JP4296766B2 - Method for producing 3-substituted anthranyl derivatives - Google Patents

Description

【０００８】
（式中、Ｒ^１及びＲ^２は、同一又は異なっていても良く、アルコキシカルボニル基、シクロ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又はシアノ基を示し、Ｘは、水素原子、ハロゲン原子又はアルキル基を示す。）
で示されるニトロベンゼン誘導体を環化反応させることを特徴とする、一般式（２）
【０００９】
【化４】

【００１０】
（式中、Ｒ^３は、Ｒ^１又はＲ^２のいずれか一方と同一である。）
で示される3-置換アントラニル誘導体の製法によって解決される。
【００１１】
【発明の実施の形態】
本発明の環化反応において使用する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、Ｒ^１及びＲ^２は、同一又は異なっていても良く、例えば、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、ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基、ヘプチルオキシカルボニル基、オクチルオキシカルボニル基、ノニルオキシカルボニル基、デシルオキシカルボニル基等のアルコキシカルボニル基（なお、これらの基は、各種異性体を含む。）；シクロプロポキシカルボニル基、シクロブトキシカルボニル基、シクロペンチルオキシカルボニル基、シクロヘキシルオキシカルボニル基、シクロヘプチルオキシカルボニル基等のシクロアルコキシカルボニル基；ベンジルオキシカルボニル基、フェネチルオキシカルボニル基、フェニルプロポキシカルボニル基、フェニルブトキシカルボニル基等のアラルキルオキシカルボニル基（なお、これらの基は、各種異性体を含む。）；フェノキシカルボニル基、トリルオキシカルボニル基、ナフチルオキシカルボニル基、アントラニルオキシカルボニル基等のアリールオキシカルボニル基（なお、これらの基は、各種異性体を含む。）；シアノ基を示す。又、Ｘは、水素原子；フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子；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、デシル基等のアルキル基を示す（なお、これらの基は、各種異性体を含む。）。
【００１２】
なお、本発明の環化反応において使用するニトロベンゼン誘導体は、例えば、一般式（３）
【００１３】
【化５】

【００１４】
（式中、Ｒ^１、Ｒ^２及びＸは、前記と同義である。）
で示される反応によって得ることが出来る化合物である（後の参考例１〜４に記載）。
【００１５】
本発明の環化反応において使用する非プロトン性極性溶媒は、反応を阻害しないものならば特に限定されないが、25℃における比誘電率が10〜50であるものが好ましく、具体的には、例えば、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-メチルピロリドン等のアミド類；1,3-ジメチル-2-イミダゾリジノン等の尿素類；ジメチルスルホキシド等のスルホキシド類；スルホラン等のスルホン類が使用される。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。又、比誘電率は、例えば、「TECNIQUES OF CHEMISTRY Volume 2 ORGANIC SOLVENTS」（WILLY-INTERSCIENCE社）に記載されている。
【００１６】
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、ニトロベンゼン誘導体1gに対して、好ましくは1〜500g、更に好ましくは4〜50gである。
【００１７】
本発明の環化反応は、例えば、ニトロベンゼン誘導体及び非プロトン性極性溶媒を混合して、攪拌しながら反応させる等の方法によって行われる（この時、必要ならば副生するアルコールを除去しながら反応させても良い）。その際の反応温度は、好ましくは5〜300℃、更に好ましくは50〜180℃であり、反応圧力は特に制限されないが、好ましくは常圧又は減圧である。
【００１８】
本発明の環化反応は、反応速度を向上させるために、有機塩基を存在させても良い。前記有機塩基としては、例えば、トリメチルアミン、トリエチルアミン、エチルジイソプロピルアミン、ジエチルイソプロピルアミン、トリイソプロピルアミン、トリブチルアミン、ベンジルジメチルアミン、ベンジルジエチルアミン等の三級アミン；ピリジン、メチルピリジン、ジメチルピリジン等のピリジン類が挙げられるが、好ましくはトリエチルアミン、エチルジイソプロピルアミン、トリイソプロピルアミン、トリブチルアミン、更に好ましくはエチルジイソプロピルアミン、トリイソプロピルアミンが使用される。なお、これらの有機塩基は、単独又は二種以上を混合して使用しても良い。
【００１９】
前記有機塩基の使用量は、ニトロベンゼン誘導体1molに対して、好ましくは0.5〜100mol、更に好ましくは1.5〜10molである。
【００２０】
本発明の環化反応によって3-置換アントラニル誘導体が得られるが、これは、例えば、反応終了後、濾過、抽出、濃縮、再結晶、晶析、蒸留、カラムクラマトグラフィー等の一般的な方法によって単離・精製される。
【００２１】
【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。
【００２２】
参考例１（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、ナトリウムメトキシド4.62g(83.8mmol)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8.37g(83.8mmol)を10分間かけてゆるやかに滴下した。反応液の温度を20〜30℃に保ちながら、純度98％の2,4-ジフルオロニトロベンゼン6.76g(41.6mmol)を1時間かけてゆるやかに滴下した後、同温度で6時間反応させた。反応終了後、氷浴で反応液の温度を10℃以下に保ちながら、トルエン10mlを加え、1mol/l塩酸41.9ml(41.19mmol)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、有機層を減圧下で濃縮した。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：ワコーゲルC-200(和光純薬社製)、展開溶媒：トルエン）で精製し、白色結晶として、純度99.4％（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-シアノ酢酸メチル7.98gを得た(2,4-ジフルオロニトロベンゼン基準の単離収率：80.0％)。
2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチルの物性値は以下の通りであった。
【００２３】
融点；43〜44℃
EI-MS(m/e)；192(M-NO₂)、CI-MS(m/e)；239(M+1)
¹H-NMR(CDCl₃,δ(ppm))；3.88(3H,s)、5.71(1H,s)、7.3〜7.4(1H,m)、7.45〜7.55(1H,m)、8.3〜8.4(1H,m)
【００２４】
実施例１（3-シアノ-5-フルオロアントラニルの合成）
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、1,3-ジメチル-2-イミダゾリジノン（25℃における比誘電率37.6）20mlを加え、攪拌しながら120℃まで昇温した。次いで、参考例１で合成した純度99.4％の2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル1.50g(6.26mmol)を1,3-ジメチル-2-イミダゾリジノン5mlに溶解した溶液を、20分間かけてゆるやかに滴下し、同温度で3時間反応させた。反応終了後、室温まで冷却し、反応液にトルエン50ml及び水50mlを加えて攪拌した。有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄した後、減圧下で濃縮した。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：トルエン）で精製し、白色結晶として、純度98.9％（高速液体クロマトグラフィーによる面積百分率）の3-シアノ-5-フルオロアントラニル0.70gを得た(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の単離収率：68.5％)。
3-シアノ-5-フルオロアントラニルの物性値は以下の通りであった。
【００２５】
融点；59〜60℃
¹H-NMR(DMSO-d₆,δ(ppm))；7.59〜7.62(1H,m)、7.89〜7.93(1H,m)、8.18〜8.19(1H,m)
【００２６】
実施例２（3-シアノ-5-フルオロアントラニルの合成）
実施例１において、溶媒をN,N-ジメチルホルムアミド（25℃における比誘電率36.7）に変えたこと以外は、実施例１と同様に反応を行った。反応終了後、反応液を高速液体クロマトグラフィーにより分析（絶対定量法）したところ、3-シアノ-5-フルオロアントラニルが0.65g生成していた(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の反応収率：63.7％)。
【００２７】
実施例３（3-シアノ-5-フルオロアントラニルの合成）
実施例１において、溶媒をジメチルスルホキシド（25℃における比誘電率46.7）に変えたこと以外は、実施例１と同様に反応を行った。反応終了後、反応液を高速液体クロマトグラフィーにより分析（絶対定量法）したところ、3-シアノ-5-フルオロアントラニルが0.69g生成していた(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の反応収率：67.4％)。
【００２８】
実施例４（3-シアノ-5-フルオロアントラニルの合成）
実施例１において、溶媒をN-メチルピロリドン（25℃における比誘電率32.0）に変えたこと以外は、実施例１と同様に反応を行った。反応終了後、反応液を高速液体クロマトグラフィーにより分析（絶対定量法）したところ、3-シアノ-5-フルオロアントラニルが0.71g生成していた(2-(5-フルオロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の反応収率：69.4％)。
【００２９】
比較例１（3-シアノ-5-フルオロアントラニルの合成）
実施例１において、溶媒を混合キシレン（25℃における比誘電率2.3）に変えたこと以外は、実施例１と同様に反応を行った。反応終了後、反応液を高速液体クロマトグラフィーにより分析（絶対定量法）したところ、3-シアノ-5-フルオロアントラニルは全く生成していなかった。
【００３０】
参考例２（2-(5-クロロ-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、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、ナトリウムメトキシド2.79g(51.6mmol)及びジメチルスルホキシド15ml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5.16g(51.6mmol)を5分間かけてゆるやかに滴下した。更に、純度98％の2,4-ジクロロニトロベンゼン5.00g(25.8mmol)を1時間かけてゆるやかに滴下した後、40〜48℃で10分間、65℃で2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4.30ml(25.7mmol)及び水20mlをゆるやかに滴下した。次いで、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で乾燥した。濾過後、濾液を減圧下で濃縮し、濃縮液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、帯黄色結晶として、純度99.0％（高速液体クロマトグラフィーによる面積百分率）の2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル6.11gを得た(2,4-ジフルオロニトロベンゼン基準の単離収率：92.0％)。
2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチルの物性値は以下の通りであった。
【００３１】
融点；98〜100℃
¹H-NMR(CDCl₃,δ(ppm))；3.88(3H,s)、5.68(1H,s)、7.62(1H,dd,J=8.8,2.2Hz)、7.77(1H,d,J=2.2Hz)、8.21(1H,d,J=8.8Hz)
【００３２】
実施例７（3-シアノ-5-クロロアントラニルの合成）
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、1,3-ジメチル-2-イミダゾリジノン（25℃における比誘電率37.6）20mlを加え、攪拌しながら120℃まで昇温した。次いで、参考例２で合成した純度99.0％の2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル1.50g(5.89mmol)を1,3-ジメチル-2-イミダゾリジノン5mlに溶解した溶液を、20分間かけてゆるやかに滴下し、同温度で3時間反応させた。反応終了後、室温まで冷却し、反応液にトルエン50ml及び水50mlを加えて攪拌した。有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄した後、減圧下で濃縮した。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：トルエン）で精製し、白色結晶として、純度99.0％（高速液体クロマトグラフィーによる面積百分率）の3-シアノ-5-クロロアントラニル0.64gを得た(2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の単離収率：60.5％)。
3-シアノ-5-クロロアントラニルの物性値は以下の通りであった。
【００３３】
融点；99〜100℃
¹H-NMR(DMSO-d₆,δ(ppm))；7.59〜7.62(1H,m)、7.89〜7.93(1H,m)、8.18〜8.19(1H,m)
【００３４】
実施例８（3-シアノ-5-クロロアントラニルの合成）
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、1,3-ジメチル-2-イミダゾリジノン（25℃における比誘電率37.6）20mlを加え、攪拌しながら120℃まで昇温した。次いで、参考例２で合成した純度99.0％の2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル1.50g(5.89mmol)を1,3-ジメチル-2-イミダゾリジノン5mlに溶解した溶液を、20分間かけてゆるやかに滴下し、減圧下（0.003〜0.006MPa）にて副生するメタノールを留去しながら、同温度で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により分析（絶対定量法）したところ、3-シアノ-5-クロロアントラニルが0.68g生成していた(2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の反応収率：64.8％)。
【００３５】
実施例９（3-シアノ-5-クロロアントラニルの合成）
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、1,3-ジメチル-2-イミダゾリジノン（25℃における比誘電率37.6）20ml及びエチルジイソプロピルアミン1.52g(11.78mmol)を加え、攪拌しながら120℃まで昇温した。次いで、参考例２で合成した純度99.0％の2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル1.50g(5.89mmol)を1,3-ジメチル-2-イミダゾリジノン5mlに溶解した溶液を、20分間かけてゆるやかに滴下し、同温度で1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により分析（絶対定量法）したところ、3-シアノ-5-クロロアントラニルが0.64g生成していた(2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の反応収率：60.8％)。
【００３６】
実施例１０（3-シアノ-5-クロロアントラニルの合成）
実施例７において、溶媒をN-メチルピロリドン（25℃における比誘電率32.0）に変えたこと以外は、実施例１と同様に反応を行った。反応終了後、反応液を高速液体クロマトグラフィーにより分析（絶対定量法）したところ、3-シアノ-5-クロロアントラニルが0.66g生成していた(2-(5-クロロ-2-ニトロフェニル)-2-シアノ酢酸メチル基準の反応収率：63.2％)。
【００３７】
参考例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、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、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20mlを加え、次いで、室温で攪拌しながら、純度99％のマロン酸ジメチル8.31g(62.3mmol)を5分間かけてゆるやかに滴下した。その後、20℃まで冷却し、2,4-ジフルオロニトロベンゼン5.10g(31.4mmol)を5分間かけてゆるやかに滴下し、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、酢酸エチル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30ml、飽和食塩水30ml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97.2％（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6.55gを得た(単離収率：75.0％)。
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。
【００３８】
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)
【００３９】
実施例１１（3-メトキシカルボニル-5-フルオロアントラニルの合成）
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、1,3-ジメチル-2-イミダゾリジノン（25℃における比誘電率37.6）20mlを加え、攪拌しながら130℃まで昇温した。次いで、参考例３で合成した純度99.4％の2-(5-フルオロ-2-ニトロフェニル)-2-マロン酸ジメチル2.00g(7.37mmol)を1,3-ジメチル-2-イミダゾリジノン10mlに溶解した溶液を、20分間かけてゆるやかに滴下し、同温度で3時間反応させた。反応終了後、室温まで冷却し、反応液にトルエン50ml及び水50mlを加えて攪拌した。有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄した後、減圧下で濃縮した。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：トルエン）で精製し、白色結晶として、純度99.4％（高速液体クロマトグラフィーによる面積百分率）の3-メトキシカルボニル-5-フルオロアントラニル0.91gを得た(2-(5-フルオロ-2-ニトロフェニル)マロン酸ジメチル基準の単離収率：63.2％)。
3-メトキシカルボニル-5-フルオロアントラニルの物性値は以下の通りであった。
【００４０】
融点；131〜132℃
¹H-NMR(DMSO-d₆,δ(ppm))；4.01(3H,s)、7.54〜7.56(1H,m)、7.57〜7.58(1H,m)、7.99〜8.03(1H,m)
【００４１】
参考例４（2-(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、ナトリウムメトキシド4.62g(83.8mmol)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8.37g(83.8mmol)を10分間かけてゆるやかに滴下した。反応液の温度を20〜30℃に保ちながら、純度98％の2-クロロニトロベンゼン6.68g(41.6mmol)を1時間かけてゆるやかに滴下した後、60℃で3時間反応させた。反応終了後、氷浴で反応液の温度を10℃以下に保ちながら、トルエン10mlを加え、1mol/l塩酸41.9ml(41.19mmol)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、有機層を減圧下で濃縮した。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：ワコーゲルC-200(和光純薬社製)、展開溶媒：トルエン）で精製し、白色結晶として、純度99.4％（高速液体クロマトグラフィーによる面積百分率）の2-(2-ニトロフェニル)-2-シアノ酢酸メチル8.66gを得た(2-クロロニトロベンゼン基準の単離収率：94.0％)。
2-(2-ニトロフェニル)-2-シアノ酢酸メチルの物性値は以下の通りであった。
【００４２】
¹H-NMR(CDCl₃,δ(ppm))；3.85(3H,s)、5.70(1H,s)、7.5〜8.2(3H,m)、8.1〜8.2(1H,m)
【００４３】
実施例１２（3-シアノアントラニルの合成）
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、1,3-ジメチル-2-イミダゾリジノン（25℃における比誘電率37.2）20mlを加え、攪拌しながら130℃まで昇温した。次いで、参考例４で合成した純度99.4％の2-(5-2-ニトロフェニル)-2-シアノ酢酸メチル2.00g(9.03mmol)を1,3-ジメチル-2-イミダゾリジノン10mlに溶解した溶液を、20分間かけてゆるやかに滴下し、同温度で3時間反応させた。反応終了後、室温まで冷却し、反応液にトルエン50ml及び水50mlを加えて攪拌した。有機層を分離し、水50ml、飽和食塩水50mlの順で洗浄した後、減圧下で濃縮した。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：トルエン）で精製し、白色結晶として、純度99.4％（高速液体クロマトグラフィーによる面積百分率）の3-メトキシカルボニル-5-フルオロアントラニル0.79gを得た(2-(2-ニトロフェニル)シアノ酢酸メチル基準の単離収率：60.2％)。
3-シアノアントラニルの物性値は以下の通りであった。
【００４４】
融点；58〜59℃
¹H-NMR(DMSO-d₆,δ(ppm))；7.44〜7.49(1H,m)、7.59〜7.64(1H,m)、7.90〜7.92(1H,m)、7.94〜8.02(1H,m)
【００４５】
【発明の効果】
本発明により、簡便な方法によって、高収率でニトロベンゼン誘導体から3-置換アントラニル誘導体を製造する、工業的に好適な3-置換アントラニル誘導体の製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 3-substituted anthranyl derivative from a nitrobenzene derivative. A 3-substituted anthranyl derivative is a useful compound as a synthetic intermediate for pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
Conventionally, the following method has been disclosed as a method for producing a 3-substituted anthranyl derivative from a nitrobenzene derivative.
(1) A method for producing 3-cyano-5-halogenoanthranyl by reacting 5-halogeno-2-nitrophenylacetonitrile with trimethylsilyl chloride in tetrahydrofuran in the presence of triethylamine is disclosed. However, in this method, the reaction time is long (21 hours when the halogen atom is a fluorine atom, 12 hours when the halogen atom is a chlorine atom), and the yield of the target product is low (33% when the halogen atom is a fluorine atom, chlorine There was a problem of 40% in the case of atoms (see Non-Patent Document 1).
(2) A process for producing methyl 5-chloroanthranyl-3-carboxylate by reacting methyl o-nitromandelate with 4-fold mol of thionyl chloride is disclosed. However, this method has a problem that the post-treatment is complicated because thionyl chloride having high toxicity is excessively used relative to the raw material, and the yield of the target product is as low as 63% (see Non-Patent Document 2). ).
(3) A method for producing 3-cyanoanthranyl in a yield of 6% by heating ethyl 2- (2-nitrophenyl) -2-cyanoacetate at 120 to 160 ° C. without solvent is disclosed. However, this method has a problem that the yield of the target product is extremely low (see Non-Patent Document 3).
(4) A method of reacting diethyl 2- (2-nitrophenyl) malonate in dry xylene for 100 hours to obtain 3-ethoxycarbonylanthranyl in a yield of 63% is disclosed. However, this method has a problem that the reaction time is long and the yield of the target product is low (see Non-Patent Document 4).
[0003]
[Non-Patent Document 1]
Synthesis, 7 , 753 (1997) (p. 754, table)
[Non-Patent Document 2]
J. Heterocycle. Chem., 16 , 1249 (1979) (Page 1251, experimental section)
[Non-Patent Document 3]
Helv. Chim. Acta., 207 , 1748 (1961) (Page 1751, Experimental section)
[Non-Patent Document 4]
J. Chem. Soc., Chem. Commun., 1995 , 2457 (page 2458, Table 1)
[0004]
As described above, there is a problem in any of the methods, and it is not satisfactory as an industrial production method.
[0005]
[Problems to be solved by the invention]
An object of the present invention is to provide an industrially suitable method for producing a 3-substituted anthranyl derivative, which solves the above-described problems and produces a 3-substituted anthranyl derivative from a nitrobenzene derivative in a high yield by a simple method. To do.
[0006]
[Means for Solving the Problems]
An object of the present invention is to solve the general formula (1) in at least one aprotic polar solvent selected from the group consisting of amides and ureas.
[0007]
[Chemical 3]

[0008]
(In the formula, R ¹ and R ² may be the same or different and each represents an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, or a cyano group, and X is a hydrogen atom, a halogen atom, Represents an atom or an alkyl group.)
A nitrobenzene derivative represented by the general formula (2):
[0009]
[Formula 4]

[0010]
(In the formula, R ³ is the same as either R ¹ or R ^2. )
This is solved by a method for producing a 3-substituted anthranyl derivative represented by the following formula.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The nitrobenzene derivative used in the cyclization reaction 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. For example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group Alkoxycarbonyl groups such as heptyloxycarbonyl group, octyloxycarbonyl group, nonyloxycarbonyl group, decyloxycarbonyl group (these groups include various isomers); cyclopropoxycarbonyl group, cyclobutoxycarbonyl group , Cycloalkoxycarbonyl groups such as cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cycloheptyloxycarbonyl group; benzyloxycarbonyl group, phenethyloxycarbonyl group, phenylpropoxy Aralkyloxycarbonyl groups such as sicarbonyl groups and phenylbutoxycarbonyl groups (these groups include various isomers); phenoxycarbonyl groups, tolyloxycarbonyl groups, naphthyloxycarbonyl groups, anthranyloxycarbonyl groups, etc. An aryloxycarbonyl group (these groups include various isomers); a cyano group. X is a hydrogen atom; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, or a nonyl group. , Represents an alkyl group such as a decyl group (note that these groups include various isomers).
[0012]
The nitrobenzene derivative used in the cyclization reaction of the present invention is, for example, the general formula (3)
[0013]
[Chemical formula 5]

[0014]
(In the formula, R ¹ , R ² and X are as defined above.)
(It is described in Reference Examples 1 to 4 later).
[0015]
The aprotic polar solvent used in the cyclization reaction of the present invention is not particularly limited as long as it does not inhibit the reaction, but preferably has a relative dielectric constant of 10 to 50 at 25 ° C. Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as 1,3-dimethyl-2-imidazolidinone; sulfoxides such as dimethyl sulfoxide; sulfolane and the like Sulfones are used. In addition, you may use these solvents individually or in mixture of 2 or more types. The relative dielectric constant is described in, for example, “TECNIQUES OF CHEMISTRY Volume 2 ORGANIC SOLVENTS” (WILLY-INTERSCIENCE).
[0016]
The amount of the solvent used is appropriately adjusted depending on the homogeneity and agitation of the solution, but is preferably 1 to 500 g, more preferably 4 to 50 g based on 1 g of the nitrobenzene derivative.
[0017]
The cyclization reaction of the present invention is performed by, for example, a method of mixing a nitrobenzene derivative and an aprotic polar solvent and reacting with stirring (at this time, the reaction is performed while removing by-produced alcohol if necessary). May be allowed). The reaction temperature at that time is preferably 5 to 300 ° C., more preferably 50 to 180 ° C., and the reaction pressure is not particularly limited, but is preferably normal pressure or reduced pressure.
[0018]
In the cyclization reaction of the present invention, an organic base may be present in order to improve the reaction rate. Examples of the organic base include tertiary amines such as trimethylamine, triethylamine, ethyldiisopropylamine, diethylisopropylamine, triisopropylamine, tributylamine, benzyldimethylamine, and benzyldiethylamine; pyridines such as pyridine, methylpyridine, and dimethylpyridine. Preferably, triethylamine, ethyldiisopropylamine, triisopropylamine, tributylamine, more preferably ethyldiisopropylamine, triisopropylamine are used. In addition, you may use these organic bases individually or in mixture of 2 or more types.
[0019]
The amount of the organic base used is preferably 0.5 to 100 mol, more preferably 1.5 to 10 mol, relative to 1 mol of the nitrobenzene derivative.
[0020]
The cyclization reaction of the present invention gives a 3-substituted anthranyl derivative, which can be obtained by a general method such as filtration, extraction, concentration, recrystallization, crystallization, distillation, column chromatography, etc. after the reaction is completed. Isolated and purified.
[0021]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
[0022]
Reference Example 1 (Synthesis of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel, 4.62 g (83.8 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide and 20 ml of dimethyl sulfoxide were added under an argon atmosphere. % Methyl cyanoacetate 8.37 g (83.8 mmol) was slowly added dropwise over 10 minutes. While maintaining the temperature of the reaction solution at 20 to 30 ° C., 6.76 g (41.6 mmol) of 98% pure 2,4-difluoronitrobenzene was slowly added dropwise over 1 hour, followed by reaction at the same temperature for 6 hours. After completion of the reaction, 10 ml of toluene was added while keeping the temperature of the reaction solution at 10 ° C. or lower in an ice bath, and 41.9 ml (41.19 mmol) of 1 mol / l hydrochloric acid was slowly added dropwise. Then, the organic layer was separated, washed with 50 ml of water and 50 ml of saturated brine in this order, and the organic layer was concentrated under reduced pressure. The obtained concentrated liquid was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene) to obtain white crystals, purity 99.4% (area percentage by high performance liquid chromatography) Of 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate (isolated yield based on 2,4-difluoronitrobenzene: 80.0%).
The physical properties of methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate were as follows.
[0023]
Melting point: 43-44 ° C
EI-MS (m / e); 192 (M-NO ₂ ), CI-MS (m / e); 239 (M + 1)
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.88 (3H, s), 5.71 (1H, s), 7.3 to 7.4 (1H, m), 7.45 to 7.55 (1H, m), 8.3 to 8.4 ( 1H, m)
[0024]
Example 1 (Synthesis of 3-cyano-5-fluoroanthranyl)
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 20 ml of 1,3-dimethyl-2-imidazolidinone (relative permittivity 37.6 at 25 ° C) under argon atmosphere In addition, the temperature was raised to 120 ° C. with stirring. Subsequently, 1.50 g (6.26 mmol) of 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate having a purity of 99.4% synthesized in Reference Example 1 was added to 5 ml of 1,3-dimethyl-2-imidazolidinone. The dissolved solution was dropped slowly over 20 minutes and reacted at the same temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 50 ml of toluene and 50 ml of water were added to the reaction solution and stirred. The organic layer was separated, washed with water (50 ml) and saturated brine (50 ml) in this order, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene), and purified as white crystals, purity 98.9% (area percentage by high performance liquid chromatography) 0.70 g of 3-cyano-5-fluoroanthranyl was obtained (isolated yield based on methyl 2- (5-fluoro-2-nitrophenyl) -2-cyanoacetate: 68.5%).
The physical properties of 3-cyano-5-fluoroanthranyl were as follows.
[0025]
Melting point: 59-60 ° C
¹ H-NMR (DMSO-d ₆ , δ (ppm)); 7.59-7.62 (1H, m), 7.89-7.93 (1H, m), 8.18-8.19 (1H, m)
[0026]
Example 2 (Synthesis of 3-cyano-5-fluoroanthranyl)
The reaction was conducted in the same manner as in Example 1 except that the solvent was changed to N, N-dimethylformamide (relative permittivity 36.7 at 25 ° C.) in Example 1. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 0.65 g of 3-cyano-5-fluoroanthranyl was formed (2- (5-fluoro-2-nitrophenyl)- Reaction yield based on methyl 2-cyanoacetate: 63.7%).
[0027]
Example 3 (Synthesis of 3-cyano-5-fluoroanthranyl)
The reaction was performed in the same manner as in Example 1 except that the solvent was changed to dimethyl sulfoxide (relative permittivity 46.7 at 25 ° C.) in Example 1. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 0.69 g of 3-cyano-5-fluoroanthranyl was formed (2- (5-fluoro-2-nitrophenyl)- Reaction yield based on methyl 2-cyanoacetate: 67.4%).
[0028]
Example 4 (Synthesis of 3-cyano-5-fluoroanthranyl)
The reaction was conducted in the same manner as in Example 1 except that the solvent was changed to N-methylpyrrolidone (relative permittivity 32.0 at 25 ° C.) in Example 1. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 0.71 g of 3-cyano-5-fluoroanthranyl was formed (2- (5-fluoro-2-nitrophenyl)- Reaction yield based on methyl 2-cyanoacetate: 69.4%).
[0029]
Comparative Example 1 (Synthesis of 3-cyano-5-fluoroanthranyl)
In Example 1, the reaction was performed in the same manner as in Example 1 except that the solvent was changed to mixed xylene (relative dielectric constant 2.3 at 25 ° C.). After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 3-cyano-5-fluoroanthranyl was not produced at all.
[0030]
Reference Example 2 (Synthesis of methyl 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate)
Under an argon atmosphere, 2.79 g (51.6 mmol) of sodium methoxide and 15 ml of dimethyl sulfoxide were added to a glass flask having an internal volume of 200 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel, and then stirred at room temperature. Then, 5.16 g (51.6 mmol) of 99% pure methyl cyanoacetate was slowly added dropwise over 5 minutes. Further, 5.00 g (25.8 mmol) of 2,4-dichloronitrobenzene having a purity of 98% was gently added dropwise over 1 hour, followed by reaction at 40 to 48 ° C. for 10 minutes and at 65 ° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added, and 4.30 ml (25.7 mmol) of 6 mol / l hydrochloric acid and 20 ml of water were slowly added dropwise with stirring. Subsequently, the organic layer was separated, washed with 50 ml of saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is 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 obtain 6.11 g of methyl 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate having a purity of 99.0% (area percentage by high performance liquid chromatography) as yellowish crystals (2,4- Isolated yield based on difluoronitrobenzene: 92.0%).
The physical properties of methyl 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate were as follows.
[0031]
Melting point: 98-100 ° C
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.88 (3H, s), 5.68 (1H, s), 7.62 (1H, dd, J = 8.8, 2.2 Hz), 7.77 (1H, d, J = 2.2Hz), 8.21 (1H, d, J = 8.8Hz)
[0032]
Example 7 (Synthesis of 3-cyano-5-chloroanthranyl)
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 20 ml of 1,3-dimethyl-2-imidazolidinone (relative permittivity 37.6 at 25 ° C) under argon atmosphere In addition, the temperature was raised to 120 ° C. with stirring. Next, 1.50 g (5.89 mmol) of 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate having a purity of 99.0% synthesized in Reference Example 2 was added to 5 ml of 1,3-dimethyl-2-imidazolidinone. The dissolved solution was dropped slowly over 20 minutes and reacted at the same temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 50 ml of toluene and 50 ml of water were added to the reaction solution and stirred. The organic layer was separated, washed with water (50 ml) and saturated brine (50 ml) in this order, and then concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene), and purified as white crystals with a purity of 99.0% (area percentage by high performance liquid chromatography) Of 3-cyano-5-chloroanthranyl (isolated yield based on methyl 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate: 60.5%).
The physical properties of 3-cyano-5-chloroanthranyl were as follows.
[0033]
Melting point: 99-100 ° C
¹ H-NMR (DMSO-d ₆ , δ (ppm)); 7.59-7.62 (1H, m), 7.89-7.93 (1H, m), 8.18-8.19 (1H, m)
[0034]
Example 8 (Synthesis of 3-cyano-5-chloroanthranyl)
Add 20 ml of 1,3-dimethyl-2-imidazolidinone (relative permittivity 37.6 at 25 ° C.) to a 200 ml glass flask equipped with a stirrer, thermometer, distillation device and dropping funnel under argon atmosphere The temperature was raised to 120 ° C. with stirring. Next, 1.50 g (5.89 mmol) of 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate having a purity of 99.0% synthesized in Reference Example 2 was added to 5 ml of 1,3-dimethyl-2-imidazolidinone. The dissolved solution was dropped slowly over 20 minutes, and the reaction was allowed to proceed at the same temperature for 3 hours while distilling off the methanol produced as a by-product under reduced pressure (0.003 to 0.006 MPa). After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 0.68 g of 3-cyano-5-chloroanthranyl was formed (2- (5-chloro-2-nitrophenyl)- (Reaction yield based on methyl 2-cyanoacetate: 64.8%).
[0035]
Example 9 (Synthesis of 3-cyano-5-chloroanthranyl)
In a 200 mL glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 20 mL of 1,3-dimethyl-2-imidazolidinone (relative permittivity 37.6 at 25 ° C.) under argon atmosphere and Ethyldiisopropylamine (1.52 g, 11.78 mmol) was added, and the temperature was raised to 120 ° C. with stirring. Next, 1.50 g (5.89 mmol) of 2- (5-chloro-2-nitrophenyl) -2-cyanoacetate having a purity of 99.0% synthesized in Reference Example 2 was added to 5 ml of 1,3-dimethyl-2-imidazolidinone. The dissolved solution was slowly dropped over 20 minutes and reacted at the same temperature for 1 hour. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 0.64 g of 3-cyano-5-chloroanthranyl was formed (2- (5-chloro-2-nitrophenyl)- (Reaction yield based on methyl 2-cyanoacetate: 60.8%).
[0036]
Example 10 (Synthesis of 3-cyano-5-chloroanthranyl)
The reaction was conducted in the same manner as in Example 1 except that the solvent was changed to N-methylpyrrolidone (relative dielectric constant 32.0 at 25 ° C.) in Example 7. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 0.66 g of 3-cyano-5-chloroanthranyl was formed (2- (5-chloro-2-nitrophenyl)- Reaction yield based on methyl 2-cyanoacetate: 63.2%).
[0037]
Reference Example 3 (Synthesis of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate)
Under an argon atmosphere, 3.40 g (62.9 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide were added to a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, and then stirred at room temperature. Then, 8.31 g (62.3 mmol) of dimethyl malonate having a purity of 99% was gradually added dropwise over 5 minutes. Thereafter, the mixture was cooled to 20 ° C., and 5.10 g (31.4 mmol) of 2,4-difluoronitrobenzene was slowly added dropwise over 5 minutes, and reacted at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate 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 30 ml of water and 30 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, 6.55 g of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate having a purity of 97.2% (area percentage by high performance liquid chromatography) was obtained (isolation yield: 75.0%).
The physical properties of dimethyl 2- (5-fluoro-2-nitrophenyl) malonate were as follows.
[0038]
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)
[0039]
Example 11 (Synthesis of 3-methoxycarbonyl-5-fluoroanthranyl)
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 20 ml of 1,3-dimethyl-2-imidazolidinone (relative permittivity 37.6 at 25 ° C) under argon atmosphere In addition, the temperature was raised to 130 ° C. with stirring. Next, 2.00 g (7.37 mmol) of dimethyl 2- (5-fluoro-2-nitrophenyl) -2-malonate having a purity of 99.4% synthesized in Reference Example 3 was added to 10 ml of 1,3-dimethyl-2-imidazolidinone. The dissolved solution was dropped slowly over 20 minutes and reacted at the same temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 50 ml of toluene and 50 ml of water were added to the reaction solution and stirred. The organic layer was separated, washed with water (50 ml) and saturated brine (50 ml) in this order, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene), and purified as white crystals with a purity of 99.4% (area percentage by high performance liquid chromatography) ) Of 3-methoxycarbonyl-5-fluoroanthranyl was obtained (isolated yield based on dimethyl 2- (5-fluoro-2-nitrophenyl) malonate: 63.2%).
The physical properties of 3-methoxycarbonyl-5-fluoroanthranyl were as follows.
[0040]
Melting point: 131-132 ° C
¹ H-NMR (DMSO-d ₆ , δ (ppm)); 4.01 (3H, s), 7.54 to 7.56 (1H, m), 7.57 to 7.58 (1H, m), 7.99 to 8.03 (1H, m)
[0041]
Reference Example 4 (Synthesis of methyl 2- (2-nitrophenyl) -2-cyanoacetate)
To a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel, 4.62 g (83.8 mmol) of sodium methoxide and 20 ml of dimethyl sulfoxide and 20 ml of dimethyl sulfoxide were added under an argon atmosphere. % Methyl cyanoacetate 8.37 g (83.8 mmol) was slowly added dropwise over 10 minutes. While maintaining the temperature of the reaction solution at 20-30 ° C., 6.68 g (41.6 mmol) of 2-chloronitrobenzene having a purity of 98% was slowly dropped over 1 hour, followed by reaction at 60 ° C. for 3 hours. After completion of the reaction, 10 ml of toluene was added while keeping the temperature of the reaction solution at 10 ° C. or lower in an ice bath, and 41.9 ml (41.19 mmol) of 1 mol / l hydrochloric acid was slowly added dropwise. Then, the organic layer was separated, washed with 50 ml of water and 50 ml of saturated brine in this order, and the organic layer was concentrated under reduced pressure. The obtained concentrated liquid was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene) to obtain white crystals, purity 99.4% (area percentage by high performance liquid chromatography) ) Of methyl 2- (2-nitrophenyl) -2-cyanoacetate was obtained (isolated yield based on 2-chloronitrobenzene: 94.0%).
The physical properties of methyl 2- (2-nitrophenyl) -2-cyanoacetate were as follows.
[0042]
¹ H-NMR (CDCl ₃ , δ (ppm)); 3.85 (3H, s), 5.70 (1H, s), 7.5 to 8.2 (3H, m), 8.1 to 8.2 (1H, m)
[0043]
Example 12 (Synthesis of 3-cyanoanthranyl)
In a 200 ml glass flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel, 20 ml of 1,3-dimethyl-2-imidazolidinone (relative permittivity 37.2 at 25 ° C) under argon atmosphere In addition, the temperature was raised to 130 ° C. with stirring. Subsequently, 2.00 g (9.03 mmol) of 2- (5-2-nitrophenyl) -2-cyanoacetate having a purity of 99.4% synthesized in Reference Example 4 was dissolved in 10 ml of 1,3-dimethyl-2-imidazolidinone. The solution was dripped gently over 20 minutes and reacted at the same temperature for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 50 ml of toluene and 50 ml of water were added to the reaction solution and stirred. The organic layer was separated, washed with water (50 ml) and saturated brine (50 ml) in this order, and then concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: toluene), and purified as white crystals with a purity of 99.4% (area percentage by high performance liquid chromatography) ) Was obtained 0.79 g of 3-methoxycarbonyl-5-fluoroanthranyl (isolated yield based on methyl 2- (2-nitrophenyl) cyanoacetate: 60.2%).
The physical properties of 3-cyanoanthranyl were as follows.
[0044]
Melting point: 58-59 ° C
¹ H-NMR (DMSO-d ₆ , δ (ppm)); 7.44-7.49 (1H, m), 7.59-7.64 (1H, m), 7.90-7.92 (1H, m), 7.94-8.02 (1H, m )
[0045]
【The invention's effect】
INDUSTRIAL APPLICABILITY According to the present invention, an industrially suitable method for producing a 3-substituted anthranyl derivative, which produces a 3-substituted anthranyl derivative from a nitrobenzene derivative in a high yield by a simple method, can be provided.

Claims (2)

In at least one aprotic polar solvent selected from the group consisting of amides and ureas, the general formula (1)

Wherein R1 and R2 may be the same or different and each represents an alkoxycarbonyl group, a cycloalkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group or a cyano group, and X is a hydrogen atom, a halogen atom or A nitrobenzene derivative represented by the general formula (2):

(Wherein R 3 is the same as either R 1 or R 2, and X is as defined above). Aprotic polar solvents, N, N- dimethylformamide, N, N- dimethylacetamide, to claim 1 is at least one solvent selected from N- methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone A process for producing the described 3-substituted anthranyl derivative.