is solved by the process for producing 5-fluorooxindole represented by
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The present invention
(A) A 2- (5-fluoro-2-nitrophenyl) malonic acid diester represented by the general formula (1) is cyclized under reducing conditions to give a 5-fluorooxindole-- represented by the general formula (2) A first step of producing a 3-carboxylic acid ester,
(B) Then, a second step of decarboxylating 5-fluorooxindole-3-carboxylic acid ester,
5-fluorooxindole is obtained as a reaction product by two steps comprising:
[0012]
Subsequently, the two steps will be sequentially described.
(A) First Step In the first step of the present invention, 2- (5-fluoro-2-nitrophenyl) malonic acid diester represented by the general formula (1) is cyclized under reducing conditions to give a general formula ( In this step, a 5-fluorooxyindole-3-carboxylic acid ester represented by 2) is obtained.
[0013]
The 2- (5-fluoro-2-nitrophenyl) malonic acid diester used in the first step of the present invention is represented by the general formula (1). In the general formula (1), R 1 and R 2 may be the same or different and are groups not involved in the reaction. Specifically, for example, an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group Show.
[0014]
As the alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. Is mentioned. These groups include various isomers.
[0015]
The cycloalkyl group is particularly preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. These groups include various isomers.
[0016]
The aralkyl group is particularly preferably an aralkyl group having 7 to 10 carbon atoms, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. These groups include various isomers.
[0017]
As the aryl group, an aryl group having 6 to 14 carbon atoms is particularly preferable, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, and an anthranyl group. These groups include various isomers.
[0018]
Although the 1st process of this invention will not be specifically limited if it is the reduction method generally performed, It is preferable to perform in the hydrogen atmosphere in presence of a catalyst.
[0019]
The catalyst contains at least one metal atom selected from the group consisting of palladium, platinum, and nickel. Specifically, for example, palladium / carbon, palladium / barium sulfate, palladium hydroxide / carbon, platinum / Carbon, palladium-platinum / carbon, platinum oxide, Raney-nickel, etc. are mentioned, but palladium / carbon is preferably used.
[0020]
The amount of the catalyst used is preferably 0.01 to 1.0% by weight, more preferably 0.05 to 0.5% by weight, in terms of metal atom, based on 2- (5-fluoro-2-nitrophenyl) malonic acid diester. In addition, you may use these catalysts individually or in mixture of 2 or more types.
[0021]
The first step of the present invention is preferably carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction, water; alcohols such as methanol and ethanol; methyl acetate; Esters such as ethyl acetate; aromatic short or hydrogen compounds such as benzene and toluene; ethers such as tetrahydrofuran and dioxane are preferable, but water, alcohols, esters, more preferably water, methanol, ethanol, Ethyl acetate is used.
[0022]
The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 3 to 50 times by weight, more preferably 2 to 5- (5-fluoro-2-nitrophenyl) malonic acid diester. 5 to 30 times by weight. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0023]
The first step of the present invention is performed by, for example, a method of mixing 2- (5-fluoro-2-nitrophenyl) malonic acid diester, catalyst and solvent in a hydrogen atmosphere and stirring. The reaction pressure at that time is preferably 0.1 to 5 MPa, more preferably 0.1 to 2 MPa, and the reaction temperature is preferably 20 to 80 ° C., more preferably 30 to 60 ° C.
[0024]
In the first step of the present invention, a solution containing 5-fluorooxindole-3-carboxylic acid ester as a main product is obtained. In the present invention, however, the solution is usually separated after separation of the catalyst if necessary. The next step is carried out as is or after concentration. However, in some cases, the produced 5-fluorooxyindole-3-carboxylic acid ester is once isolated by a general method such as recrystallization, distillation, column chromatography, etc., and then the next step is performed. Also good.
[0025]
Further, the general formula (2) obtained in the first step of the present invention.
[0026]
[Chemical 8]
(In the formula, R 1 has the same meaning as described above.)
Is a novel compound useful as an intermediate of 5-fluorooxyindole. In the solution, the general formula (4)
[0028]
[Chemical 9]
(In the formula, R 1 has the same meaning as described above.)
It may be in equilibrium with the enol type shown by
[0030]
(B) Second Step In the second step of the present invention, 5-fluorooxyindole-3-carboxylic acid ester represented by the general formula (2) obtained in the first step is decarboxylated to give 5-fluorooxy This is a process for obtaining indole.
[0031]
The second step of the present invention is not particularly limited as long as it is a general decarboxylation method, but it is preferably performed in the presence of an acid.
[0032]
Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, acetic acid, and the like. Preferably, hydrochloric acid and sulfuric acid are used.
[0033]
The amount of the acid used is preferably 1 to 10 times mol, more preferably 2 to 5 times mol, with respect to the 5-fluorooxyindole-3-carboxylic acid ester. In addition, you may use these acids individually or in mixture of 2 or more types.
[0034]
In the second step of the present invention, the reaction is preferably carried out in the presence of a solvent, and the solvent to be used is not particularly limited as long as it does not inhibit the reaction. Water; methanol, ethanol, n-butyl alcohol, t- Examples include alcohols such as butyl alcohol, ethers such as tetrahydrofuran and dioxane; hydrocarbons such as cyclohexane and toluene, preferably water, alcohols and ethers, more preferably water, methanol and ethanol. .
[0035]
The amount of the solvent used is appropriately adjusted depending on the uniformity and agitation of the solution, but is preferably 2 to 20 times by weight, more preferably 4 to 10% by weight with respect to the 5-fluorooxyindole-3-carboxylic acid ester. Is double. In addition, you may use these solvents individually or in mixture of 2 or more types.
[0036]
In the second step of the present invention, for example, in an inert gas atmosphere, the 5-fluorooxindole-3-carboxylic acid ester obtained in the first step or a reaction solution containing this, an acid and a solvent are mixed, It is carried out by a method such as stirring. The reaction temperature at that time is preferably 20 to 110 ° C., more preferably 50 to 90 ° C., and the reaction pressure is not particularly limited.
[0037]
The 5-fluorooxindole obtained in the second step of the present invention is separated and purified by a general method such as recrystallization, distillation, column chromatography or the like.
[0038]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0039]
Reference Example 1 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 3.40 g (62.9 mmol) of sodium methoxide and 30 ml of dimethyl sulfoxide were added to a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a distillation apparatus, and a dropping funnel, and then stirred at room temperature. Then, 8.48 g (62.9 mmol) of dimethyl malonate having a purity of 98% was slowly added dropwise over 5 minutes. Furthermore, 10 ml of cyclohexane was added, and after raising the temperature to 100 to 105 ° C., the produced methanol was azeotropically distilled (evaporated) together with cyclohexane. After repeating this operation (distilling off methanol) twice, the mixture was cooled to 70 ° C., and 5.10 g (31.4 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 10 minutes. The reaction was carried out at 1 ° C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of toluene was added, and 5.25 ml (31.4 mmol) of 6 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, the organic layer was separated, washed with water (50 ml) and saturated brine (50 ml) in that order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: hexane: ethyl acetate = 9: 1 (volume ratio)) to give white crystals, 5.60 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate with a purity of 98% (area percentage of high performance liquid chromatography) was obtained (isolation yield 64%).
The physical properties of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate were as follows.
[0040]
EI-MS (m / e); 225 (M-NO 2 ), CI-MS (m / e); 272 (M + 1)
1 H-NMR (CDCl 3 , δ (ppm)); 3.82 (6H, s), 5.40 (1H, s), 7.20 to 7.35 (2H, m), 8.1 to 8.2 (1H, m)
[0041]
Example 1
98% pure 2- (5-fluoro-2-nitrophenyl) malon synthesized according to Reference Example 1 in a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a gas introduction tube under an argon atmosphere 3.93 g (14.2 mmol) of dimethyl acid, 0.5 g of 5 wt% palladium / carbon (49% water-containing product) (0.12 mmol as palladium atom) and 50 ml of ethyl acetate were added. Subsequently, the inside of the system was replaced with hydrogen and reacted at 20 ° C. for 2 hours under a hydrogen pressure of 0.15 MPa. After completion of the reaction, the reaction solution was filtered to remove the catalyst, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: chloroform), As white crystals, 2.76 g of 5-fluoro-3-methoxycarbonyloxyindole having a purity of 99% (area percentage by high performance liquid chromatography) was obtained (isolation yield: 92%).
5-Fluoro-3-methoxycarbonyloxyindole is a novel compound having the following physical properties. From the integral value of 1 H-NMR, keto type and enol type were present at a ratio of 1: 2.2 in deuterated chloroform.
[0042]
Melting point: 142-143 ° C
EI-MS (m / e); 209 (M +), CI-MS (m / e); 210 (M + 1)
FT-IR (KBr method, cm −1 ); 3300-2600, 1647, 1569, 1481, 1204, 1160, 1108
1 H-NMR (CDCl 3 , δ (ppm));
Keto type: 3.82 (3H, s), 4.48 (1H, s), 6.81 to 6.88 (1H, m), 6.99 (1H, ddd, J = 2.7, 8.5, 8.5Hz), 7.08 to 7.13 (1H, m) 8.18 (1H, s)
Enol type: 3.97 (3H, s), 6.81 to 6.88 (1H, m), 6.96 to 7.02 (1H, m), 7.39 (1H, dd, J = 2.3, 9.4Hz), 8.24 (1H, s)
[0043]
Example 2
A 98% pure 2- (5-fluoro-2-2) compound synthesized according to Reference Example 1 under an argon atmosphere in a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer, a reflux condenser and a gas introduction tube. 60.0 g (0.22 mol) of dimethyl nitrophenyl) malonate and 228 g of methanol were added. While stirring, while maintaining the liquid temperature at 40 to 45 ° C., 3.0 g of 5 wt% palladium / carbon (49% water-containing product) (0.72 mmol as palladium atom) was added. Subsequently, the reaction was carried out at the same temperature for 3 hours while blowing hydrogen at a flow rate of 123 ml / min at normal pressure. After completion of the reaction, the reaction solution was filtered to remove the catalyst, and then the filtrate was concentrated under reduced pressure. To the resulting concentrate, 80 ml of methanol and 240 ml of water were added and cooled to 10 ° C. Next, the precipitated crystals were filtered and dried to obtain 54.5 g of 5-fluoro-3-methoxycarbonyloxyindole having a purity of 80% (analyzed by high performance liquid chromatography) as white crude crystals (isolated product). 94%).
[0044]
Example 3
5-Fluoro-3-methoxy with a purity of 80% (analyzed by high performance liquid chromatography) synthesized in Example 2 was placed in a glass flask having an internal volume of 500 ml equipped with a stirrer, thermometer, dropping funnel and reflux condenser. Crude crystals of carbonyloxyindole (26.5 g, 0.10 mol), methanol (66.9 g), and 6 mol / l hydrochloric acid (52.0 ml, 0.31 mol) were added and reacted at 70-80 ° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 55.0 ml (0.44 mol) of 8 mol / l sodium hydroxide aqueous solution was added, and the mixture was stirred at 40 ° C. for 30 minutes. Then 8.3 ml (0.10 mol) of 12 mol / l hydrochloric acid was added. After distilling off methanol under reduced pressure, the reaction solution was cooled to 0 to 5 ° C., and a solid was precipitated. The obtained solid was recrystallized from isopropyl alcohol / water to obtain 12.6 g of 5-fluorooxindole having a purity of 99% (area percentage by high performance liquid chromatography) as white crystals (isolation yield 80%).
The physical property values of 5-fluorooxindole were as follows.
[0045]
Melting point: 141-142 ° C
EI-MS (m / e); 151 (M +), CI-MS (m / e); 152 (M + 1)
Elemental analysis: carbon 63.56%, hydrogen 4.02%, nitrogen 9.29%
(Theoretical value (C 8 H 6 NOF); carbon 63.57%, hydrogen 4.00%, nitrogen 9.27%)
FT-IR (KBr method, cm −1 ); 3400-2500, 1700, 1633, 1485, 1317, 1195, 745, 673, 591
1 H-NMR (CDCl 3 , δ (ppm)); 3.56 (2H, s), 6.75 to 6.85 (1H, m), 6.85 to 7.00 (2H, m), 9.03 (1H, brs)
[0046]
【Effect of the invention】
According to the present invention, industrially suitable 5-fluorooxindole is obtained in a high yield from 2- (5-fluoro-2-nitrophenyl) malonic acid diester which is easily available by a simple method. A method for producing oxindole can be provided.
Claims (1)
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000327345A JP4937442B2 (en) | 2000-10-26 | 2000-10-26 | Process for producing 5-fluorooxindole |
| EP01951925A EP1310486A4 (en) | 2000-07-19 | 2001-07-19 | PROCESS FOR THE PRODUCTION OF 5-FLUOROOXYINDOL AND FOR THE PRODUCTION OF THE INTERMEDIATE LEVEL |
| PCT/JP2001/006260 WO2002006228A1 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxyindole and for producing intermediate therefor |
| AU2001272757A AU2001272757A1 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxyindole and for producing intermediate therefor |
| CA002416397A CA2416397A1 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxyindole and for producing intermediate therefor |
| US10/333,316 US6900335B2 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxindole and for producing intermediates therefor |
| US11/093,603 US7342040B2 (en) | 2000-07-19 | 2005-03-30 | 5-fluorooxindole-3-carboxylic acid ester |
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| JP2000327345A JP4937442B2 (en) | 2000-10-26 | 2000-10-26 | Process for producing 5-fluorooxindole |
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| JP2008221896A Division JP2009040790A (en) | 2008-08-29 | 2008-08-29 | Process for producing 5-fluorooxindole |
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| JP4937442B2 true JP4937442B2 (en) | 2012-05-23 |
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