JP4000758B2 - Process for producing 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative - Google Patents
Process for producing 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
本発明は、2,4-ジハロゲノニトロベンゼン誘導体から、簡便な方法で2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体を製造する方法に関する。2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体は、医薬・農薬等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、2,4-ジハロゲノニトロベンゼン誘導体から2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体を製造する方法としては、水素化ナトリウムの存在下、ジメチルスルホキシド中で、2,4-ジハロゲノニトロベンゼンにマロン酸ジメチルを反応させて2-(5-ハロゲノ-2-ニトロフェニル)マロン酸ジメチルを合成する方法が開示されている（Synthesis,1993,51）。しかしながら、この方法では発火性が高い水素化ナトリウムを用いていることや反応により水素ガスが発生するため煩雑な操作が必要となり、工業的製法としては問題があった。
【０００３】
【発明が解決しようとする課題】
本発明の課題は、上記問題点を解決し、簡便な方法にて2,4-ジハロゲノニトロベンゼン誘導体から2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体を製造することが出来る、工業的に好適な2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体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、金属無機酸塩の存在下、一般式（１）
【０００５】
【化４】
（式中、Ｒ1、Ｒ2及びＲ3は、反応に関与しない基を示し、Ｘ1及びＸ2は、ハロゲン原子を示す。）
で示される2,4-ジハロゲノニトロベンゼン誘導体に、一般式（２）
【０００７】
【化５】
（式中、Ｒ4は、アルコキシカルボニル基、アラルキルオキシカルボニル基、アリールオキシカルボニル基、アシル基又はシアノ基を示し、Ｒ5は、反応に関与しない基を示す。）
で示される2-モノ置換酢酸エステル誘導体を有機溶媒中で反応させることを特徴とする、一般式（３）
【０００９】
【化６】
（式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5及びＸ2は、前記と同義である。）
で示される2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体の製造法によって解決される。
【００１１】
【発明の実施の形態】
本発明の反応において使用する2,4-ジハロゲノニトロベンゼン誘導体は、前記の一般式（１）で示される。その一般式（１）において、Ｒ1、Ｒ2及びＲ3は、反応に関与しない基であり、具体的には、水素原子；ハロゲン原子；置換基を有していても良い、アルキル基、シクロアルキル基、アラルキル基、アリール基、アルコキシ基又はアリールオキシ基を示す。
【００１２】
前記ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
【００１３】
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。これらのアルキル基は、各種異性体を含む。
【００１４】
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、シクロヘキシル基、シクロヘプチル基等が挙げられる。これらのシクロアルキル基は、各種異性体も含む。
【００１５】
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、フェニルブチル基等が挙げられる。これらのアラルキル基は、各種異性体を含む。
【００１６】
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。これらのアリール基は、各種異性体を含む。
【００１７】
前記アルコキシ基としては、特に炭素数１〜１２のアルコキシ基が好ましく、例えば、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ベンジルオキシ基等が挙げられる。これらのアルコキシ基は、各種異性体を含む。
【００１８】
前記アリールオキシ基としては、特に炭素数６〜１４のアリールオキシ基が好ましく、例えば、フェノキシ基、トリルオキシ基等が挙げられる。これらのアリールオキシ基は、各種異性体を含む。
【００１９】
前記のアルキル基、シクロアルキル基、アラルキル基、アリール基、アルコキシ基又はアリールオキシ基は、置換基を有していても良い。その置換基としては、炭素原子を介して出来る置換基、酸素原子を介して出来る置換基、窒素原子を介して出来る置換基の中から選ばれる少なくとも一つが挙げられる。
【００２０】
前記炭素原子を介して出来る置換基としては、例えば、メチル基、エチル基、プロピル基等のアルキル基；ベンジル基等のアラルキル基；フェニル基等のアリール基；シアノ基が挙げられる。
【００２１】
前記酸素原子を介して出来る置換基としては、例えば、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ベンジルオキシ基等のアルコキシ基；フェノキシ基等のアリールオキシ基；アセチルオキシ基、ベンゾイルオキシ基等のアシルオキシ基が挙げられる。
【００２２】
前記窒素原子を介して出来る置換基としては、例えば、ニトロ基；アミノ基が挙げられる。
【００２３】
又、一般式（１）において、Ｘ1及びＸ2は、ハロゲン原子を示し、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。
【００２４】
本発明の反応において使用する2-モノ置換酢酸エステル誘導体は、前記の一般式（２）で示される。その一般式（２）において、Ｒ4は、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、ブトキシカルボニル基等のアルコキシカルボニル基；ベンジルオキシカルボニル基等のアラルキルオキシカルボニル基；フェノキシカルボニル基等のアリールオキシカルボニル基；アセチル基、プロピオニル基、ベンゾイル基等のアシル基；シアノ基が挙げられる。これらの基は、各種異性体も含む。Ｒ5は、反応に関与しない基であり、具体的には、メチル基、エチル基、プロピル基等のアルキル基；ベンジル基等のアラルキル基；フェニル基等のアリール基を示す。
【００２５】
前記2-モノ置換酢酸エステル誘導体の使用量は、2,4-ジハロゲノニトロベンゼン誘導体に対して、好ましくは1.0〜5.0倍モル、更に好ましくは1.2〜3.0倍モルである。
【００２６】
本発明の反応において使用する金属無機酸塩の金属原子としては、例えば、リチウム原子、ナトリウム原子、カリウム原子等のアルカリ金属原子；マグネシウム原子、カルシウム原子等のアルカリ土類金属原子が挙げられるが、好ましくはアルカリ金属原子、更に好ましくはナトリウム原子、カリウム原子である。
【００２７】
本発明の反応において使用する金属無機酸塩の無機酸としては、例えば、炭酸、燐酸等が挙げられるが、好ましくは炭酸である。
【００２８】
前記金属無機酸塩としては、例えば、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウム、炭酸マグネシム、炭酸カルシウム、リン酸ナトリウム、リン酸水素ナトリウムが挙げられるが、好ましくは炭酸ナトリウム、炭酸カリウムが使用される。
【００２９】
前記金属無機酸塩の使用量は、2,4-ジハロゲノニトロベンゼン誘導体に対して、好ましくは1.0〜5.0倍モル、更に好ましくは1.2〜3.0倍モルである。これら金属アルコキシドは、単独又は二種以上を混合して使用しても良い。
【００３０】
本発明の反応で使用する有機溶媒としては、反応を阻害しないものならば特に限定されず、例えば、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類；ヘキサン、シクロヘキサン等の脂肪族炭化水素類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類；N,N-ジメチルホルムアミド、N,N'-ジメチルイミダゾリジノン等のアミド類；アセトニトリル、プロピオニトリル等のニトリル類；ジメチルスルホキシド等が挙げられるが、好ましくは脂肪族炭化水素類、芳香族炭化水素類、アミド類、ニトリル類、ジメチルスルホキシド、更に好ましくはシクロへキサン、トルエン、アセトニトリル、N,N-ジメチルホルムアミドが使用される。
【００３１】
前記有機溶媒の使用量は、反応溶液の均一性や攪拌性により適宜調節するが、2,4-ジハロゲノニトロベンゼン誘導体に対して、好ましくは1〜50重量倍、更に好ましくは1.5〜20重量倍である。これら有機溶媒は、単独又は二種以上を混合して使用しても良い。
【００３２】
本発明の反応は、例えば、2,4-ジハロゲノニトロベンゼン誘導体、2-モノ置換酢酸エステル誘導体、金属無機酸塩及び有機溶媒を混合して反応させるが、本発明の好ましい態様としては、2-モノ置換酢酸エステル誘導体、金属無機酸塩及び有機溶媒を混合し、好ましくは20〜140℃、更に好ましくは40〜120℃にて、2,4-ジハロゲノニトロベンゼン誘導体を添加して反応させるものである。また、クラウンエーテルやポリエチレングリコール等を添加して、反応を促進させることも出来る。
【００３３】
本発明の反応によって得られた目的とする2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体は、例えば、反応終了後に、カラムクロマトグラフィー、蒸留、再結晶等の一般的な方法によって分離・精製される。
【００３４】
【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ない。
【００３５】
実施例１
攪拌装置、温度計、還流冷却器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、炭酸カリウム6.51g(47.2mmol)、N,N-ジメチルホルムアミド20ml、純度99％のマロン酸ジメチル6.24g(46.7mmol)及び純度98％の2,4-ジフルオロニトロベンゼン5.00g(30.8mmol)を加え、攪拌しながら、室温にて1時間、更に70℃まで昇温して5時間反応させた。反応終了後、室温まで冷却した後、酢酸エチル100mlを加え、攪拌しながら6mol/l塩酸10.5ml(62.8mmol)をゆるやかに滴下した。次いで、水50mlを加えた後に有機層を分離し、水20ml、飽和食塩水20mlの順で洗浄して、無水硫酸マグネシウムを加えて乾燥させた。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6.22gを得た(単離収率73％)。
【００３６】
実施例２
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積100mlのガラス製フラスコに、アルゴン雰囲気下、炭酸カリウム8.29g(60.0mmol)、アセトニトリル30ml、純度99％のマロン酸ジメチル8.09g(60.0mmol)及び純度98％の2,4-ジフルオロニトロベンゼン5.00g(30.0mmol)を加え、攪拌しながら、70℃で10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50mlを加え、攪拌しながら12mol/l塩酸7.5ml(90mmol)をゆるやかに滴下した。次いで、有機層を分離し、水20ml、飽和食塩水20mlの順で洗浄して、無水硫酸マグネシウムを加えて乾燥させた。濾過後、この有機層を高速液体クロマトグラフィーで分析（絶対定量法）したところ、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチルが6.61g(反応収率81％)生成していた。
【００３７】
実施例３
実施例２において、有機溶媒をテトラヒドロフランに変えたこと以外は、実施例２と同様に反応を行った。その結果、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチルが6.65g(反応収率82％)生成していた。
【００３８】
実施例４
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積500mlのガラス製フラスコに、アルゴン雰囲気下、炭酸カリウム55.3g(0.40mol)、N,N-ジメチルホルムアミド200ml、純度98％のマロン酸ジメチル54.0g(0.40mol)及び純度98％の2,4-ジフルオロニトロベンゼン32.5g(0.20mmol)を加え、攪拌しながら、70℃で3時間反応応させた。反応終了後、室温まで冷却した後、トルエン160mlを加え、攪拌しながら12mol/l塩酸50ml(0.60mol)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の順で洗浄して、無水硫酸マグネシウムを加えて乾燥させた。濾過後、この有機層を高速液体クロマトグラフィーで分析（絶対定量法）したところ、2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチルが45.3g(反応収率84％)生成していた。
【００３９】
実施例５
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積100mlのガラス製フラスコに、アルゴン雰囲気下、炭酸カリウム3.03g(21.9mmol)、N,N-ジメチルホルムアミド5.0ml、純度99％のシアノ酢酸メチル2.17g(21.7mmol)及び純度98％の2,4-ジフルオロニトロベンゼン1.45g(8.94mmol)を加え、攪拌しながら、60℃で6時間反応させた。反応終了後、室温まで冷却した後、酢酸エチル50mlを加え、攪拌しながら12mol/l塩酸2.9ml(34.8mmol)をゆるやかに滴下した。次いで、有機層を分離し、水20ml、飽和食塩水30mlの順で洗浄して、無水硫酸マグネシウムを加えて乾燥させた。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：トルエン）で精製し、黄色油状物として、純度99％（高速液体クロマトグラフィーの面積百分率）の2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル1.81gを得た(単離収率84％)。
【００４０】
実施例６
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積100mlのガラス製フラスコに、アルゴン雰囲気下、炭酸カリウム8.68g(62.9mmol)、N,N-ジメチルホルムアミド20ml、純度99％のアセト酢酸メチル7.30g(62.2mmol)及び純度98％の2,4-ジフルオロニトロベンゼン5.00g(30.8mmol)を加え、攪拌しながら、25℃で5時間反応させた。反応終了後、室温まで冷却した後、酢酸エチル100mlを加え、攪拌しながら6mol/l塩酸15.7ml(94.2mmol)をゆるやかに滴下した。次いで、水50mlを加えた後に有機層を分離し、水20ml、飽和食塩水30mlの順で洗浄して、無水硫酸マグネシウムを加えて乾燥させた。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、黄色油状物として、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)-2-アセト酢酸メチル6.08gを得た(単離収率76％)。
【００４１】
実施例７
攪拌装置、温度計、還流冷却器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、炭酸カリウム7.13g(51.6mmol)、N,N-ジメチルホルムアミド20ml、純度99％のシアノ酢酸メチル5.06g(50.6mmol)及び純度99％の2,4-ジクロロニトロベンゼン5.00g(25.8mmol)を加え、攪拌しながら、45℃で4時間反応させた。反応終了後、室温まで冷却した後、酢酸エチル100mlを加え、攪拌しながら6mol/l塩酸12.9ml(77.4mmol)をゆるやかに滴下した。次いで、水50mlを加えた後に有機層を分離し、飽和食塩水50mlで洗浄して、無水硫酸マグネシウムを加えて乾燥させた。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=20:1(容量比)）で精製し、白色結晶として、純度95％（高速液体クロマトグラフィーの面積百分率）の2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル5.76gを得た(単離収率83％)。
【００４２】
実施例８
攪拌装置、温度計、還流冷却器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、炭酸カリウム7.13g(51.6mmol)、N,N-ジメチルホルムアミド20ml、純度99％のアセト酢酸メチル6.05g(51.6mmol)及び純度99％の2,4-ジクロロニトロベンゼン5.00g(25.8mmol)を加え、攪拌しながら、70℃で3時間反応させた。反応終了後、室温まで冷却した後、酢酸エチル100mlを加え、攪拌しながら6mol/l塩酸12.9ml(77.4mmol)をゆるやかに滴下した。次いで、水30mlを加えた後に有機層を分離し、飽和食塩水30mlで洗浄して、無水硫酸マグネシウムを加えて乾燥させた。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=40:1(容量比)）で精製し、黄色油状物として、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-クロロ-2-ニトロフェニル)-2-アセト酢酸メチル4.33gを得た(単離収率61％)。
【００４３】
【発明の効果】
本発明により、簡便な方法にて2,4-ジハロゲノニトロベンゼン誘導体から2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体を製造することが出来る、工業的に好適な2-(5-ハロゲノ-2-ニトロフェニル)-2-置換酢酸エステル誘導体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 method for producing a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative from a 2,4-dihalogenonitrobenzene derivative by a simple method. 2- (5-Halogeno-2-nitrophenyl) -2-substituted acetate derivatives are useful compounds as intermediates for the synthesis of pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
Conventionally, as a method for producing a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative from a 2,4-dihalogenonitrobenzene derivative, 2 in dimethyl sulfoxide in the presence of sodium hydride is used. A method of synthesizing dimethyl 2- (5-halogeno-2-nitrophenyl) malonate by reacting dimethyl 4-monohalogenonitrobenzene with dimethyl malonate has been disclosed (Synthesis, 1993 , 51). However, in this method, sodium hydride having high ignitability is used, and hydrogen gas is generated due to the reaction, so that complicated operation is required, and there is a problem as an industrial production method.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to solve the above problems and to produce a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative from a 2,4-dihalogenonitrobenzene derivative by a simple method. An industrially suitable method for producing a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative is provided.
[0004]
[Means for Solving the Problems]
The subject of this invention is general formula (1) in presence of a metal inorganic acid salt.
[0005]
[Formula 4]
(In the formula, R 1 , R 2 and R 3 represent groups not involved in the reaction, and X 1 and X 2 represent halogen atoms.)
A 2,4-dihalogenonitrobenzene derivative represented by the general formula (2)
[0007]
[Chemical formula 5]
(In the formula, R 4 represents an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an acyl group, or a cyano group, and R 5 represents a group that does not participate in the reaction.)
Wherein the 2-mono-substituted acetic acid ester derivative is reacted in an organic solvent.
[0009]
[Chemical 6]
(Wherein R 1 , R 2 , R 3 , R 4 , R 5 and X 2 are as defined above.)
This is solved by a method for producing a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative represented by the following formula.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The 2,4-dihalogenonitrobenzene derivative used in the reaction of the present invention is represented by the above general formula (1). In the general formula (1), R 1 , R 2 and R 3 are groups that do not participate in the reaction, specifically, a hydrogen atom; a halogen atom; an alkyl group which may have a substituent, A cycloalkyl group, an aralkyl group, an aryl group, an alkoxy group or an aryloxy group;
[0012]
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
[0013]
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 alkyl groups include various isomers.
[0014]
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 cycloalkyl groups include various isomers.
[0015]
As the aralkyl group, an aralkyl group having 7 to 10 carbon atoms is particularly preferable, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, and a phenylbutyl group. These aralkyl groups include various isomers.
[0016]
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 aryl groups include various isomers.
[0017]
As said alkoxy group, a C1-C12 alkoxy group is especially preferable, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a benzyloxy group etc. are mentioned. These alkoxy groups include various isomers.
[0018]
As the aryloxy group, an aryloxy group having 6 to 14 carbon atoms is particularly preferable, and examples thereof include a phenoxy group and a tolyloxy group. These aryloxy groups include various isomers.
[0019]
The alkyl group, cycloalkyl group, aralkyl group, aryl group, alkoxy group or aryloxy group may have a substituent. Examples of the substituent include at least one selected from a substituent formed through a carbon atom, a substituent formed through an oxygen atom, and a substituent formed through a nitrogen atom.
[0020]
Examples of the substituent formed through the carbon atom include an alkyl group such as a methyl group, an ethyl group, and a propyl group; an aralkyl group such as a benzyl group; an aryl group such as a phenyl group; and a cyano group.
[0021]
Examples of the substituent formed through the oxygen atom include an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a benzyloxy group; an aryloxy group such as a phenoxy group; an acetyloxy group, a benzoyloxy group, and the like And acyloxy groups.
[0022]
Examples of the substituent formed through the nitrogen atom include a nitro group and an amino group.
[0023]
Moreover, in General formula (1), X < 1 > and X < 2 > show a halogen atom and a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are mentioned.
[0024]
The 2-monosubstituted acetate derivative used in the reaction of the present invention is represented by the above general formula (2). In the general formula (2), R 4 represents an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group; an aryl such as a phenoxycarbonyl group An oxycarbonyl group; an acyl group such as an acetyl group, a propionyl group, and a benzoyl group; and a cyano group. These groups include various isomers. R 5 is a group not involved in the reaction, and specifically represents an alkyl group such as a methyl group, an ethyl group, or a propyl group; an aralkyl group such as a benzyl group; and an aryl group such as a phenyl group.
[0025]
The amount of the 2-mono-substituted acetic acid ester derivative used is preferably 1.0 to 5.0 times mol, more preferably 1.2 to 3.0 times mol, relative to the 2,4-dihalogenonitrobenzene derivative.
[0026]
Examples of the metal atom of the metal inorganic acid salt used in the reaction of the present invention include alkali metal atoms such as lithium atom, sodium atom and potassium atom; alkaline earth metal atoms such as magnesium atom and calcium atom, Preferred are alkali metal atoms, more preferred are sodium atoms and potassium atoms.
[0027]
Examples of the inorganic acid of the metal inorganic acid salt used in the reaction of the present invention include carbonic acid and phosphoric acid, and carbonic acid is preferred.
[0028]
Examples of the metal inorganic acid salt include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, sodium hydrogen phosphate, preferably sodium carbonate, potassium carbonate. Is used.
[0029]
The amount of the metal inorganic acid salt used is preferably 1.0 to 5.0 times mol, more preferably 1.2 to 3.0 times mol, with respect to the 2,4-dihalogenonitrobenzene derivative. These metal alkoxides may be used alone or in combination of two or more.
[0030]
The organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aliphatic hydrocarbons such as hexane and cyclohexane Aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide and N, N′-dimethylimidazolidinone; nitriles such as acetonitrile and propionitrile; dimethyl sulfoxide and the like Preferably, aliphatic hydrocarbons, aromatic hydrocarbons, amides, nitriles, dimethyl sulfoxide, more preferably cyclohexane, toluene, acetonitrile, N, N-dimethylformamide are used.
[0031]
The amount of the organic solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 1 to 50 times by weight, more preferably 1.5 to 20 times by weight with respect to the 2,4-dihalogenonitrobenzene derivative. It is. These organic solvents may be used alone or in combination of two or more.
[0032]
In the reaction of the present invention, for example, a 2,4-dihalogenonitrobenzene derivative, a 2-monosubstituted acetate derivative, a metal inorganic acid salt, and an organic solvent are mixed and reacted. A mono-substituted acetic acid ester derivative, a metal inorganic acid salt and an organic solvent are mixed, and preferably reacted at 20 to 140 ° C., more preferably at 40 to 120 ° C., by adding a 2,4-dihalogenonitrobenzene derivative. is there. Moreover, crown ether, polyethylene glycol, or the like can be added to promote the reaction.
[0033]
The target 2- (5-halogeno-2-nitrophenyl) -2-substituted acetic acid ester derivative obtained by the reaction of the present invention is, for example, a common product such as column chromatography, distillation, recrystallization and the like after completion of the reaction. Separated and purified by various methods.
[0034]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0035]
Example 1
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 6.51 g (47.2 mmol) potassium carbonate, 20 ml N, N-dimethylformamide, 99% pure malon under argon atmosphere 6.24 g (46.7 mmol) of dimethyl acid and 5.00 g (30.8 mmol) of 2,4-difluoronitrobenzene with a purity of 98% were added, and the mixture was allowed to react for 1 hour at room temperature with stirring and further to 70 ° C for 5 hours It was. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added, and 10.5 ml (62.8 mmol) of 6 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, 50 ml of water was added, and then the organic layer was separated. The organic layer was washed with 20 ml of water and 20 ml of saturated saline in this 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, 6.22 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate having a purity of 98% (area percentage of high performance liquid chromatography) was obtained (isolation yield 73%).
[0036]
Example 2
To a glass flask having an internal volume of 100 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel, in an argon atmosphere, potassium carbonate 8.29 g (60.0 mmol), acetonitrile 30 ml, purity 99% dimethyl malonate 8.09 g ( 60.0 mmol) and 98% purity 2,4-difluoronitrobenzene (5.00 g, 30.0 mmol) were added, and the mixture was reacted at 70 ° C. for 10 hours with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 50 ml of toluene was added, and 7.5 ml (90 mmol) of 12 mol / l hydrochloric acid was slowly added dropwise with stirring. Subsequently, the organic layer was separated, washed with water (20 ml) and saturated brine (20 ml) in that order, and dried over anhydrous magnesium sulfate. After filtration, the organic layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 6.61 g (reaction yield 81%) of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was formed. .
[0037]
Example 3
In Example 2, the reaction was performed in the same manner as in Example 2 except that the organic solvent was changed to tetrahydrofuran. As a result, 6.65 g (reaction yield 82%) of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced.
[0038]
Example 4
In a glass flask with an internal volume of 500 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 55.3 g (0.40 mol) of potassium carbonate, 200 ml of N, N-dimethylformamide, 98% pure malon under argon atmosphere 54.0 g (0.40 mol) of dimethyl acid and 32.5 g (0.20 mmol) of 2,4-difluoronitrobenzene having a purity of 98% were added and reacted at 70 ° C. for 3 hours with stirring. After completion of the reaction, the mixture was cooled to room temperature, 160 ml of toluene was added, and 50 ml (0.60 mol) of 12 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 organic layer was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 45.3 g (reaction yield: 84%) of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced. .
[0039]
Example 5
In a glass flask having an internal volume of 100 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel, under an argon atmosphere, 3.03 g (21.9 mmol) of potassium carbonate, 5.0 ml of N, N-dimethylformamide, purity 99% 2.17 g (21.7 mmol) of methyl cyanoacetate and 1.45 g (8.94 mmol) of 2,4-difluoronitrobenzene having a purity of 98% were added and reacted at 60 ° C. for 6 hours with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 50 ml of ethyl acetate was added, and 2.9 ml (34.8 mmol) of 12 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, the organic layer was separated, washed with water (20 ml) and saturated brine (30 ml) in that order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrated solution was purified by silica gel column chromatography (filler: Daisogel 1002W, developing solvent: toluene) to give a yellow oily substance with a purity of 99% (high-performance liquid chromatography area) 1.81 g of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate (isolation yield 84%).
[0040]
Example 6
Into a 100 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, an argon atmosphere, potassium carbonate 8.68 g (62.9 mmol), N, N-dimethylformamide 20 ml, purity 99% acetoacetate 7.30 g (62.2 mmol) of methyl acetate and 5.00 g (30.8 mmol) of 2,4-difluoronitrobenzene having a purity of 98% were added and reacted at 25 ° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added, and 15.7 ml (94.2 mmol) of 6 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, after adding 50 ml of water, the organic layer was separated, washed with water (20 ml) and saturated brine (30 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)) as a yellow oil. Thus, 6.08 g of methyl 2- (5-fluoro-2-nitrophenyl) -2-acetoacetate having a purity of 98% (area percentage of high performance liquid chromatography) was obtained (isolation yield 76%).
[0041]
Example 7
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 7.13 g (51.6 mmol) potassium carbonate, 20 ml N, N-dimethylformamide, 99% purity cyano under argon atmosphere Methyl acetate (5.06 g, 50.6 mmol) and 99% pure 2,4-dichloronitrobenzene (5.00 g, 25.8 mmol) were added, and the mixture was reacted at 45 ° C. for 4 hours with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added, and 12.9 ml (77.4 mmol) of 6 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, 50 ml of water was added, and then the organic layer was separated, washed with 50 ml of saturated brine, 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 = 20: 1 (volume ratio)) to give white crystals. 5.76 g of methyl 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate having a purity of 95% (area percentage of high performance liquid chromatography) was obtained (isolation yield 83%).
[0042]
Example 8
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 7.13 g (51.6 mmol) potassium carbonate, 20 ml N, N-dimethylformamide, 99% purity acetoacetate under argon atmosphere 6.05 g (51.6 mmol) of methyl acetate and 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene having a purity of 99% were added and reacted at 70 ° C. for 3 hours with stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added, and 12.9 ml (77.4 mmol) of 6 mol / l hydrochloric acid was slowly added dropwise with stirring. Next, 30 ml of water was added, and then the organic layer was separated, washed with 30 ml of saturated brine, 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 = 40: 1 (volume ratio)) as a yellow oil. Thus, 4.33 g of methyl 2- (5-chloro-2-nitrophenyl) -2-acetoacetate having a purity of 98% (area percentage of high performance liquid chromatography) was obtained (isolation yield 61%).
[0043]
【The invention's effect】
According to the present invention, a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative can be produced from a 2,4-dihalogenonitrobenzene derivative by a simple method. A method for producing a-(5-halogeno-2-nitrophenyl) -2-substituted acetate derivative can be provided.
Claims (5)
で示される２，４−ジフルオロニトロベンゼンに、一般式（２）
で示される２−モノ置換酢酸エステル誘導体を有機溶媒中で反応させることを特徴とする、一般式（３）
で示される２−（５−フルオロ−２−ニトロフェニル）−２−置換酢酸エステル誘導体の製造法。In the presence of a metal inorganic acid salt in which the inorganic acid is carbonic acid, the general formula (1)
And 2,4-difluoronitrobenzene represented by the general formula (2)
A 2-mono-substituted acetic acid ester derivative represented by the general formula (3) is reacted in an organic solvent.
A method for producing a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetate derivative represented by the formula:
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| JP2000239655A JP4000758B2 (en) | 2000-08-08 | 2000-08-08 | Process for producing 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivative |
| EP01951925A EP1310486A4 (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 |
| US10/333,316 US6900335B2 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxindole and for producing intermediates therefor |
| CA002416397A CA2416397A1 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxyindole and for producing intermediate therefor |
| PCT/JP2001/006260 WO2002006228A1 (en) | 2000-07-19 | 2001-07-19 | Process for producing 5-fluorooxyindole and for producing intermediate therefor |
| US11/093,603 US7342040B2 (en) | 2000-07-19 | 2005-03-30 | 5-fluorooxindole-3-carboxylic acid ester |
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