JP2004203767A - Method for producing 2-(5-fluoro-2-nitrophenyl)-2-substituted acetate derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing a 2-(5-fluoro-2-nitrophenyl)-2-substituted acetate derivative, by which the 2-(5-fluoro-2-nitrophenyl)-2-substituted acetic ester derivative can be produced from a 2,4-difluoronitobenzene derivative in a high yield by the simple method. <P>SOLUTION: This method for producing a 2-(5-fluoro-2-nitrophenyl)-2-substituted acetic ester derivative is characterized by reacting a 2,4-difluoronitrobenzene derivative with 2-mono-substituted acetic ester derivative in the presence of a metal alkoxide in an organic solvent at -25 to 15°C. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【０００７】
（式中、Ｒ¹、Ｒ²及びＲ³は、反応に関与しない基を示す。）
で示される2,4-ジフルオロニトロベンゼン誘導体と、一般式（２）
【０００８】
【化６】

【０００９】
（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とを、-25〜15℃にて、有機溶媒中で反応させることを特徴とする、一般式（３）
【００１０】
【化７】

【００１１】
（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵は、前記と同義である。）
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法によって解決される。
【００１２】
【発明の実施の形態】
本発明の反応において使用する2,4-ジフルオロ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；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。
【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。なお、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。なお、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。なお、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。なお、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。なお、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。なお、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、硫黄原子を介して出来る置換基等が挙げられる。
【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、ブチル基、ペンチル基、ヘキシル基等のアルキル基；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、シクロブチル基等のシクロアルキル基；ビニル基、アリル基、プロペニル基、シクロプロペニル基、シクロブテニル基、シクロペンテニル基等のアルケニル基；キノリル基、ピリジル基、ピロリジル基、ピロリル基、フリル基、チエニル基等の複素環基；フェニル基、トリル基、フルオロフェニル基、キシリル基、ビフェニル基、ナフチル基、アントリル基、フェナントリル基等のアリール基；アセチル基、プロピオニル基、アクリロイル基、ピバロイル基、シクロヘキシルカルボニル基、ベンゾイル基、ナフトイル基、トルオイル基等のアシル基（アセタール化されていても良い）；カルボキシル基；メトキシカルボニル基、エトキシカルボニル基等のアルコキシカルボニル基；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；トリフルオロメチル基等のハロゲン化アルキル基；シアノ基が挙げられる。なお、これらの基は、各種異性体を含む。
【００２１】
前記酸素原子を介して出来る置換基としては、例えば、ヒドロキシ基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基、ヘプチルオキシ基、ベンジルオキシ基、ピペラジルオキシ基、ピラニルオキシ基等のアルコキシ基；フェノキシ基、トルイルオキシ基、ナフチルオキシ基等のアリールオキシ基が挙げられる。なお、これらの基は、各種異性体を含む。
【００２２】
前記窒素原子を介して出来る置換基としては、例えば、メチルアミノ基、エチルアミノ基、ブチルアミノ基、シクロへキシルアミノ基、フェニルアミノ基、ナフチルアミノ基等の第一アミノ基；ジメチルアミノ基、ジエチルアミノ基、ジブチルアミノ基、メチルエチルアミノ基、メチルブチルアミノ基、ジフェニルアミノ基、N-メチル-N-メタンスルホニルアミノ基等の第二アミノ基；モルホリノ基、チオモルホリノ基、ピペリジノ基、ピペラジニル基、ピラゾリジニル基、ピロリジノ基、インドリル基等の複素環式アミノ基；イミノ基が挙げられる。なお、これらの基は、各種異性体を含む。
【００２３】
前記硫黄原子を介して出来る置換基としては、例えば、メルカプト基；チオメトキシ基、チオエトキシ基、チオプロポキシ基等のチオアルコキシ基；チオフェノキシ基、チオトルイルオキシ基、チオナフチルオキシ基等のチオアリールオキシ基等が挙げられる。なお、これらの基は、各種異性体を含む。
【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、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が挙げられる。なお、これらの基は、各種異性体を含む。
【００２５】
前記2-モノ置換酢酸エステル誘導体の使用量は、2,4-ジフルオロニトロベンゼン誘導体1モルに対して、好ましくは1.0〜6.0モル、更に好ましくは2.0〜4.0モルである。
【００２６】
本発明の反応において使用する金属アルコキシドの金属原子としては、例えば、理化学辞典第４版（岩波書店出版）に記載されている、リチウム原子、ナトリウム原子、カリウム原子等の１Ａ族原子（１族原子）；マグネシウム原子、カルシウム原子等の２Ａ族原子（２族原子）；アルミニウム等の３Ｂ族原子（１３族原子）が挙げられる。
【００２７】
前記金属アルコキシドとしては、例えば、リチウムメトキシド、ナトリウムメトキシド、カリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、カリウムt-ブトキシド等の１Ａ族金属アルコキシド；マグネシウムメトキシド、カルシウムメトキシド等の２Ａ族金属アルコキシド；アルミニウムイソプロポキシド等の３Ｂ族金属アルコキシドが使用される。
【００２８】
前記金属アルコキシドの使用量は、2,4-ジフルオロニトロベンゼン誘導体1モルに対して、好ましくは1.0〜6.0モル、更に好ましくは2.0〜4.0モルである。なお、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。
【００２９】
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-ジメチルアセトアミド等のアミド類；N,N'-ジメチルイミダゾリジノン等のイミド類；メタノール、エタノール、イソプロピルアルコール等のアルコール類；アセトン、メチルイソブチルケトン、シクロヘキサノン等のケトン類；アセトニトリル、プロピオニトリル等のニトリル類；ジメチルスルホン、ジエチルスルホン等のスルホン類；ジメチルスルホキシド等のスルホキシド類が挙げられるが、好ましくはアミド類、イミド類、アルコール類、ニトリル類、スルホン類、スルホキシド類、更に好ましくはN,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N,N'-ジメチルイミダゾリジノン、メタノール、エタノール、イソプロピルアルコール、アセトニトリル、ジメチルスルホン、ジメチルスルホキシドが使用される。なお、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。
【００３０】
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-ジフルオロニトロベンゼン誘導体1gに対して、好ましくは1〜50g、更に好ましくは3〜20gである。
【００３１】
本発明の反応は、例えば、2,4-ジフルオロニトロベンゼン誘導体、2-モノ置換酢酸エステル誘導体、金属アルコキシド及び有機溶媒を混合して、攪拌しながら反応させ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-30〜15℃、更に好ましくは-25〜15℃であり、反応圧力は特に制限されない。
【００３２】
本発明の反応によって得られた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は、例えば、反応終了後に、カラムクロマトグラフィー、濃縮、蒸留、濾過、再結晶、晶析等の一般的な方法によって分離・精製される。
【００３３】
【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。
【００３４】
実施例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、純度99％のナトリウムメトキシド6.55g(120mmol)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16.2g(120mmol)を5分間かけてゆるやかに滴下した。10℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン6.49g(40mmol)を30分間かけてゆるやかに滴下し、攪拌しながら同温度にて6時間反応させた。反応終了後、反応液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9.69g生成していた(反応収率：89.3％)。
【００３５】
比較例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、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、純度99％のナトリウムメトキシド6.55g(120mmol)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16.2g(120mmol)を5分間かけてゆるやかに滴下した。60℃まで昇温した後、純度98％の2,4-ジフルオロニトロベンゼン6.49g(40mmol)を30分間かけてゆるやかに滴下し、攪拌しながら同温度にて6時間反応させた。反応終了後、反応液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8.80g生成していた(反応収率：81.2％)。
【００３６】
実施例２（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、純度99％のナトリウムメトキシド6.55g(120mmol)及びN,N'-ジメチルイミダゾリジノン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16.2g(120mmol)を5分間かけてゆるやかに滴下した。-10℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン6.49g(40mmol)を30分間かけてゆるやかに滴下し、攪拌しながら同温度にて6時間反応させた。反応終了後、反応液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10.1g生成していた(反応収率：93.1％)。
【００３７】
実施例３（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、純度99％のナトリウムメトキシド6.55g(120mmol)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16.2g(120mmol)を5分間かけてゆるやかに滴下した。10℃まで冷却した後、メタノール10mlを加えた。次いで、-10℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン6.49g(40mmol)を30分間かけてゆるやかに滴下し、攪拌しながら同温度にて6時間反応させた。反応終了後、反応液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9.94g生成していた(反応収率：91.6％)。
【００３８】
実施例４（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、純度99％のナトリウムメトキシド6.55g(120mmol)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16.2g(120mmol)を5分間かけてゆるやかに滴下した。10℃まで冷却した後、アセトニトリル10mlを加えた。次いで、-10℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン6.49g(40mmol)を30分間かけてゆるやかに滴下し、攪拌しながら同温度にて24時間反応させた。反応終了後、反応液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9.82g生成していた(反応収率：90.5％)。
【００３９】
実施例５（2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチルの合成）
攪拌装置、温度計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、純度99％のナトリウムメトキシド5.03g(92.2mmol)及びジメチルスルホキシド20mlを加え、次いで、室温で攪拌しながら、純度99％のシアノ酢酸メチル9.21g(92.2mmol)を10分間かけてゆるやかに滴下した。-15〜-10℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン6.80g(41.9mmol)を1時間かけてゆるやかに滴下し、攪拌しながら同温度にて3時間反応させた。反応終了後、反応液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)-2-シアノ酢酸メチルが9.50g生成していた(反応収率：95.2％)。
【００４０】
比較例２（2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチルの合成）
攪拌装置、温度計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、純度99％のナトリウムメトキシド5.03g(92.2mmol)及びジメチルスルホキシド20mlを加え、次いで、30℃で攪拌しながら、純度99％のシアノ酢酸メチル9.21g(92.2mmol)を10分間かけてゆるやかに滴下した。同温度で純度98％の2,4-ジフルオロニトロベンゼン6.80g(41.9mmol)を1時間かけてゆるやかに滴下し、攪拌しながら同温度にて3時間反応させた。反応終了後、反応液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)-2-シアノ酢酸メチルが8.41g生成していた(反応収率：84.3％)。
【００４１】
実施例６（2-シクロブチリル-2-(5-フルオロ-2-ニトロフェニル)酢酸メチルの合成）
攪拌装置、温度計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、純度99％のナトリウムメトキシド3.27g(120mmol)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3-シクロプロピル-3-オキソプロパン酸メチル8.70g(60mmol)を30分間かけてゆるやかに滴下した。-10〜0℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン3.25g(20mmol)を1時間かけてゆるやかに滴下し、攪拌しながら同温度にて6時間反応させた。反応終了後、酢酸エチル50ml、3mol/l塩酸13mlを加えた。次いで、有機層を取り出し、水50ml、飽和食塩水50mlの順で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、得られた濃縮物をシリカゲルカラムクロマトグラフィー（充填剤：ワコーゲルC-200(和光純薬社製)、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による面積百分率）の2-シクロブチリル-2-(5-フルオロ-2-ニトロフェニル)酢酸メチル4.31gを得た(単離収率：75％、ケト型：エノール型＝1:2)。
なお、2-シクロブチリル-2-(5-フルオロ-2-ニトロフェニル)酢酸メチルは、以下の物性値を有する新規な化合物である。
【００４２】
¹H-NMR(CDCl₃,δ(ppm))；
ケト型：0.79〜0.82(4H,m)、1.16(1H,m)、3.81(3H,s)、5.66(1H,s)、7.12〜7.13(2H,m)、8.06〜8.07(1H,m)
エノール型：1.16〜1.20(4H,m)、1.24〜1.64(4H,m)、3.65(3H,s)、6.95〜7.05(1H,m)、7.15〜7.23(2H,m)、8.07〜8.11(1H,m)、13.10(1H,s)
【００４３】
実施例７（2-(5-フルオロ-2-ニトロフェニル)-2-イソブチリル酢酸メチルの合成）
攪拌装置、温度計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、純度99％のナトリウムメトキシド3.27g(120mmol)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4-メチル-3-オキソペンタン酸メチル8.83g(60mmol)を30分間かけてゆるやかに滴下した。-10〜0℃まで冷却した後、純度98％の2,4-ジフルオロニトロベンゼン3.25g(20mmol)を1時間かけてゆるやかに滴下し、攪拌しながら同温度にて6時間反応させた。反応終了後、酢酸エチル50ml、3mol/l塩酸13mlを加えた。次いで、有機層を取り出し、水50ml、飽和食塩水50mlの順で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、得られた濃縮物をシリカゲルカラムクロマトグラフィー（充填剤：ワコーゲルC-200(和光純薬社製)、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による面積百分率）の2-(5-フルオロ-2-ニトロフェニル)-2-イソブチリル酢酸メチル4.15gを得た(単離収率：71％、ケト型：エノール型＝1:3)。
なお、2-(5-フルオロ-2-ニトロフェニル)-2-イソブチリル酢酸メチルは、以下の物性値を有する新規な化合物である。
【００４４】
¹H-NMR(CDCl₃,δ(ppm))；
ケト型：1.04(6H,s)、1.16(1H,m)、3.73(3H,s)、5.72(1H,s)、6.70〜6.95(1H,m)、7.20〜7.27(2H,m)、8.06〜8.08(1H,m)
エノール型：1.16〜1.20(4H,m)、1.24〜1.64(4H,m)、3.65(3H,s)、6.70〜6.95(1H,m)、7.14〜7.17(1H,m)、8.06〜8.08(1H,m)、13.00(1H,s)
【００４５】
【発明の効果】
本発明により、簡便な方法にて、高収率で2,4-ジフルオロニトロベンゼン誘導体から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を製造することが出来る、工業的に好適な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法を提供することが出来る。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a 2- (5-halogeno-2-nitrophenyl) -2-substituted acetic acid ester derivative from a 2,4-difluoronitrobenzene derivative by a simple method. A 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative is a compound useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and the like.
[0002]
[Prior art]
Conventionally, as a method for producing a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative from a 2,4-difluoronitrobenzene derivative, in the presence of sodium methoxide in dimethyl sulfoxide, A method is disclosed in which 4-difluoronitrobenzene and dimethyl malonate are reacted at 80 ° C. to synthesize dimethyl 2- (5-fluoro-2-nitrophenyl) malonate with a reaction yield of 76% (for example, Patent Document 1). However, in this method, the yield of the target product is low, and there is a problem as an industrial production method.
[0003]
[Patent Document 1]
WO 02/06228 pamphlet [0004]
[Problems to be solved by the invention]
An object of the present invention is to solve the above problems and to produce a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative from a 2,4-difluoronitrobenzene derivative in high yield. It is intended to provide a process for producing an industrially suitable 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative.
[0005]
[Means for Solving the Problems]
An object of the present invention is to provide a compound of the formula (1) in the presence of a metal alkoxide
[0006]
Embedded image

[0007]
(In the formula, R ¹ , R ² and R ³ represent groups not participating in the reaction.)
A 2,4-difluoronitrobenzene derivative represented by the general formula (2)
[0008]
Embedded image

[0009]
(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 compound is reacted with a 2-monosubstituted acetic acid ester derivative represented by the general formula (3) at -25 to 15 ° C in an organic solvent.
[0010]
Embedded image

[0011]
(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)
This is solved by a method for producing a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative represented by the following formula:
[0012]
BEST MODE FOR CARRYING OUT THE INVENTION
The 2,4-difluoronitrobenzene derivative used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), R ¹ , R ² and R ³ are groups that do not participate in the reaction, and specifically include a hydrogen atom; an alkyl group and a cycloalkyl group which may have a substituent. , An aralkyl group, an aryl group, an alkoxy group or an aryloxy group.
[0013]
As the alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable, and examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Is mentioned. These alkyl groups include various isomers.
[0014]
As the cycloalkyl group, a cycloalkyl group having 3 to 7 carbon atoms is particularly preferable, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. In addition, these cycloalkyl groups also include various isomers.
[0015]
The aralkyl group is 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. Note that these aralkyl groups include various isomers.
[0016]
The aryl group is particularly preferably an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, and an anthranyl group. Note that these aryl groups include various isomers.
[0017]
As the alkoxy group, an alkoxy group having 1 to 12 carbon atoms is particularly preferable, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a benzyloxy group. In addition, these alkoxy groups include various isomers.
[0018]
The aryloxy group is particularly preferably an aryloxy group having 6 to 14 carbon atoms, and examples thereof include a phenoxy group and a tolyloxy group. In addition, these aryloxy groups include various isomers.
[0019]
The above alkyl group, cycloalkyl group, aralkyl group, aryl group, alkoxy group or aryloxy group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and the like.
[0020]
Examples of the substituent formed through the carbon atom include an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cyclobutyl group. Alkenyl groups such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group and cyclopentenyl group; quinolyl group, pyridyl group, pyrrolidyl group, pyrrolyl group, furyl group, thienyl group, etc. Heterocyclic group; aryl group such as phenyl group, tolyl group, fluorophenyl group, xylyl group, biphenyl group, naphthyl group, anthryl group, phenanthryl group; acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, benzoyl Group, naphthoyl group Acyl groups such as toluoyl groups (which may be acetalized); carboxyl groups; alkoxycarbonyl groups such as methoxycarbonyl groups and ethoxycarbonyl groups; aryloxycarbonyl groups such as phenoxycarbonyl groups; and halogenation such as trifluoromethyl groups. An alkyl group; a cyano group; These groups include various isomers.
[0021]
Examples of the substituent formed through the oxygen atom include a hydroxy group; a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, a heptyloxy group, a benzyloxy group, a piperazyloxy group, and a pyranyloxy group. And the like; and an aryloxy group such as a phenoxy group, a toluyloxy group, and a naphthyloxy group. These groups include various isomers.
[0022]
Examples of the substituent formed through the nitrogen atom include primary amino groups such as methylamino group, ethylamino group, butylamino group, cyclohexylamino group, phenylamino group, and naphthylamino group; dimethylamino group, diethylamino Group, dibutylamino group, methylethylamino group, methylbutylamino group, diphenylamino group, secondary amino group such as N-methyl-N-methanesulfonylamino group; morpholino group, thiomorpholino group, piperidino group, piperazinyl group, Heterocyclic amino groups such as pyrazolidinyl group, pyrrolidino group and indolyl group; and imino groups. These groups include various isomers.
[0023]
Examples of the substituent formed through the sulfur atom include a mercapto group; a thioalkoxy group such as a thiomethoxy group, a thioethoxy group, and a thiopropoxy group; and a thioaryloxy group such as a thiophenoxy group, a thiotoluyloxy group, and a thionaphthyloxy group. And the like. These groups include various isomers.
[0024]
The 2-monosubstituted acetic ester derivative used in the reaction of the present invention is represented by the above general formula (2). In the general formula (2), R ⁴ is an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, 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 also include various isomers. R ⁵ is a group that does not participate in the reaction, and specific examples include an alkyl group such as a methyl group, an ethyl group, and a propyl group; an aralkyl group such as a benzyl group; and an aryl group such as a phenyl group. These groups include various isomers.
[0025]
The amount of the 2-monosubstituted acetic acid ester derivative to be used is preferably 1.0 to 6.0 mol, more preferably 2.0 to 4.0 mol, per 1 mol of the 2,4-difluoronitrobenzene derivative.
[0026]
As the metal atom of the metal alkoxide used in the reaction of the present invention, for example, a Group 1A atom (Group 1 atom) such as a lithium atom, a sodium atom, and a potassium atom described in the 4th edition of the Physical and Chemical Dictionary (Iwanami Shoten Publishing Co., Ltd.) ); A Group 2A atom (Group 2 atom) such as a magnesium atom and a calcium atom; and a Group 3B atom (Group 13 atom) such as aluminum.
[0027]
Examples of the metal alkoxide include Group 1A metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and potassium t-butoxide; Group 2A such as magnesium methoxide and calcium methoxide Metal alkoxide; Group 3B metal alkoxide such as aluminum isopropoxide is used.
[0028]
The amount of the metal alkoxide to be used is preferably 1.0 to 6.0 mol, more preferably 2.0 to 4.0 mol, per 1 mol of the 2,4-difluoronitrobenzene derivative. In addition, you may use these metal alkoxides individually or in mixture of 2 or more types.
[0029]
The organic solvent used in the reaction of the present invention is not particularly limited as long as it does not inhibit the reaction, and examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; and aliphatic hydrocarbons such as hexane and cyclohexane. Aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; imides such as N, N'-dimethylimidazolidinone; methanol, ethanol, Alcohols such as isopropyl alcohol; ketones such as acetone, methyl isobutyl ketone and cyclohexanone; nitriles such as acetonitrile and propionitrile; sulfones such as dimethyl sulfone and diethyl sulfone; and sulfoxides such as dimethyl sulfoxide. Preferably Amides, imides, alcohols, nitriles, sulfones, sulfoxides, more preferably N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, methanol, ethanol, isopropyl Alcohol, acetonitrile, dimethyl sulfone, dimethyl sulfoxide are used. In addition, you may use these organic solvents individually or in mixture of 2 or more types.
[0030]
The amount of the organic solvent used is appropriately adjusted depending on the uniformity of the reaction solution and the stirring property, but is preferably 1 to 50 g, more preferably 3 to 20 g, based on 1 g of the 2,4-difluoronitrobenzene derivative.
[0031]
The reaction of the present invention is carried out by, for example, a method of mixing a 2,4-difluoronitrobenzene derivative, a 2-monosubstituted acetic acid ester derivative, a metal alkoxide, and an organic solvent and reacting them with stirring. The reaction temperature at that time is preferably -30 to 15 ° C, more preferably -25 to 15 ° C, and the reaction pressure is not particularly limited.
[0032]
The 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic ester derivative obtained by the reaction of the present invention is, for example, after the completion of the reaction, column chromatography, concentration, distillation, filtration, recrystallization, crystallization Separation and purification.
[0033]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0034]
Example 1 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 6.55 g (120 mmol) of sodium methoxide having a purity of 99% and 30 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel. Then, 16.2 g (120 mmol) of dimethyl malonate having a purity of 98% was slowly added dropwise over 5 minutes. After cooling to 10 ° C., 6.49 g (40 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 30 minutes, and the mixture was reacted at the same temperature for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 9.69 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced (reaction yield: 89.3%) ).
[0035]
Comparative Example 1 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 6.55 g (120 mmol) of 99% pure sodium methoxide and 30 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a dropping funnel. While stirring with, 16.2 g (120 mmol) of 98% pure dimethyl malonate was slowly added dropwise over 5 minutes. After the temperature was raised to 60 ° C., 6.49 g (40 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 30 minutes, and the mixture was reacted at the same temperature for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 8.80 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced (reaction yield: 81.2%) ).
[0036]
Example 2 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
In a 200 ml glass flask equipped with a stirrer, thermometer and dropping funnel, under an argon atmosphere, 6.55 g (120 mmol) of sodium methoxide of 99% purity and 30 ml of N, N'-dimethylimidazolidinone were added, Then, with stirring at room temperature, 16.2 g (120 mmol) of 98% pure dimethyl malonate was slowly added dropwise over 5 minutes. After cooling to −10 ° C., 6.49 g (40 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 30 minutes, and the mixture was reacted at the same temperature for 6 hours with stirring. After the reaction was completed, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 10.1 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced (reaction yield: 93.1%) ).
[0037]
Example 3 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 6.55 g (120 mmol) of sodium methoxide having a purity of 99% and 30 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel. Then, 16.2 g (120 mmol) of dimethyl malonate having a purity of 98% was slowly added dropwise over 5 minutes. After cooling to 10 ° C., 10 ml of methanol was added. Next, after cooling to −10 ° C., 6.49 g (40 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 30 minutes, and reacted at the same temperature for 6 hours with stirring. After the reaction was completed, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method), and it was found that 9.94 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced (reaction yield: 91.6%) ).
[0038]
Example 4 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 6.55 g (120 mmol) of sodium methoxide having a purity of 99% and 30 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel. Then, 16.2 g (120 mmol) of dimethyl malonate having a purity of 98% was slowly added dropwise over 5 minutes. After cooling to 10 ° C., 10 ml of acetonitrile were added. Next, after cooling to −10 ° C., 6.49 g (40 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 30 minutes, and reacted at the same temperature for 24 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 9.82 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate was produced (reaction yield: 90.5%) ).
[0039]
Example 5 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
Under a argon atmosphere, 5.03 g (92.2 mmol) of 99% pure sodium methoxide and 20 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel, and then stirred at room temperature. Then, 9.21 g (92.2 mmol) of 99% pure methyl cyanoacetate was slowly added dropwise over 10 minutes. After cooling to -15 to -10 ° C, 6.80 g (41.9 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 1 hour, and the mixture was reacted at the same temperature for 3 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method), and it was found that 9.50 g of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate was produced (reaction yield). : 95.2%).
[0040]
Comparative Example 2 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
Under an argon atmosphere, 5.03 g (92.2 mmol) of 99% pure sodium methoxide and 20 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer, and a dropping funnel, and then stirred at 30 ° C. Then, 9.21 g (92.2 mmol) of 99% pure methyl cyanoacetate was slowly added dropwise over 10 minutes. At the same temperature, 6.80 g (41.9 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 1 hour, and the mixture was reacted at the same temperature for 3 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method), and it was found that 8.41 g of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate was produced (reaction yield). : 84.3%).
[0041]
Example 6 (Synthesis of methyl 2-cyclobutyryl-2- (5-fluoro-2-nitrophenyl) acetate)
3.27 g (120 mmol) of 99% pure sodium methoxide and 30 ml of dimethyl sulfoxide were added to a 200-ml glass flask equipped with a stirrer, a thermometer and a dropping funnel under an argon atmosphere, and then stirred at room temperature. Then, 8.70 g (60 mmol) of methyl 3-cyclopropyl-3-oxopropanoate having a purity of 98% was slowly added dropwise over 30 minutes. After cooling to −10 to 0 ° C., 3.25 g (20 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 1 hour, and the mixture was reacted at the same temperature for 6 hours with stirring. After completion of the reaction, 50 ml of ethyl acetate and 13 ml of 3 mol / l hydrochloric acid were added. Next, the organic layer was taken out, washed with 50 ml of water and 50 ml of saturated saline in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the obtained concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane / ethyl acetate = 9/1 (volume) Ratio)) to give 4.31 g of methyl 2-cyclobutyryl-2- (5-fluoro-2-nitrophenyl) acetate as a yellow oil having a purity of 98% (area percentage by high performance liquid chromatography). Isolation yield: 75%, keto type: enol type = 1: 2).
In addition, methyl 2-cyclobutyryl-2- (5-fluoro-2-nitrophenyl) acetate is a novel compound having the following physical property values.
[0042]
¹ H-NMR (CDCl ₃ , δ (ppm));
Keto type: 0.79 to 0.82 (4H, m), 1.16 (1H, m), 3.81 (3H, s), 5.66 (1H, s), 7.12 to 7.13 (2H, m), 8.06 to 8.07 (1H, m)
Enol type: 1.16 to 1.20 (4H, m), 1.24 to 1.64 (4H, m), 3.65 (3H, s), 6.95 to 7.05 (1H, m), 7.15 to 7.23 (2H, m), 8.07 to 8.11 ( 1H, m), 13.10 (1H, s)
[0043]
Example 7 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-isobutyryl acetate)
In a 200-ml glass flask equipped with a stirrer, a thermometer and a dropping funnel, under an argon atmosphere, 3.27 g (120 mmol) of 99% pure sodium methoxide and 30 ml of dimethyl sulfoxide were added, and then the mixture was stirred at room temperature. Then, 8.83 g (60 mmol) of methyl 4-methyl-3-oxopentanoate having a purity of 98% was slowly added dropwise over 30 minutes. After cooling to −10 to 0 ° C., 3.25 g (20 mmol) of 2,4-difluoronitrobenzene having a purity of 98% was slowly added dropwise over 1 hour, and reacted at the same temperature for 6 hours with stirring. After completion of the reaction, 50 ml of ethyl acetate and 13 ml of 3 mol / l hydrochloric acid were added. Next, the organic layer was taken out, washed with 50 ml of water and 50 ml of saturated saline in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane / ethyl acetate = 9/1 (volume) Ratio)) to give 4.15 g of methyl 2- (5-fluoro-2-nitrophenyl) -2-isobutyrylacetate as a yellow oil having a purity of 98% (area percentage by high performance liquid chromatography). Isolation yield: 71%, keto type: enol type = 1: 3).
Incidentally, methyl 2- (5-fluoro-2-nitrophenyl) -2-isobutyryl acetate is a novel compound having the following physical property values.
[0044]
¹ H-NMR (CDCl ₃ , δ (ppm));
Keto type: 1.04 (6H, s), 1.16 (1H, m), 3.73 (3H, s), 5.72 (1H, s), 6.70-6.95 (1H, m), 7.20-7.27 (2H, m), 8.06 ~ 8.08 (1H, m)
Enol type: 1.16 to 1.20 (4H, m), 1.24 to 1.64 (4H, m), 3.65 (3H, s), 6.70 to 6.95 (1H, m), 7.14 to 7.17 (1H, m), 8.06 to 8.08 ( 1H, m), 13.00 (1H, s)
[0045]
【The invention's effect】
According to the present invention, a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative can be produced from a 2,4-difluoronitrobenzene derivative in high yield by a simple method, It is possible to provide a method for producing a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetic acid ester derivative which is suitable for the above.

Claims (3)

Formula (1) in the presence of a metal alkoxide

(In the formula, R ¹ , R ² and R ³ represent groups not participating in the reaction.)
A 2,4-difluoronitrobenzene derivative represented by the general formula (2)

(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 compound is reacted with a 2-monosubstituted acetic acid ester derivative represented by the general formula (3) at -25 to 15 ° C in an organic solvent.

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.)
A method for producing a 2- (5-fluoro-2-nitrophenyl) -2-substituted acetate derivative represented by the formula: The 2- (5-fluoro-2-nitrophenyl) according to claim 1, wherein the organic solvent is at least one organic solvent selected from the group consisting of amides, imides, alcohols, nitriles, sulfones, and sulfoxides. ) Preparation of 2-substituted acetate derivatives. General formula (4)

(In the formula, R ⁶ represents an isopropyl group or a cyclopropyl group.)
A 2- (5-fluoro-2-nitrophenyl) -2-acyl acetic acid ester derivative represented by the formula: