JP4302974B2 - Method for producing oxazole compound - Google Patents

Description

【０００５】
しかしながら、本法は、Ｌ−アスパラギン酸のモノベンジルエステルの入手が困難であること、アセチル基からベンゾイル基への変換が必要であること、ベンジルエステル基からメチルエステル基への変換が必要であること等、工業的な製造方法として問題がある。また、Ｊ．Ｍｅｄ．Ｃｈｅｍ．，３５巻、１４号、２６２５ページ（１９９２年）には、以下の合成方法が開示されている
１）アスパラギン酸のβーモノメチルエステルのベンゾイル化によるＮ−ベンゾイルアスパラギン酸モノメチルエステルの合成
２）該化合物のアセチル化、脱炭酸によるＮ−ベンゾイルアミノケトカルボ ン酸メチルエステルの合成
３）該化合物のオキシ塩化リンによる脱水閉環反応による、２−（５−メチル−２−フェニル−４−オキサゾリル）酢酸メチルエステルの合成
【化６１】

【０００６】
しかしながら、本法は、Ｌ−アスパラギン酸のモノメチルエステルの入手が困難であること、後述するように、アセチル化、脱炭酸反応が円滑に進行しない等、工業的な製造方法として問題がある。さらに、特開平１２−１４３６４３号公報には、前述の方法の改良法が開示されている。しかしながら、本法も、入手が困難なＬ−アスパラギン酸のモノメチルエステルを出発原料に用いていること、アセチル化、脱炭酸反応が円滑に進行しないこと、ｐ−トルエンスルホン酸を用いる反応では、オキサゾール環の生成が困難であること、等の問題があった。
【０００７】
【特許文献１】
米国特許５，７２８，７２０号
【０００８】
【特許文献２】
特開平１２−１４３６４３号
【０００９】
【非特許文献１】
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，３５巻、１４号、2625ページ（1992年）
【００１０】
【発明が解決しようとする課題】
本発明は、入手の容易なアスパラギン酸を出発原料として、簡便かつ安価な、２−（５−メチル−２−アリール−４−オキサゾリル）酢酸誘導体の製造方法を提供することを課題としている。
【００１１】
【課題を解決するための手段】
本発明者らは、特開平１２−１４３６４３号公報記載の合成ルートを考察し、２−（５−メチル−２−アリール−４−オキサゾリル）酢酸誘導体合成のための初期の中間体である、化学式（１０）（ただし、Ｌ体、Ｄ体、ラセミ体のいずれであってもよく、Ａｒは置換アリールまたは無置換アリール、Ｒは低級アルキル基を表す）
【化６２】

で表されるＮ−アリールカルボニルアスパラギン酸エステルに注目した。本中間体の合成方法を鋭意検討し、入手容易なアスパラギン酸を出発原料とし、これを塩基の存在下に塩化ベンゾイルと反応させることにより、化学式（１）（ただし、Ｌ体、Ｄ体、ラセミ体のいずれであってもよく、Ａｒは置換アリールまたは無置換アリールを表す）
【化６３】

で表されるＮ−アリールカルボニルアスパラギン酸を合成し、これを無水酢酸中で処理することにより、化学式（２）（ただし、Ｌ体、Ｄ体、ラセミ体のいずれであってもよく、Ａｒは置換アリールまたは無置換アリールを表す）
【化６４】

で表されるＮ−アリールカルボニルアスパラギン酸無水物が得られた。環状酸無水物のアルコール分解によって、ジカルボン酸のモノエステルが得られることは良く知られている。しかしながら、化学式（２）で表されるＮ−アリールカルボニルアスパラギン酸無水物の場合、所望の化学式（１０）で表されるＮ−アリールカルボニルアスパラギン酸−β−モノエステルと不要のＮ−アリールカルボニルアスパラギン酸−α−モノエステルの２種の化合物の生成が考えられる。本発明者らは、本反応を試行し、所望のモノエステルが比較的良好な収率で得られることを発見した。
【００１２】
ついで、該モノエステルを用いて、特開平１２−１４３６４３号公報記載の方法で、アセチル化、脱炭酸を試みたところ、所望のＮ−アリールカルボニルアミノ−α−アセチル−β−カルボン酸エステルは得られなかった。
【００１３】
α−アミノ酸を塩基存在下にアシル化条件で処理すると、以下に示すように、
【化６５】

１）アミノ酸のアミノ基のアシル化
２）アズラクトン環の生成
３）アズラクトン環のα位のアシル化
４）脱炭酸
が連続的に生じ、Ｎ−アシルアミノ−α−ケトンが得られることは、Ｄａｋｉｎ−Ｗｅｓｔ反応として良く知られている。本発明者らは、化学式（１０）で表されるＮ−アリールカルボニルアスパラギン酸−β−モノエステルを原料として、アシル化剤として無水酢酸を用い、種々の条件でＤａｋｉｎ−Ｗｅｓｔ反応を試みたところ、選択された条件で、アズラクトン環のα−位がアセチル化された、化学式（１１）
【化６６】

で表されるアセチルアズラクトン化合物（Ａｒは置換アリールまたは無置換アリール、Ｒは低級アルキル基を表す）が得られることを見いだした。該化合物は安定であり、脱炭酸が進行しにくく、所望の化学式（８）で表されるケトカルボン酸エステルを得ることは困難であった。このため、化学式（１１）で表されるアセチルアズラクトン化合物を加水分解することで、化学式（１２）
【化６７】

で表されるＮ−アリールカルボニル−α−アセチルアスパラギン酸モノエステル（Ａｒは置換アリールまたは無置換アリール、Ｒは低級アルキル基を表す）を得た。ついで、該化合物の脱炭酸を試行したところ、驚くべきことに、得られた生成物は所望の化学式（８）で表されるケトカルボン酸エステルではなく、化学式（３）
【化６８】

で表される新規なラクトン化合物（Ａｒは置換アリールまたは無置換アリールを表す）および化学式（９）で表されるケトカルボン酸であった。これらの２種の化合物は、水性溶媒中から化学式（３）で表される新規なラクトン化合物を優先的に晶析させることで、容易に分離できることを見いだした。
【００１４】
本発明者らは、前述の反応で得られた２種の脱炭酸生成物を中間体として、最終的な目的化合物である、化学式（７）
【化６９】

で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（Ａｒは置換アリールまたは無置換アリール、Ｒは低級アルキル基を表す）の合成について鋭意検討を進めた。式（３）で表される新規なラクトン化合物は、化学式（９）
【化７０】

で表されるケトカルボン酸の脱水生成物（ただし、Ｌ体、Ｄ体、ラセミ体のいずれであってもよく、Ａｒは置換アリールまたは無置換アリール、Ｒは低級アルキル基を表す）であり、なおかつ、式（６）
【化７１】

で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（Ａｒは置換アリールまたは無置換アリールを表す）の等価体とみなせる。本発明者らは、ラクトン化合物は酸性化合物で処理することで、環開裂とオキサゾール環への再環化により、所望の化学式（６）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸へと変換できること、および、該化合物をエステル化することにより、化学式（７）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステルが得られることを見いだした。
【００１５】
また、化学式（３）で表される新規なラクトン化合物は、適当な条件で加水分解することにより、化学式（９）で表されるケトカルボン酸へと誘導可能なことを見いだした。
【００１６】
一方、化学式（９）で表されるケトカルボン酸化合物は、エステル化することにより、化学式（８）で表されるケトカルボン酸エステルに誘導できることを見いだした。該エステルは、公知の方法により、所望の化学式（７）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステルへと誘導できる。本発明の概要を以下に示す。なお、Ａｒは置換アリールまたは無置換アリールを、Ｒはメチル基、エチル基、プロピル基、ブチル基などの低級アルキル基を表している。
【００１７】
【化７２】

【００１８】
本発明者らは、さらに簡便な２−（５−メチル−２−アリール−４−オキサゾリル）酢酸誘導体の製造法について検討をおこなった。すなわち、前述したように、化学式（１０）で表されるＮ−アリールカルボニルアスパラギン酸モノエステルを中間体としてＤａｋｉｎ−Ｗｅｓｔ反応をおこなって、最終的に得られる化学式（９）で表されるケトカルボン酸化合物は、α位のカルボン酸が脱炭酸した化合物であることに着目した。例えば、化学式（１）で表されるＮ−アリールカルボニルアスパラギン酸のような、α、β−ジカルボン酸をＤａｋｉｎ−Ｗｅｓｔ反応条件下に処理した場合、α位のアシル化を経てα位のカルボキシル基の選択的な脱炭酸が可能であれば、化学式（９）で表されるケトカルボン酸が生成することが期待できる。該化合物は、前述したように、エステル化することで、既知の化学式（８）で表されるケトカルボン酸エステルに誘導できる。しかるに、これまで、化学式（１）で表されるＮ−アリールカルボニルアスパラギン酸を基質としてＤａｋｉｎ−Ｗｅｓｔ反応をおこなった例は知られていない。
【００１９】
類似の反応として、アスパラギン酸を、無水酢酸、およびピリジン中で反応させた例がＤａｋｉｎ、およびＷｅｓｔによって報告されている（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，７８．７４５（１９２８））。彼らは、本反応は中間体としてβ−アセトアミノ−γ−アセトキシ−γ−バレロラクトンを経由し、該化合物の加水分解体として最終的に、β−アセチルアミノレブリン酸が得られることを報告している。
【００２０】
【化７３】

【００２１】
後者の化合物は、化学式（９）で表されるケト酸のアセチル類縁体である。しかしながら、これらの化合物は単離されておらず、その物理的性質は示されていないことから、あくまで推定された生成物と言わざるを得ない。すなわち、Ｎ−アリールカルボニルアスパラギン酸を基質として使用した場合のＤａｋｉｎ−Ｗｅｓｔ反応の生成物については、彼らの報告から推定は可能なものの、単離、同定はされていない。本発明者らは、この点について鋭意検討を進めた結果、本発明を完成するに至った。
【００２２】
本発明者らは、化学式（１）で表されるＮ−アリールカルボニルアスパラギン酸を基質として、種々の条件でＤａｋｉｎ−Ｗｅｓｔ反応を試みた。最初に、塩基の非存在下に無水酢酸との反応を試みたところ、化学式（２）で表されるＮ−アリールカルボニルアスパラギン酸無水物が得られた。ついで、該化合物を塩基性条件下に無水酢酸で処理し、生成物を詳細に検討したところ、当初予想した、化学式（９）で表されるケトカルボン酸化合物は生成せず、新規な３種の化合物が生成していることを見いだした。３種の化合物のうちの１種は、既に述べた化学式（３）で表されるラクトン化合物であり、他の１種は化学式（４）で表されるアセチルアズラクトン化合物であり、さらに他の１種は化学式（４）で表されるアセチルアズラクトン化合物のさらなるアセチル化生成物である、化学式（５）で表されるジアセチルアズラクトン化合物であることが判明した。これらの化合物は、前述のの文献でＤａｋｉｎ、およびＷｅｓｔが提示した、β−アシルアミノ−γ−アセトキシ−γ−バレロラクトンとは全く異なる構造を有しており、本発明者らによって初めて発見されたものである。
【００２３】
既に述べたように、化学式（３）で表される新規なラクトン化合物は、化学式（６）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸、および化学式（７）で表される該化合物のエステルへの誘導が可能である。一方、化学式（４）で表される新規なアセチルアズラクトン化合物、および化学式（５）で表される新規なジアセチルアズラクトン化合物について、その反応性は未知である。本発明者らは、式一般（４）で表されるアセチルアズラクトン化合物も、既に、α位のアセチル化、α位のカルボキシル基の脱炭酸、および脱水反応が既に終了しており、化学式（６）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸の等価体として利用できるのではないかと考えた。さらに、化学式（５）で表される新規なジアセチルアズラクトン化合物は化学式（４）で表されるアセチルアズラクトン化合物のさらなるアセチル体であり、脱アセチル条件下で化学式（４）で表されるアセチルアズラクトン化合物を生成するものと考え、鋭意、検討を続けた結果、これらの化合物は、特定の酸性化合物の存在下に処理することで、環の再構成が進行し、所望の、化学式（６）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸を与えること、加水分解することで、化学式（９）で表されるケトカルボン酸を与えることを見いだし、本発明を完成するに至った。本発明の概要を以下に示す。
【００２４】
【化７４】

【００２５】
【発明の効果】
本発明によれば、入手の容易なアスパラギン酸を出発原料として、簡便かつ安価に２−（５−メチル−２−アリール−４−オキサゾリル）酢酸誘導体を製造することができる。
【００２６】
【発明の実施の形態】
本発明の内容を、さらに詳細に説明する。
化学式（１）
【化７５】

で表されるＮ−アリールカルボニルアスパラギン酸のＡｒは置換アリールまたは無置換アリールであって、置換基としてはハロゲン基（フルオロ、クロロ、ブロモ、ヨード）、アルキル基（メチル、エチル、プロピル、ブチルなど）、ニトロ基などが、副反応を伴わないため好ましい。
【００２７】
Ｎ−アリールカルボニルアスパラギン酸（１）よりＮ−アリールカルボニルアスパラギン酸無水物（２）を生成させる反応は、Ｎ−アリールカルボニルアスパラギン酸（１）１モルに対して０．９〜１０モル、好ましくは１．０〜５．０モル、より好ましくは１．０〜２．０モルの無水酢酸を用い、室温〜110℃、好ましくは70〜110℃、より好ましくは80〜100℃で行われる。反応溶媒は用いても用いなくてもよく、反応液の流動性・容積効率・収率等を考慮して、酢酸又は芳香族炭化水素、例えばベンゼン、トルエン、エチルベンゼン、クメン、キシレン、メシチレン、モノクロロベンゼン、ジクロロベンゼン等から適切な溶媒を選ぶことが出来る。この際に用いられる反応溶媒の使用量も特に制限は無いが反応液の流動性・容積効率・収率等を考慮して、Ｎ−アリールカルボニルアスパラギン酸重量を基準にして、好ましくは0.5〜10倍、より好ましくは2〜5倍量で用いられる。このＮ−アリールカルボニルアスパラギン酸無水物の反応液を冷却して、Ｎ−アリールカルボニルアスパラギン酸無水物（２）を固液分離して取り出すことが出来る。Ｎ−アリールカルボニルアスパラギン酸無水物（２）を単離することなく、反応液をそのまま用いて次のラクトン化合物（３）、アセチルアズラクトン化合物式（４）及びジアセチルアズラクトン化合物（５）を生成させる反応、又はＮ−アリールカルボニルアスパラギン酸モノエステル（１０）を生成させる反応に使用することが出来る。
【００２８】
Ｎ−アリールカルボニルアスパラギン酸無水物（２）よりラクトン化合物（３）、アセチルアズラクトン化合物式（４）及びジアセチルアズラクトン化合物（５）を生成させる反応は、Ｎ−アリールカルボニルアスパラギン酸無水物１モルに対して無水酢酸１．０〜１０モル、好ましくは１．０〜５．０モル、より好ましくは１．０〜２．０モルと塩基０．００１モル〜１０モル、好ましくは０．０１〜１モル、より好ましくは０．０２〜０．５モルを用いる。塩基としてはトリエチルアミン、ジイソプロピルエチルアミン、トリーｎ−ブチルアミン、ピリジン、２−ピコリン、３−ピコリン、４−ピコリン、２，３−ルチジン、２，４−ルチジン、２，５−ルチジン、２，６−ルチジン、３，４−ルチジン、３，５−ルチジン、２，４，６−コリジン、１−メチルピペリジン、４−ジメチルアミノピリジン、１−メチルモルフォリン、水酸化カリウム、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸水素ナトリウム、酢酸カリウム、酢酸ナトリウム等の有機及び無機の塩基を使用することが出来る。反応温度は室温〜120℃、好ましくは50〜110℃、より好ましくは80〜100℃で行われる。このラクトン化合物（３）、アセチルアズラクトン化合物式（４）及びジアセチルアズラクトン化合物（５）の反応液は、そのまま次の反応に供してもよい。一方、反応液を冷却晶析又は濃縮後冷却晶析して、固液分離して取り出し、単独でそれぞれの反応に供してもよい。この反応液を濃縮し酢酸、無水酢酸及び溶媒を溜去すると化学式（３）で表されるラクトン化合物、化学式（４）で表されるアセチルアズラクトン化合物及び化学式（５）で表されるジアセチルアズラクトン化合物が得られ、これは２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成させる反応、及びケトカルボン酸エステル（８）及び２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応に使用することが出来る。
【００２９】
ラクトン化合物（３）より２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルを用いる。反応温度は５０℃〜１５０℃、好ましくは８０℃〜１３０℃、より好ましくは１００〜１２５℃で行われる。この反応液を水等に分散して析出した結晶を固液分離して取り出せばよい。この反応液をそのまま２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応に使用することも出来る。
【００３０】
アセチルアズラクトン化合物式（４）より２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルを用いる。反応温度は５０℃〜１５０℃、好ましくは８０℃〜１３０℃、より好ましくは１００〜１２５℃で行われる。この反応液を水等に分散して析出した結晶を固液分離して取り出せばよい。この反応液をそのまま２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応に使用することも出来る。
【００３１】
ジアセチルアズラクトン化合物（５）より２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルを用いる。反応温度は５０℃〜１５０℃、好ましくは８０℃〜１３０℃、より好ましくは１００〜１２５℃で行われる。この反応液を水等に分散して析出した結晶を固液分離して取り出せばよい。この反応液をそのまま２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応に使用することも出来る。
【００３２】
ラクトン化合物（３）、アセチルアズラクトン化合物式（４）及びジアセチルアズラクトン化合物（５）を含む反応混合物より２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルを用いる。反応温度は５０℃〜１５０℃、好ましくは８０℃〜１３０℃、より好ましくは１００〜１２５℃で行われる。この反応液を水等に分散して析出した結晶を固液分離して取り出せばよい。前述した化学式（６）で表される２−（５−メチル−２−アリール−４−オキサゾリル）酢酸を単離することなく反応液をそのまま２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応に使用する時は２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）１．０モルに対して低級アルコール５〜１００モル、好ましくは１０〜５０モル、より好ましくは２０〜３０モルを用いる。反応温度は４０〜７０℃、好ましくは６０〜７０℃である。低級アルコールとしてはメタノール、エタノール、プロパノール、ブタノールなどを好ましく用いることができる。
【００３３】
アセチルアズラクトン化合物式（４）よりケトカルボン酸エステル（８）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルと低級アルコール５〜１００モル、好ましくは１０〜５０モル、より好ましくは２０〜３０モルを用いる。反応温度は４０℃〜７０℃、好ましくは６０℃〜７０℃で行われる。この反応液を濃縮し水、トルエン等に分散し溶媒抽出、抽出層を濃縮することでケトカルボン酸エステル（８）の結晶を析出させ固液分離することが出来る。
【００３４】
ジアセチルアズラクトン化合物式（５）よりケトカルボン酸エステル（８）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルと低級アルコール５〜１００モル、好ましくは１０〜５０モル、より好ましくは２０〜３０モルを用いる。反応温度は４０℃〜７０℃、好ましくは６０℃〜７０℃で行われる。この反応液を濃縮し水、トルエン等に分散し溶媒抽出、抽出層を濃縮することでケトカルボン酸エステル（８）の結晶を析出させ固液分離することが出来る。
【００３５】
ラクトン化合物（３）、アセチルアズラクトン化合物式（４）及びジアセチルアズラクトン化合物（５）を含む濃縮液よりケトカルボン酸エステル（８）及び２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応は、反応基質１．０モルに対して硫酸０．１〜５モル、好ましくは０．２〜２モル、より好ましくは０．３〜１．０モルと低級アルコール５〜１００モル、好ましくは１０〜５０モル、より好ましくは２０〜３０モルを用いる。反応温度は４０℃〜７０℃、好ましくは６０℃〜７０℃で行われる。この反応液を濃縮し水、トルエン等に分散し溶媒抽出、抽出層を濃縮することでケトカルボン酸エステル（８）の結晶を析出させ固液分離することが出来る。固液分離した母液を濃縮すると２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）が得られる。
【００３６】
Ｎ−アリールカルボニルアスパラギン酸無水物（２）よりＮ−アリールカルボニルアスパラギン酸モノエステル（１０）を生成させる反応は、Ｎ−アリールカルボニルアスパラギン酸無水物（２）１モルに対して低級アルコール０．５〜２モル、好ましくは０．８〜１．２モル、より好ましくは１．０モルを用いる。反応温度は室温〜100℃、好ましくは50〜90℃、より好ましくは60〜80℃で行われる。この反応液は生成物を単離することなくアセチルアズラクトン化合物（１１）を生成させる反応に用いることが出来る。Ｎ−アリールカルボニルアスパラギン酸モノエステル（１０）１．０モルに対して無水酢酸０．５〜２０モル、好ましくは１．０〜１５モル、より好ましくは２．０〜１０モルと塩基０．００１モル〜２０モル、好ましくは０．０１〜１０モル、より好ましくは０．１〜５モルを用いる。塩基としてはトリエチルアミン、ジイソプロピルエチルアミン、トリーｎ−ブチルアミン、ピリジン、２−ピコリン、３−ピコリン、４−ピコリン、２，３−ルチジン、２，４−ルチジン、２，５−ルチジン、２，６−ルチジン、３，４−ルチジン、３，５−ルチジン、２，４，６−コリジン、１−メチルピペリジン、４−ジメチルアミノピリジン、１−メチルモルフォリン、水酸化カリウム、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸水素ナトリウム、酢酸カリウム、酢酸ナトリウム等の有機及び無機の塩基を使用することが出来る。反応温度は室温〜120℃、好ましくは50〜110℃、より好ましくは70〜100℃で行われる。この反応液を濃縮後、水等の溶媒を加え、析出したアセチルアズラクトン化合物（１１）を固液分離することができる。反応液は生成物を単離することなくＮ−アリールカルボニル-α-アセチルアスパラギン酸モノエステル（１２）を生成させる反応に用いることも出来る。
【００３７】
アセチルアズラクトン化合物（１１）よりＮ−アリールカルボニル-α-アセチルアスパラギン酸モノエステル（１２）を生成させる反応はアセチルアズラクトン化合物（１１）１．０モルに対して水０．５〜２．０モル、好ましくは０．８〜１．２モル、より好ましくは１．０モルを用いる。反応温度は室温〜100℃、好ましくは50〜90℃、より好ましくは60〜80℃で行われる。この反応液をそのままラクトン化合物（３）を生成させる反応に用いることが出来る。一方反応液を濃縮、抽出等の操作を施し固液分離することにより所望の式（１２）であらわされるＮ−アリールカルボニル-α-アセチルアスパラギン酸モノエステルを取り出してもよい。
【００３８】
Ｎ−アリールカルボニル-α-アセチルアスパラギン酸モノエステル（１２）よりラクトン化合物（３）及びケトカルボン酸（９）を生成させる反応はＮ−アリールカルボニル-α-アセチルアスパラギン酸モノエステル（１２）を酸性化合物の存在下に反応する。酸性化合物の使用量には特に制限はなく反応液の流動性・容積効率・収率等を考慮して選べばよい。反応温度は50〜200℃、好ましくは100〜180℃、より好ましくは130〜150℃で行われる。反応液を濃縮し水を加えて析出したラクトン化合物（３）を固液分離して取り出すことができる。ラクトン化合物（３）を固液分離した分離母液を静置すると結晶が析出するのでこれを固液分離することでケトカルボン酸（９）の取り出しも可能である。この反応液をそのまま又は濃縮し２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成させる反応に用いることも出来る。
【００３９】
ケトカルボン酸（９）よりケトカルボン酸エステル（８）を生成させる反応は、反応基質１．０モルに対して硫酸、塩酸の様な酸性化合物０．００１〜５モル、好ましくは０．０１〜２モル、より好ましくは０．１〜０．５モルと低級アルコール３〜１００モル、好ましくは５〜５０モル、より好ましくは７〜３０モルを用いる。反応温度は４０℃〜７０℃、好ましくは６０℃〜７０℃で行われる。反応液を濃縮し水、トルエン等に分散し溶媒抽出、抽出層を濃縮することでケトカルボン酸エステル（８）の結晶を析出させ固液分離することが出来る。反応液を濃縮し２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成する反応に用いることが出来る。
【００４０】
２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）より２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応は、反応基質１．０モルに対して硫酸、塩酸の様な酸性化合物０．００１〜５モル、好ましくは０．０１〜２モル、より好ましくは０．１〜０．５モルと低級アルコール３〜１００モル、好ましくは５〜５０モル、より好ましくは７〜３０モルを用いる。反応温度は４０℃〜７０℃、好ましくは６０℃〜７０℃で行われる。この反応液を濃縮し水、トルエン等に分散し溶媒抽出、抽出層を濃縮することで２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を単離する事が出来る。
【００４１】
ラクトン化合物（３）及びケトカルボン酸（９）生成反応液より２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）を生成させる反応は、反応基質１．０モルに対して硫酸、塩酸等の様な酸性化合物０．００１〜５モル、好ましくは０．０１〜２モル、より好ましくは０．１〜０．５モルと低級アルコール３〜１００モル、好ましくは５〜５０モル、より好ましくは７〜３０モルを用いる。反応温度は４０℃〜７０℃、好ましくは６０℃〜７０℃で行われる。反応液を濃縮し水、トルエン等に分散し溶媒抽出することで２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）とケトカルボン酸エステル（８）の混合物を得ることが出来る。この混合物１．０モルに対してオキシ塩化リン０．０１〜２モル、好ましくは０．１〜１．０モル、より好ましくは０．２〜０．８モルを用いて、反応温度５０〜１２０℃、好ましくは８０〜１２０℃、より好ましくは９０〜１１０℃で反応することによりケトカルボン酸エステル（８）を２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）にする事が出来る。この反応液を水、トルエン等に分散し溶媒抽出・濃縮することで２−（５−メチル−２−アリール−４−オキサゾリル）酢酸エステル（７）が得らる。
【００４２】
ラクトン化合物（３）よりケトカルボン酸（９）を生成する反応は、ラクトン化合物を水に分散し、水の量に制限はなく流動性・容積効率・収率を考慮し得らぶことが出来る。ラクトン化合物（３）１．０モルに対してアルカリ（例えば水酸化ナトリウム）０．５〜１０モル、好ましくは０．０．９〜２モル、より好ましくは１．０〜１．５モルを用い。反応温度は室温℃〜１００℃、好ましくは４０℃〜８０℃、より好ましくは５０〜７０℃で行われる。この反応液を硫酸等で酸性化し析出した結晶を固液分離しケトカルボン酸（９）が得られる。
【００４３】
アセチルアズラクトン化合物（４）及びジアセチルアズラクトン化合物（５）よりケトカルボン酸化合物（９）を生成する反応は、アセチルアズラクトン化合物（４）及びジアセチルアズラクトン化合物（５）を水に分散して行う。このときの水の量は流動性、容積効率、収率を考慮して適当な量とすることができる。硫酸、塩酸、酢酸のような酸性化合物の存在下に加水分解を行ってもよい。反応温度は０〜１００℃、好ましくは４０〜９０℃、さらには６０〜８０℃で行われることが好ましい。この反応液を冷却し析出した結晶を固液分離することによりケトカルボン酸化合物（９）を得ることができる。
【００４４】
ケトカルボン酸（９）よりアセチルアズラクトン化合物（４）を生成する反応は、ケトカルボン酸（９）を酢酸又はトルエン等の芳香族炭化水素に分散し、その使用量に制限はなく流動性・容積効率・収率を考慮し選ぶことが出来る。ケトカルボン酸（９）１．０モルに対し無水酢酸０．５〜２０モル、好ましくは１．０〜１０モル、より好ましくは１．５〜８モルを用いる。P-トルエンスルホン酸等の酸は使用する酸に応じてケトカルボン酸（９）１．０重量に対し０．０００１重量〜１０．０重量の範囲で使用する。反応温度は室温℃〜１２０℃、好ましくは５０℃〜１００℃、より好ましくは６０〜８０℃で行われる。反応液を濃縮液し水を加え析出した結晶をを固液分離しアセチルアズラクトン化合物（４）が得られる。反応液を濃縮することで生成物を単離することなく２−（５−メチル−２−アリール−４−オキサゾリル）酢酸（６）を生成する反応に用いることも出来る。
【００４５】
次に本発明を実施例によって詳細に説明するが、ここに述べる実施例は本発明を説明するためのもので、本発明を限定するものと解してはならない。
【００４６】
【実施例】
（実施例１）
L-アスパラギン酸からN-ベンゾイルアスパラギン酸(1)の合成
Ｌ-アスパラギン酸66.6gを水320gに分散した。このスラリー液を攪拌しながら、20〜30℃で48％水酸化ナトリウム水溶液を滴下し、系内のｐＨを9.5〜10.0に調整した。この溶液を攪拌しながら、塩化ベンゾイル70.3ｇを20〜30℃で、系内のｐＨを9.5〜10.5に保ちながら３時間かけて加えた。系内のｐＨを9.5〜10.5で20〜30℃で１時間攪拌後、40〜45℃で12wt％塩酸水溶液（306.3g）に反応液を分散させた。スラリー液を20〜25℃に冷却し、濾過後、結晶を水200gで洗浄した。得られた結晶を乾燥し、N-ベンゾイルアスパラギン酸(1)114.0gを得た。収率96％
mp 180.5-182.0℃(dec.)
MS ESI(neg) m/z 236[M-H]
IR(KBr) ν=3323(NH), 2940(OH), 1706(C=O), 1649(C=O, amide)
¹H-NMR(DMSO, ppm) δ=2.78, 2.91(2H, ABX system, J_AB=16.6 Hz, J_AX=5.8 Hz, J_BX=7.8 Hz, CH₂), 4.80(1H, q, J_AX=5.8 Hz, J_BX=7.8 Hz, CH), 7.83-7.86(5H, aromatic H), 8.73(1H, d, J=7.8 Hz, NH), 12.56(2H, br, CO₂H)
【００４７】
（実施例２）
N-ベンゾイルアスパラギン酸(1)からN-ベンゾイルアスパラギン酸無水物(2)の合成
N-ベンゾイルアスパラギン酸(1)103.4gを酢酸206.8g、無水酢酸229.4gの混合液に分散した。87〜89℃で４時間攪拌後６℃に冷却し、濾過後、結晶をｔ-ブチル-メチルエーテル101.8gで洗浄した。得られた結晶を乾燥し、N-ベンゾイルアスパラギン酸無水物(2)88.9gを得た。収率93％
式(2)N-ベンゾイル-L-アスパラギン酸無水物
mp 198.6-204.6℃(dec.)
MS (APCI) m/z 220[M+H], 252[M+H+MeOH]
IR(KBr) ν=3328(NH), 1864(C=O), 1784(C=O)
¹H-NMR(DMSO-d₆, ppm) δ=3.02, 3.32(2H, ABX system, J_AB=18.6 Hz, J_AX=10.0 Hz, J_BX=5.8 Hz, CH₂), 4.83(1H, J_AX=10.0 Hz, J_BX=5.8 Hz, CH), 7.4-7.9(5H, arom H), 9.49(1H, d, J=7.0 Hz, NH)
【００４８】
（実施例３）
N-ベンゾイルアスパラギン酸(1)からN-ベンゾイルアスパラギン酸モノメチルエステル(10)の合成
N-ベンゾイルアスパラギン酸(1)95.0gを酢酸190.0g、無水酢酸212.4gの混合液に分散した。87〜89℃で４時間攪拌後65〜70℃に冷却し、メタノールを３時間かけて添加した。さらに同温度範囲で６時間攪拌を行い均一な溶液とした。その後、減圧濃縮を行い溶媒を除去した後、酢酸エチルから再結晶し、N-ベンゾイルアスパラギン酸モノメチルエステル(10)45.0gを得た。収率45％
mp 121-122℃(AcOEt)
MS (ESI) m/z 250[M-H]
IR(KBr) ν(cm^-1)=3331(NH), 3170(OH), 1759(C=O), 1722(C=O, ester), 1675(C=O, amide)
¹H-NMR(CDCl₃, ppm) δ=3.04, 3.18(2H, ABX system, J_AB=17.6 Hz, J_AX=4.4 Hz, J_BX=4.5 Hz, CH₂), 3.78(3H, s, CO₂CH₃), 5.07(1H, J_AX=4.4 Hz, J_BX=4.5 Hz, CH), 7.26(1H, s, NH), 7.4-7.8(5H, arom H), 9.1(1H, br, CO₂H)
【００４９】
（実施例４）
N-ベンゾイルアスパラギン酸モノメチルエステル(10)からアセチルアズラクトン化合物(11)の合成
N-ベンゾイルアスパラギン酸モノメチルエステル(10)132.2gに無水酢酸537.2gを加え攪拌を始めた。２０℃以下に冷却しながらトリエチルアミン362.1g及びDMAP6.4gを添加した。室温で１時間攪拌後90℃に加温し２時間反応させた。水5266gに反応混合物を分散し、酢酸エチルで抽出を行った。有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥させた後、活性炭処理を施し、減圧濃縮を行いアセチルアズラクトン化合物(11)94.2gを得た。収率65％
mp 100-101℃(i-PrOH)
MS (APCI) m/z 276[M+H]
IR(KBr) ν(cm^-1)= 1793(C=O, lactone), 1741(C=O, ester), 1646(C=N)
¹H-NMR(CDCl₃, ppm) δ=1.83(3H, s, COCH₃,), 3.10(1H, d, J=18 Hz, CH₂), 3.73(1H, d, J=18 Hz, CH₂), 3.84(3H, s, CO₂CH₃), 7.2-8.0(5H, m, arom H)
【００５０】
（実施例５）
アセチルアズラクトン化合物(11)からラクトン化合物(3)の合成
アセチルアズラクトン化合物(11)47.1gに酢酸262.4g及び水4.6gを加えオートクレーブで130〜150℃にて８時間反応を行った。反応混合物を減圧濃縮した後析出した結晶を濾取し、酢酸エチルで洗浄した。得られた粗結晶をメタノールにて再結晶を行い、ラクトン化合物(3)5.6gを得た。収率15％
mp 172-173℃(CH₃OH)
MS (APCI) m/z 218[M+H], 235[M+NH₄]
IR(KBr) ν(cm^-1)=3311(NH), 1725(C=O, lactone), 1698(C=O, amide)
¹H-NMR(CDCl₃, ppm) δ=1.52(3H, d, CH₃, J=6.6 Hz), 5.27(1H, q, CH, J=6.6 Hz), 6.17(1H, s, =CH-), 7.5-7.8(5H, m, arom H), 11.0(1H, br, NH)
【００５１】
（実施例６）
アセチルアズラクトン化合物(11)からN-ベンゾイル-α-アセチルアスパラギン酸モノメチルエステル(12)の合成
アセチルアズラクトン化合物(11)0.55gを酢酸3.1g、水0.36gの混合液に加え攪拌しながら70〜80℃で６時間加熱した。反応液を減圧濃縮した。濃縮残渣0.6gをクロロホルム20gに溶解し、水40g×２回で洗浄後、有機層を無水硫酸マグネシウムで乾燥し、濾過後、濾液を減圧濃縮した。濃縮残渣0.5gを酢酸エチル3.0ml、n-ヘキサン3.8mlの混合溶媒で再結晶を行い、N-ベンゾイル-α-アセチルアスパラギン酸モノメチルエステル(12)0.25gを得た。収率43％
mp 115.9-118.9℃(AcOEt/hexane.)
MS (APCI) m/z 294[M+H]
IR(KBr) ν(cm^-1)= 3352(NH), 3165(OH), 1774(C=O), 1741(C=O)
¹H-NMR(CDCl₃, ppm) δ=2.20(3H, s, COCH₃,), 3.57(1H, d, J=18 Hz, CH₂), 3.76(1H, d, J=18 Hz, CH₂), 3.79(3H, s, CO₂CH₃), 7.4-7.8(5H, m, arom H)
【００５２】
（実施例７）
N-ベンゾイルアスパラギン酸(1)からアセチルアズラクトン化合物(4)及びジアセチルアズラクトン化合物(5)の合成
酢酸114.5g及び無水酢酸123.2gの混合液中に式N-ベンゾイルアスパラギン酸(１)60.3gを攪拌しながら添加し、98℃で２時間反応させた。次に２，３−ルチジン28.0gを添加し、90℃で２時間、114℃で２時間反応させた後減圧濃縮を行い溶媒を除去した。濃縮残渣に水100ml及びクロロホルム100mlを加え抽出を行った後有機層を水100mlで洗浄した。有機層を５％塩酸、活性炭処理、２Ｎ水酸化ナトリウム水溶液、２Ｎ塩酸、及び水で洗浄した後無水硫酸ナトリウムで乾燥し、減圧濃縮にて溶媒を除去し、濃縮残渣22.3gを得た。濃縮残渣1.0gをカラムクロマトグラフィーを行って精製しアセチルアズラクトン化合物(4)0.3g及びジアセチルアズラクトン化合物式(5)0.2gを得た。
アセチルアズラクトン化合物(4)
mp 92.0-93.0℃(hexane)
MS (APCI) m/z 218[M+H], 250[M+H+MeOH]
IR(KBr) ν(cm^-1)= 1789(C=O), 1650(C=N)
¹H-NMR(CDCl₃, ppm) δ=1.91(3H, s, COCH₃), 2.93, 3.06(2H, ABX system, J_AB=18.7 Hz, J_AX=8.2 Hz, J_BX=2.0 Hz, CH₂), 4.62(1H, q, J_AX=8.2 Hz, J_BX=2.0 Hz, CH), 7.4-8.0(5H, arom H)
ジアセチルアズラクトン化合物(5)
mp 90.7-91.7℃(hexane)
MS (APCI) m/z 260[M+H]
IR(KBr) ν(cm^-1)= 1789(C=O), 1716(C=O), 1647(C=N)
¹H-NMR(CDCl₃, ppm) δ=1.74(3H, s, COCH₃), 2.27(3H, s, OCOCH₃), 2.89(1H, d, J=18 Hz), 3.65(1H, d, J=18 Hz), 7.4-8.1(5H, arom H)
【００５３】
（実施例８）
N-ベンゾイルアスパラギン酸(1)からラクトン化合物(3),アセチルアズラクトン化合物(4)及びジアセチルアズラクトン化合物(5)の合成
攪拌機付1000ml四つ口コルベンにトルエン450ml、無水酢酸92.0g、N-ベンゾイルアスパラギン酸(1)107.0g、酢酸ナトリウム27.0gを入れ、90〜100℃で４時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)44.8%、アセチルアズラクトン化合物(4)41.9%、ジアセチルアズラクトン化合物(5)12.0%で原料のN-ベンゾイルアスパラギン酸は0.1%以下で反応は終了していた。この反応液を80℃/35Torr(4.655kPa)まで濃縮した。濃縮液に氷冷下で水150mlを加え析出した結晶を濾過・乾燥し結晶85.0gを得た。得られた結晶をHPLC分析するとその組成比はラクトン化合物(3)35.2%、アセチルアズラクトン化合物(4)51.8%、ジアセチルアズラクトン化合物(5)13.0%であった。
【００５４】
（実施例９）
N-ベンゾイルアスパラギン酸(1)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)の合成
攪拌機付1000ml四つ口コルベンにトルエン450ml、無水酢酸92.0g、N-ベンゾイルアスパラギン酸(1)107.0g、酢酸ナトリウム27.0gを入れ90〜100℃で４時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)44.8%、アセチルアズラクトン化合物(4)41.9%、ジアセチルアズラクトン化合物(5)12.0%で原料のN-ベンゾイルアスパラギン酸は0.1%以下で反応は終了していた。この反応液を80℃/35Torr(4.655kPa)まで濃縮し、トルエン・酢酸・無水酢酸を439.0g回収した。濃縮残液に98%硫酸100gを70〜110℃で滴下し、その後125℃で３時間反応した。反応液をHPLC分析すると2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)を93.5%含有していた。水480gに反応液を20〜30℃で分散、48%水酸化ナトリウム水溶液83.3gを加えて析出した結晶を濾過・水洗・乾燥し、2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)89.1gを得た。収率90.9%
mp 102℃(CH₃CN/H₂O)
MS (ESI) m/z 216[M-H]
IR(KBr) ν(cm^-1)=3430(OH), 2924(OH), 1712(C=O), 1650(C=N)
¹H-NMR(CDCl₃, ppm) δ=2.35(3H, s, CH₃), 3.64(2H, s, CH₂), 7.4-7.5(3H, m, arom H), 7.9-8.0(2H, arom H), 9.22(1H, br, OH)
【００５５】
（実施例１０）
N-ベンゾイルアスパラギン酸(1)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)の合成
攪拌機付1000ml四つ口コルベンにトルエン450ml、無水酢酸92.0g、N-ベンゾイルアスパラギン酸(1)107.0g、酢酸ナトリウム27.0gを入れ90〜100℃で４時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)44.8%、アセチルアズラクトン化合物(4)41.9%、ジアセチルアズラクトン化合物(5)12.0%で原料のN-ベンゾイルアスパラギン酸は0.1%以下で反応は終了していた。この反応液を80℃35Torr(4.655kPa)まで濃縮し、トルエン・酢酸・無水酢酸を439.0g回収した。濃縮残液に98%硫酸100gを70〜110℃で滴下し、その後125℃で３時間反応した。反応液をHPLC分析すると2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)を93.5%含有していた。反応液を50℃に冷却し、メタノール430gを加え65〜68℃で３時間反応した。反応液をHPLC分析すると、その面積比は2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)90.1%、2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)4.7%であった。このエステル化反応液を60℃で50Torr(6.65kPa)まで濃縮しメタノール341.2gを回収した。攪拌機付1000ml四つ口コルベンにトルエン200ml、水500ml、炭酸水素ナトリウム142.8gを入れ攪拌下20〜30℃で上記エステル化濃縮液を滴下した。滴下後、内容液を分液ロートに移し分液するとトルエン抽出層257.6g、水層704.8gを得た。トルエン抽出層を80℃/5Torr(0.665kPa)まで濃縮し2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)80.1gを得た。収率76.8%
MS (ACPI) m/z 232[M+H]
IR(KBr) ν(cm^-1)=1744(C=O), 1644(C=N)
¹H-NMR(CDCl₃, ppm) δ=2.36(3H, s, CH₃), 3.57(2H, s, CH₂), 3.73(3H, s, CO₂CH₃), 7.4-7.5(3H, m, arom H), 7.9-8.0(2H, arom H)
【００５６】
（実施例１１）
N-ベンゾイルアスパラギン酸(1)〜ラクトン化合物(3)及びケトカルボン酸(9)の合成
酢酸114.5g、無水酢酸100g、酢酸ナトリウム20.0gにN-ベンゾイルアスパラギン酸60.2gを加え114℃で２時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3) 33.5%、アセチルアズラクトン化合物(4) 43.1%、ジアセチルアズラクトン化合物(5) 20.6%であった。反応液を85℃まで冷却し水13.0gを加え85℃で７時間反応した。反応液をHPLC分析するとその面積比はケトカルボン酸(9)19.5%、ラクトン化合物(3)76.0%であった。反応液を70℃/50Torr(6.65kPa)まで減圧濃縮し、60℃で水50.0gを加え10℃に冷却し析出した結晶を濾過・水洗・乾燥し、ラクトン化合物(3)35.5gを得た。収率68.7%
ラクトン晶析母液を１夜放置しておくとさらに結晶が析出した。これを濾過・水洗・乾燥しケトカルボン酸化合物(9)9.4gを得た。収率16.8%
mp 129-130℃
MS (APCI) m/z 236[M+H]
IR(KBr) ν(cm^-1)= 3298(NH), 3053(OH), 1725(C=O), 1696(C=O)
¹H-NMR(CDCl₃, ppm) δ=2.15(3H, s, COCH₃), 2.60, 2.89(2H, ABX system, J_AB=16.6 Hz, J_AX=6.4 Hz, J_BX=7.1 Hz, CH₂), 4.71(1H, q, J_AX=6.4 Hz, J_BX=7.1 Hz, CH), 7.4-7.9(5H, arom H), 8.92(NH, d, J=7.5 Hz), 12.4(1H, br, CO₂H)
【００５７】
（実施例１２）
N-ベンゾイルアスパラギン酸(1)からケトカルボン酸メチルエステル(8)及び２−（５−メチルー２−フェニルー４−オキサゾリル）酢酸メチルエステル(7)混合物の合成とケトカルボン酸メチルエステル(8)の単離
攪拌機付1000ml四つ口コルベンに酢酸183.2g、無水酢酸197.1g、N-ベンゾイルアスパラギン酸(1)91.2g、酢酸ナトリウム24.0gを入れ90〜100℃で４時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)29.2%、アセチルアズラクトン化合物(4)46.1%、ジアセチルアズラクトン化合物(5)20.0%で原料のN-ベンゾイルアスパラギン酸は0.1%以下で反応は終了していた。この反応液を70℃/15Torr(1.995kPa)まで濃縮し、酢酸・無水酢酸を321.1g回収した。この濃縮液に98%硫酸185g、メタノール420.0gを40〜60℃で加え、その後65℃で14時間反応した。反応液をHPLC分析するとその面積比はケトカルボン酸メチルエステル(8)63.3%、2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)27.5%であった。反応液を45℃/170Torr(22.61kPa)まで濃縮し、水1400.0g・トルエン300ml・炭酸水素ナトリウム235.0g中に濃縮液を20〜25℃で分散した。この分散液を分液ロートに移しトルエン層318.7g、水層2013.2gを得た。水層をさらにトルエン200mlで抽出し、トルエン２次抽出層178.3gを得た。先に得られたトルエン層と合わせて水200mlで洗浄、減圧濃縮しトルエン450mlを溜出させた。濃縮液を5℃まで冷却し析出した結晶を濾過・トルエン洗浄・減圧乾燥し、ケトカルボン酸メチルエステル(8)29.6gを得た。収率34.2%
mp 63-69℃
MS (APCI )m/z 250[M+H]
IR(KBr) ν(cm^-1)=3285(NH), 1739(C=O), 1724(C=O), 1641(C=O)
¹H-NMR(CDCl₃, ppm) δ=2.31(3H, s, COCH₃), 2.91, 3.12(2H, ABX system, J_AB=17.2 Hz, J_AX=4.4 Hz, J_BX=4.6 Hz, CH₂), 3.71(3H, s, CO₂CH₃), 4.96(1H, q, J_AX=4.4 Hz, J_BX=4.6 Hz, CH), 7.4-7.9(5H, arom H)
【００５８】
（実施例１３）
実施例１２の母液からの2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)の単離
実施例12のケトカルボン酸メチルエステル分離母液にトルエン450ml、オキシ塩化リン30.0gを加え105℃で7時間反応し、反応液をHPLC分析するとその面積比は2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)84.1%、ケトカルボン酸メチルエステル(8)1.8%であった。水300.0g、炭酸水素ナトリウム65.0g中にこの反応液を20〜25℃で分散した。トルエン層を分液し90℃/3Torr(0.399kPa)まで減圧濃縮し、2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)43.2gを得た。収率48.6%
【００５９】
（実施例１４）
N-ベンゾイルアスパラギン酸(1)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7) の合成
攪拌機付1000ml四つ口コルベンに酢酸183.2g、無水酢酸197.1g、N-ベンゾイルアスパラギン酸(1)91.2g、酢酸ナトリウム24.0gを入れ90〜100℃で４時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)29.2%、アセチルアズラクトン化合物(4)46.1%、ジアセチルアズラクトン化合物(5)20.0%で原料のN-ベンゾイルアスパラギン酸は0.1%以下で反応は終了していた。この反応液を70℃/15Torr(1.995kPa)まで濃縮し、酢酸・無水酢酸を321.0g回収した。この濃縮液に98%硫酸185g、メタノール420.0gを40〜60℃で加え、その後65℃で14時間反応した。反応液をHPLC分析するとその面積比はケトカルボン酸メチルエステル(8)63.3%、2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)27.5%であった。反応液を45℃/170Torr(22.61kPa)まで濃縮し、水1400.0g、トルエン300ml、炭酸水素ナトリウム235.0g中に濃縮液を20〜25℃で分散した。この分散液を分液しトルエン層319.0gを得た。水層をさらにトルエン200mlで抽出し、トルエン２次抽出層178.3gを得た。得られたトルエン層を混合し、110℃まで昇温しトルエン40mlを溜出させた。オキシ塩化リン60.0gを加え105℃で7時間反応し、反応液をHPLC分析するとその面積比は2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)91.0%、ケトカルボン酸メチルエステル(8)は未検出であった。水350.0g・炭酸水素ナトリウム65.0g炭酸ナトリウム43.0g中にこの反応液を20〜25℃で分散した。析出した無機塩を濾過しトルエン100mlで洗浄し、得られた濾液を分液してトルエン層501.1gを得た。トルエン層を90℃3Torr(0.399kPa)まで減圧濃縮し、2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)72.0gを得た。収率81.0%
【００６０】
（実施例１５）
ケトカルボン酸化合物(9)からアセチルアズラクトン化合物(4)の合成
酢酸15.0g、無水酢酸20.0gにp-トルエンスルホン酸0.1gケトカルボン酸7.1gを加え70℃で1.5時間反応した。反応液をHPLC分析するとその面積はアセチルアズラクトン化合物(4)94.9%、ケトカルボン酸化合物(9)1.2%であった。反応液を70℃/15Torr(1.995kPa)まで減圧濃縮し水50mlを加え析出した結晶を濾過・水洗・乾燥しアセチルアズラクトン化合物(4)6.0gを得た。収率91.5%
【００６１】
（実施例１６）
ラクトン化合物(3)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)の合成
98%硫酸5.0gにラクトン化合物(3)5.0gを加え70℃で４時間反応した。反応液をHPLC分析するとその面積比は式(6)の2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)100%でラクトン化合物(3)は未検出であった。
【００６２】
（実施例１７）
アセチルアズラクトン化合物(4)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)の合成
98%硫酸5.0gにアセチルアズラクトン化合物(4)5.0gを加え120℃で3時間反応した。反応液をHPLC分析するとその面積比は2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)100%でアセチルアズラクトン化合物(4)は未検出であった。
【００６３】
（実施例１８）
ジアセチルアズラクトン化合物(5)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)の合成
98%硫酸5.0gにジアセチルアズラクトン化合物(5)5.0gを加え120℃で3時間反応した。反応液をHPLC分析するとその面積比は2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)100%でジアセチルアズラクトン化合物(5)は未検出であった。
【００６４】
（実施例１９）
アセチルアズラクトン化合物(4)からケトカルボン酸メチルエステル(8)の合成メタノール10.0g、98%硫酸10.0gにアセチルアズラクトン化合物(4)5.0gを加え65℃で24時間反応した。反応液をHPLC分析するとその面積比はケトカルボン酸メチルエステル(8)97.5%でアセチルアズラクトン化合物(4)は未検出であった。
【００６５】
（実施例２０）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物(2)0.2g、無水酢酸0.3g、トルエン1.2mlにN-メチルモルホリン0.05g、ジメチルアミノピリジン0.01gを加え、70℃で１時間反応した。反応液をHPLC分析するとその面積比はのラクトン化合物(3)14.4%、アセチルアズラクトン化合物(4)22.0%、ジアセチルアズラクトン化合物(5)27.7%であった。
【００６６】
（実施例２１）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物0.1g、無水酢酸0.2g、ジメチルアミノピリジン0.01gを加え、115℃で１時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)6.7%、アセチルアズラクトン化合物(4)30.6%、ジアセチルアズラクトン化合物(5)47.3%であった。
【００６７】
（実施例２２）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物0.1g、無水酢酸0.3g、2.3-ルチジン0.05gを加え、115℃で１時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)3.0%、アセチルアズラクトン化合物(4)27.2%、ジアセチルアズラクトン化合物(5)24.3%、N-ベンゾイルアスパラギン酸無水物(2)38.8%であった。
【００６８】
（実施例２３）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物(2)0.1g、無水酢酸0.4g、ピリジン0.05gを加え、70℃で１時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)2.5%、アセチルアズラクトン化合物(4)47.2%、ジアセチルアズラクトン化合物(5)24.9%であった。
【００６９】
（実施例２４）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物1.0g、無水酢酸4.5g、酢酸4.3g、トリエチルアミン1.0gを加え、70℃で2時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)2.0%、アセチルアズラクトン化合物(4)37.5%、ジアセチルアズラクトン化合物(5)42.2%であった。
【００７０】
（実施例２５）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物1.0g、無水酢酸2.0g、トリエチルアミン0.4gを加え、90℃で2時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)2.8%、アセチルアズラクトン化合物(4)16.8%、ジアセチルアズラクトン化合物(5)35.2%であった。
【００７１】
（実施例２６）
N-ベンゾイルアスパラギン酸無水物(2)からラクトン化合物(3)、アセチルアズラクトン化合物(4)、ジアセチルアズラクトン化合物(5)を含む混合物の合成
N-ベンゾイルアスパラギン酸無水物(2)21.9g、無水酢酸10.2g、酢酸ナトリウム6.0gにトルエン100mlを加え、95℃で12時間反応した。反応液をHPLC分析するとその面積比はラクトン化合物(3)45.0%、アセチルアズラクトン化合物(4) 41.9%、ジアセチルアズラクトン化合物(5)12.1%であった。反応液を90℃で35Torr(4.655kPa)まで濃縮し、濃縮残液に室温で水50mlを加え析出した結晶を濾過・水洗・減圧乾燥し式(3)(4)(5)の化合物の混合結晶19.3gを得た。得られた結晶をHPLC分析するとその組成比はラクトン化合物(3)35.2%、アセチルアズラクトン化合物(4)51.8%、ジアセチルアズラクトン化合物(5)13.0%であった。収率87.1%
【００７２】
（実施例２７）
ラクトン(3)からケトカルボン酸化合物(9)の合成
10%NaOH水溶液5mlに ラクトン化合物(3)0.1gを加え60℃で１時間反応した。反応液に濃硫酸1.5gを加え反応液をHPLC分析するとその面積比はケトカルボン酸化合物(9)100%であった。
【００７３】
（実施例２８）
2-(5-メチルー2-フェニル-4-オキサゾリル)酢酸(6)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)の合成
2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)45.0g、メタノール200g、硫酸1.0gを加え65〜68℃で３時間反応した。反応後、40℃15Torr(1.995kPa)まで濃縮した。水50g、炭酸水素ナトリウム1.7g、トルエン200ml中に濃縮液を室温で分散し、トルエン層を分液した。トルエン層を硫酸マグネシウムで乾燥後濃縮し2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)44.7gを得た。収率93.3%
【００７４】
（実施例２９）
2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)から2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)の合成
2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸(6)45.0g、10%HCl-メタノール220gを加え65〜68℃で３時間反応した。反応後、40℃15Torr(1.995kPa)まで濃縮した。水50g、トルエン200ml中に濃縮液を室温で分散し、トルエン層を分液した。トルエン層を硫酸マグネシウムで乾燥後濃縮し2-(5-メチル-2-フェニル-4-オキサゾリル)酢酸メチルエステル(7)45.6gを得た。収率95.3%
【００７５】
（実施例３０）
L-アスパラギン酸からN-(4-メチルフェニル)アスパラギン酸の合成
L-アスパラギン酸26.6gを水128gに分散した。このスラリー液を攪拌しながら、20〜30℃で48％水酸化ナトリウム水溶液を滴下し、系内のｐＨを9.5〜10.0に調整した。この溶液を攪拌しながら、p-トルオイルクロライド30.9gを20〜30℃で、系内のｐＨを9.5〜10.5に保ちながら３時間かけて加えた。系内のｐＨを9.5〜10.5に保ちながら20〜30℃で１時間攪拌後、40〜45℃で12wt%塩酸水溶液（122.5g）に反応液を分散させた。スラリー液を20〜25℃に冷却し、濾過後、結晶を水100gで洗浄した。得られた結晶を乾燥し、N-(4-メチルフェニル)アスパラギン酸46.6gを得た。収率93%
【００７６】
（実施例３１）
N-(4-メチルフェニル)アスパラギン酸(1)から2-[2-(4-メチルフェニル)-4-メチルオキサゾリル]酢酸メチルエステルの合成
攪拌機付1000ml四つ口コルベンにトルエン50ml、無水酢酸10.2g、N-(4-トルオイル)アスパラギン酸12.6g、酢酸ナトリウム3.0gを入れ90〜100℃で４時間反応させた。反応液を HPLC分析するとその面積比はラクトン化合物24.0%、アセチルアズラクトン化合物52.9%、ジアセチルアズラクトン化合物10.0%で原料のN-(4-メチルフェニル)アスパラギン酸は0.1%以下で反応は終了していた。この反応液を80℃35Torr(5.655kPa)まで濃縮し、濃縮残液に98%硫酸11.1gを70〜110℃で滴下し、その後125℃で３時間反応させた。反応液を HPLC分析すると2-[2-(4-メチルフェニル)-4-メチルオキサゾリル]酢酸を90.5％含有していた。反応液を50℃に冷却し、メタノール46.0gを加え65〜68℃で３時間反応させた。反応液を HPLC分析するとその面積比は2-[2-(4-メチルフェニル)-4-メチルオキサゾリル]酢酸メチルエステル90.0％、2-[2-(4-メチルフェニル)-4-メチルオキサゾリル]酢酸5.1％であった。このエステル化反応液を60℃で50Torr(6.65kPa)まで濃縮した。攪拌機付1000ml四つ口コルベンにトルエン22ml、水55ml、炭酸水素ナトリウム15.7gを入れ攪拌下、10〜15℃で上記エステル化濃縮液を滴下した。滴下後、内容液を分液ロートに移して分液しトルエン抽出層35.7gを得た。トルエン抽出層を80℃、5Torr(0.655kPa)まで濃縮し、2-[2-(4-メチルフェニル)-4-メチルオキサゾリル]酢酸メチルエステル8.7gを得た。収率71.0%
mp 62-63℃
MS (APCI )m/z 246[M+H]
IR(KBr) ν(cm^-1)=1737(C=O), 1653(C=N)
¹H-NMR(CDCl₃, ppm) δ=2.35(3H, s, CH₃), 2.38(3H, s, CH₃),3.57(2H, s, CH₃),3.73(3H, s, CH₃), 7.22(2H, d, J=8.1Hz, arom H),7.86(2H, d, J=8.1Hz, arom H)
【００７７】
（比較例１）
N-ベンゾイルアスパラギン酸モノメチルエステル(10)からケトカルボン酸 メチルエステル(8)の合成（特開2000-143643の追試）
N-ベンゾイルアスパラギン酸モノメチルエステル(10)1.0g、無水酢酸1.6g、トルエン4.5g、N-メチルモルホリン20mgにジメチルアミノピリジン5mgを加え55〜60℃で4時間反応した。反応液はタール様でHPLC分析すると未反応N-ベンジルアスパラギン酸モノメチルエステル(10)が面積比33%で目的のケトカルボン酸メチルエステル(8)は検出されなかった。
【００７８】
（比較例２）
N-ベンゾイルアスパラギン酸モノメチルエステル(10)からケトカルボン酸メチルエステル(8)の合成（organic syntheses coll.,vol.4 参考）
N-ベンゾイルアスパラギン酸モノメチルエステル(10)0.4g、無水酢酸1.0g、ピリジン0.7gを加え100℃で6時間反応した。反応液はタール様でHPLC分析すると未反応N-ベンジルアスパラギン酸モノメチルエステルが面積比23.2%(10)で目的のケトカルボン酸メチルエステル(8)は検出されなかった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an industrial method for producing an oxazole compound useful as an intermediate for medicines and agricultural chemicals.
[0002]
[Prior art]
Oxazole compounds are important as pharmaceutical and agrochemical intermediates. For example, 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid and its derivatives have recently attracted attention as intermediates for antidiabetic drugs, and their usefulness is disclosed in International Publication WO95 / 18125. Is disclosed. Various methods for producing these compounds have been proposed. For example, US Pat. No. 5,728,720 discloses the following synthesis method.
[0003]
1) Synthesis of N-acetylaminoketocarboxylic acid benzyl ester by reaction of β-monobenzyl ester of aspartic acid with acetic anhydride
2) Synthesis of aminoketocarboxylic acid methyl ester by deacetylation of the compound by hydrochloric acid-methanol treatment and transesterification
3) Synthesis of N-benzoylaminoketocarboxylic acid methyl ester by benzoylation of the free amino group of the compound
4) Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester by dehydration ring closure reaction of the compound
[0004]
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[0005]
However, in this method, it is difficult to obtain monobenzyl ester of L-aspartic acid, conversion from acetyl group to benzoyl group is necessary, and conversion from benzyl ester group to methyl ester group is necessary. There is a problem as an industrial manufacturing method. In addition, J.H. Med. Chem. , 35, 14, 2625 (1992), the following synthesis method is disclosed.
1) Synthesis of N-benzoylaspartic acid monomethyl ester by benzoylation of β-monomethyl ester of aspartic acid
2) Synthesis of N-benzoylaminoketocarboxylic acid methyl ester by acetylation and decarboxylation of the compound
3) Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester by dehydration ring closure reaction of the compound with phosphorus oxychloride
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[0006]
However, this method has problems as an industrial production method in that it is difficult to obtain monomethyl ester of L-aspartic acid and, as described later, acetylation and decarboxylation reactions do not proceed smoothly. Further, JP-A-12-143743 discloses an improved method of the above-described method. However, this method also uses a monomethyl ester of L-aspartic acid which is difficult to obtain as a starting material, the acetylation and decarboxylation reactions do not proceed smoothly, and in the reaction using p-toluenesulfonic acid, There were problems such as difficulty in ring formation.
[0007]
[Patent Document 1]
US Pat. No. 5,728,720
[0008]
[Patent Document 2]
JP-A-12-143743
[0009]
[Non-Patent Document 1]
J. et al. Med. Chem. , 35, 14, 2625 (1992)
[0010]
[Problems to be solved by the invention]
An object of the present invention is to provide a simple and inexpensive method for producing a 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid derivative using readily available aspartic acid as a starting material.
[0011]
[Means for Solving the Problems]
The present inventors considered a synthetic route described in JP-A No. 12-143743, and represented a chemical formula as an initial intermediate for synthesizing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid derivatives. (10) (However, any of L-form, D-form, and racemic form may be sufficient, Ar represents substituted aryl or unsubstituted aryl, and R represents a lower alkyl group.)
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The N-arylcarbonylaspartate represented by The method for synthesizing this intermediate has been intensively studied, and aspartic acid, which is readily available, is used as a starting material, and this is reacted with benzoyl chloride in the presence of a base to give the chemical formula (1) (however, L-form, D-form, racemic And Ar represents substituted aryl or unsubstituted aryl)
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N-arylcarbonylaspartic acid represented by the following formula (2) (wherein L, D, and racemate may be used, Ar is Represents substituted or unsubstituted aryl)
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N-arylcarbonylaspartic anhydride represented by the following formula was obtained. It is well known that monoesters of dicarboxylic acids can be obtained by alcoholysis of cyclic acid anhydrides. However, in the case of the N-arylcarbonylaspartic anhydride represented by the chemical formula (2), the desired N-arylcarbonylaspartic acid-β-monoester represented by the chemical formula (10) and unnecessary N-arylcarbonylasparagine The formation of two compounds of acid-α-monoesters is conceivable. The present inventors tried this reaction and found that the desired monoester was obtained in a relatively good yield.
[0012]
Subsequently, when the acetylation and decarboxylation were attempted using the monoester by the method described in JP-A-12-143634, the desired N-arylcarbonylamino-α-acetyl-β-carboxylic acid ester was obtained. I couldn't.
[0013]
When α-amino acid is treated with acylation conditions in the presence of a base, as shown below,
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1) Acylation of amino group of amino acid
2) Formation of azlactone ring
3) Acylation of α-position of azlactone ring
4) Decarboxylation
It is well known as the Dakin-West reaction that is continuously generated and N-acylamino-α-ketone is obtained. The inventors of the present invention have tried Dakin-West reaction under various conditions using N-arylcarbonylaspartic acid-β-monoester represented by the chemical formula (10) as a raw material and acetic anhydride as an acylating agent. Wherein the α-position of the azlactone ring is acetylated under the selected conditions (11)
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It was found that an acetylazlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl, and R represents a lower alkyl group) was obtained. The compound was stable, decarboxylation did not proceed easily, and it was difficult to obtain a ketocarboxylic acid ester represented by the desired chemical formula (8). For this reason, by hydrolyzing the acetyl azlactone compound represented by the chemical formula (11), the chemical formula (12)
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N-arylcarbonyl-α-acetylaspartic acid monoester represented by the formula (Ar represents substituted aryl or unsubstituted aryl, and R represents a lower alkyl group). Then, when decarboxylation of the compound was tried, surprisingly, the obtained product was not the ketocarboxylic acid ester represented by the desired chemical formula (8) but the chemical formula (3).
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A lactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl) and a ketocarboxylic acid represented by the chemical formula (9). It was found that these two compounds can be easily separated by preferentially crystallizing a novel lactone compound represented by the chemical formula (3) from an aqueous solvent.
[0014]
The present inventors use the two types of decarboxylation products obtained by the above reaction as intermediates, and are the final target compound, chemical formula (7)
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The synthesis of 2- (5-methyl-2-aryl-4-oxazolyl) acetate represented by the formula (Ar is substituted aryl or unsubstituted aryl, R represents a lower alkyl group) was intensively studied. The novel lactone compound represented by the formula (3) has the chemical formula (9)
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A dehydration product of ketocarboxylic acid represented by the formula (wherein L may be L, D, or racemic, Ar represents a substituted aryl or unsubstituted aryl, and R represents a lower alkyl group), and , Formula (6)
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2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (Ar represents substituted aryl or unsubstituted aryl). The inventors of the present invention treat the lactone compound with an acidic compound, and thereby perform 2- (5-methyl-2-aryl-) represented by the desired chemical formula (6) by ring cleavage and recyclization to the oxazole ring. Conversion to 4-oxazolyl) acetic acid, and 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester represented by chemical formula (7) is obtained by esterifying the compound I found.
[0015]
Moreover, it discovered that the novel lactone compound represented by Chemical formula (3) can be induced | guided | derived to the ketocarboxylic acid represented by Chemical formula (9) by hydrolyzing on suitable conditions.
[0016]
On the other hand, it was found that the ketocarboxylic acid compound represented by the chemical formula (9) can be derived into a ketocarboxylic acid ester represented by the chemical formula (8) by esterification. The ester can be derived into a desired 2- (5-methyl-2-aryl-4-oxazolyl) acetate ester represented by the chemical formula (7) by a known method. The outline of the present invention is shown below. Ar represents substituted aryl or unsubstituted aryl, and R represents a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group.
[0017]
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[0018]
The present inventors have examined a simpler method for producing a 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid derivative. That is, as described above, the ketocarboxylic acid represented by the chemical formula (9) finally obtained by performing the Dakin-West reaction using the N-arylcarbonylaspartic acid monoester represented by the chemical formula (10) as an intermediate. It was noted that the compound was a compound obtained by decarboxylation of the α-position carboxylic acid. For example, when an α, β-dicarboxylic acid such as N-arylcarbonylaspartic acid represented by the chemical formula (1) is treated under Dakin-West reaction conditions, the α-position carboxyl group undergoes acylation at the α-position. If selective decarboxylation of is possible, it can be expected that a ketocarboxylic acid represented by the chemical formula (9) is produced. As described above, the compound can be derived into a ketocarboxylic acid ester represented by the known chemical formula (8) by esterification. However, there has not been known an example in which a Dakin-West reaction is performed using N-arylcarbonylaspartic acid represented by the chemical formula (1) as a substrate.
[0019]
An example of a similar reaction in which aspartic acid was reacted in acetic anhydride and pyridine has been reported by Dakin and West (J. Biol. Chem., 78.745 (1928)). They report that this reaction passes through β-acetamino-γ-acetoxy-γ-valerolactone as an intermediate, and finally β-acetylaminolevulinic acid is obtained as a hydrolyzate of the compound. .
[0020]
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[0021]
The latter compound is an acetyl analog of keto acid represented by chemical formula (9). However, since these compounds have not been isolated and their physical properties have not been shown, they must be regarded as presumed products. That is, the product of the Dakin-West reaction when N-arylcarbonylaspartic acid is used as a substrate can be estimated from their report, but has not been isolated or identified. As a result of intensive studies on this point, the present inventors have completed the present invention.
[0022]
The present inventors tried Dakin-West reaction under various conditions using N-arylcarbonylaspartic acid represented by the chemical formula (1) as a substrate. At first, when an attempt was made to react with acetic anhydride in the absence of a base, N-arylcarbonylaspartic anhydride represented by the chemical formula (2) was obtained. Subsequently, the compound was treated with acetic anhydride under basic conditions, and the product was examined in detail. As a result, the initially expected ketocarboxylic acid compound represented by the chemical formula (9) was not produced, and three new kinds of compounds were produced. It was found that a compound was formed. One of the three compounds is a lactone compound represented by the chemical formula (3) already described, the other one is an acetylazlactone compound represented by the chemical formula (4), and One was found to be a diacetyl azlactone compound represented by chemical formula (5), which is a further acetylated product of the acetyl azlactone compound represented by chemical formula (4). These compounds have a completely different structure from β-acylamino-γ-acetoxy-γ-valerolactone presented by Dakin and West in the above-mentioned literature, and were first discovered by the present inventors. Is.
[0023]
As described above, the novel lactone compound represented by the chemical formula (3) includes 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid represented by the chemical formula (6), and the chemical formula (7). It is possible to derive the ester represented by On the other hand, the reactivity of the novel acetyl azlactone compound represented by the chemical formula (4) and the novel diacetyl azlactone compound represented by the chemical formula (5) is unknown. The present inventors have already completed the α-position acetylation, the α-position carboxyl group decarboxylation, and the dehydration reaction in the acetylazlactone compound represented by the general formula (4). It was thought that it could be used as an equivalent of 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid represented by 6). Furthermore, the novel diacetyl azlactone compound represented by the chemical formula (5) is a further acetylated form of the acetyl azlactone compound represented by the chemical formula (4), and the acetyl represented by the chemical formula (4) under deacetylation conditions. As a result of continuing intensive investigations on the assumption that an azlactone compound is produced, these compounds are processed in the presence of a specific acidic compound, so that the reconstitution of the ring proceeds and the desired chemical formula (6 It was found that 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid represented by formula (9) was given and hydrolyzed to give ketocarboxylic acid represented by chemical formula (9). It came to be completed. The outline of the present invention is shown below.
[0024]
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[0025]
【The invention's effect】
According to the present invention, a 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid derivative can be easily and inexpensively produced using readily available aspartic acid as a starting material.
[0026]
DETAILED DESCRIPTION OF THE INVENTION
The contents of the present invention will be described in more detail.
Chemical formula (1)
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In the N-arylcarbonylaspartic acid represented by the formula, Ar is substituted aryl or unsubstituted aryl, and examples of the substituent include halogen groups (fluoro, chloro, bromo, iodo), alkyl groups (methyl, ethyl, propyl, butyl, etc.) ), A nitro group and the like are preferred because they do not involve side reactions.
[0027]
The reaction for producing N-arylcarbonylaspartic anhydride (2) from N-arylcarbonylaspartic acid (1) is preferably 0.9 to 10 moles, preferably 1 to 10 moles per mole of N-arylcarbonylaspartic acid (1). The reaction is carried out at 1.0 to 5.0 mol, more preferably 1.0 to 2.0 mol of acetic anhydride at room temperature to 110 ° C, preferably 70 to 110 ° C, more preferably 80 to 100 ° C. The reaction solvent may or may not be used, and in consideration of the fluidity, volumetric efficiency, yield, etc. of the reaction solution, acetic acid or aromatic hydrocarbons such as benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, mono An appropriate solvent can be selected from chlorobenzene, dichlorobenzene and the like. The amount of the reaction solvent used at this time is not particularly limited, but preferably 0.5 to 10 based on the weight of N-arylcarbonylaspartic acid in consideration of fluidity, volumetric efficiency, yield and the like of the reaction solution. It is used twice, more preferably 2 to 5 times. The reaction solution of N-arylcarbonylaspartic anhydride can be cooled, and N-arylcarbonylaspartic anhydride (2) can be separated out by solid-liquid separation. Without isolating N-arylcarbonylaspartic anhydride (2), the reaction solution is used as it is to produce the following lactone compound (3), acetyl azlactone compound formula (4) and diacetyl azlactone compound (5). It can be used for the reaction to form or N-arylcarbonylaspartic acid monoester (10).
[0028]
The reaction for producing the lactone compound (3), the acetyl azlactone compound formula (4) and the diacetyl azlactone compound (5) from the N-arylcarbonyl aspartic acid anhydride (2) is performed using 1 mol of N-arylcarbonyl aspartic acid anhydride. Acetic anhydride 1.0 to 10 mol, preferably 1.0 to 5.0 mol, more preferably 1.0 to 2.0 mol and base 0.001 mol to 10 mol, preferably 0.01 to 1 mol, more preferably 0.02 to 0.5 mol is used. Bases include triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, and 2,6-lutidine 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1-methylpiperidine, 4-dimethylaminopyridine, 1-methylmorpholine, potassium hydroxide, sodium hydroxide, potassium carbonate, carbonic acid Organic and inorganic bases such as sodium, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium acetate, sodium acetate can be used. The reaction temperature is room temperature to 120 ° C, preferably 50 to 110 ° C, more preferably 80 to 100 ° C. The reaction solution of this lactone compound (3), acetyl azlactone compound formula (4) and diacetyl azlactone compound (5) may be subjected to the next reaction as it is. On the other hand, the reaction solution may be cooled and crystallized or concentrated and then cooled and crystallized, separated into solid and liquid, taken out, and used alone for each reaction. When this reaction solution is concentrated and acetic acid, acetic anhydride and the solvent are distilled off, the lactone compound represented by the chemical formula (3), the acetyl azlactone compound represented by the chemical formula (4) and the diacetyl az represented by the chemical formula (5) A lactone compound is obtained, which reaction produces 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6), and the ketocarboxylic acid ester (8) and 2- (5-methyl-2-aryl). -4-Oxazolyl) acetic acid ester (7) can be used for the reaction.
[0029]
The reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6) from the lactone compound (3) is preferably 0.1 to 5 mol of sulfuric acid, preferably 1.0 mol of the reaction substrate. 0.2-2 mol, more preferably 0.3-1.0 mol is used. The reaction temperature is 50 ° C to 150 ° C, preferably 80 ° C to 130 ° C, more preferably 100 to 125 ° C. The reaction solution is dispersed in water or the like, and the precipitated crystals may be separated by solid-liquid separation and taken out. This reaction solution can also be used as it is for the reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7).
[0030]
The reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6) from the acetylazlactone compound formula (4) is performed using 0.1 to 5 mol of sulfuric acid per 1.0 mol of the reaction substrate. , Preferably 0.2-2 mol, more preferably 0.3-1.0 mol. The reaction temperature is 50 ° C to 150 ° C, preferably 80 ° C to 130 ° C, more preferably 100 to 125 ° C. The reaction solution is dispersed in water or the like, and the precipitated crystals may be separated by solid-liquid separation and taken out. This reaction solution can also be used as it is for the reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7).
[0031]
The reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6) from the diacetyl azlactone compound (5) is carried out by using 0.1 to 5 mol of sulfuric acid with respect to 1.0 mol of the reaction substrate, Preferably 0.2-2 mol, more preferably 0.3-1.0 mol is used. The reaction temperature is 50 ° C to 150 ° C, preferably 80 ° C to 130 ° C, more preferably 100 to 125 ° C. The reaction solution is dispersed in water or the like, and the precipitated crystals may be separated by solid-liquid separation and taken out. This reaction solution can also be used as it is for the reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7).
[0032]
Reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6) from a reaction mixture containing a lactone compound (3), an acetyl azlactone compound formula (4) and a diacetyl azlactone compound (5) Uses 0.1 to 5 mol, preferably 0.2 to 2 mol, more preferably 0.3 to 1.0 mol of sulfuric acid with respect to 1.0 mol of the reaction substrate. The reaction temperature is 50 ° C to 150 ° C, preferably 80 ° C to 130 ° C, more preferably 100 to 125 ° C. The reaction solution is dispersed in water or the like, and the precipitated crystals may be separated by solid-liquid separation and taken out. Without isolating 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid represented by the chemical formula (6) described above, the reaction solution was directly used as 2- (5-methyl-2-aryl-4-oxazolyl). ) When used in the reaction to produce the acetate ester (7), 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6) per 1.0 mole of lower alcohol 5-100 moles, preferably 10-50 mol, more preferably 20-30 mol is used. The reaction temperature is 40 to 70 ° C, preferably 60 to 70 ° C. As the lower alcohol, methanol, ethanol, propanol, butanol and the like can be preferably used.
[0033]
The reaction for producing the ketocarboxylic acid ester (8) from the acetylazlactone compound formula (4) is 0.1 to 5 mol of sulfuric acid, preferably 0.2 to 2 mol, more preferably 1.0 mol of the reaction substrate. 0.3-1.0 mol and lower alcohol 5-100 mol, preferably 10-50 mol, more preferably 20-30 mol are used. The reaction temperature is 40 ° C to 70 ° C, preferably 60 ° C to 70 ° C. The reaction solution is concentrated, dispersed in water, toluene or the like, extracted with a solvent, and the extracted layer is concentrated to precipitate the ketocarboxylic acid ester (8) crystal and separate into solid and liquid.
[0034]
Reaction which produces | generates ketocarboxylic acid ester (8) from diacetyl azlactone compound formula (5) is 0.1-5 mol with respect to 1.0 mol of reaction substrates, Preferably it is 0.2-2 mol, More preferably 0.3-1.0 mol and lower alcohol 5-100 mol, preferably 10-50 mol, more preferably 20-30 mol are used. The reaction temperature is 40 ° C to 70 ° C, preferably 60 ° C to 70 ° C. The reaction solution is concentrated, dispersed in water, toluene or the like, extracted with a solvent, and the extracted layer is concentrated to precipitate the ketocarboxylic acid ester (8) crystal and separate into solid and liquid.
[0035]
From the concentrated solution containing the lactone compound (3), the acetyl azlactone compound formula (4) and the diacetyl azlactone compound (5), ketocarboxylic acid ester (8) and 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid The reaction for forming the ester (7) is carried out with 0.1 to 5 mol of sulfuric acid, preferably 0.2 to 2 mol, more preferably 0.3 to 1.0 mol with respect to 1.0 mol of the reaction substrate. 5 to 100 mol, preferably 10 to 50 mol, more preferably 20 to 30 mol are used. The reaction temperature is 40 ° C to 70 ° C, preferably 60 ° C to 70 ° C. The reaction solution is concentrated, dispersed in water, toluene or the like, extracted with a solvent, and the extracted layer is concentrated to precipitate the ketocarboxylic acid ester (8) crystal and separate into solid and liquid. Concentration of the solid-liquid separated mother liquor gives 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7).
[0036]
The reaction for producing the N-arylcarbonylaspartic acid monoester (10) from the N-arylcarbonylaspartic acid anhydride (2) is carried out by reacting 0.5 mol of lower alcohol with respect to 1 mol of N-arylcarbonylaspartic acid anhydride (2). ˜2 mol, preferably 0.8 to 1.2 mol, more preferably 1.0 mol is used. The reaction temperature is room temperature to 100 ° C, preferably 50 to 90 ° C, more preferably 60 to 80 ° C. This reaction solution can be used for the reaction for producing the acetylazlactone compound (11) without isolating the product. Acetic anhydride 0.5 to 20 mol, preferably 1.0 to 15 mol, more preferably 2.0 to 10 mol and base 0.001 to 1.0 mol of N-arylcarbonylaspartic acid monoester (10) Mol to 20 mol, preferably 0.01 to 10 mol, more preferably 0.1 to 5 mol is used. Bases include triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, and 2,6-lutidine 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1-methylpiperidine, 4-dimethylaminopyridine, 1-methylmorpholine, potassium hydroxide, sodium hydroxide, potassium carbonate, carbonic acid Organic and inorganic bases such as sodium, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium acetate, sodium acetate can be used. The reaction temperature is room temperature to 120 ° C, preferably 50 to 110 ° C, more preferably 70 to 100 ° C. After concentrating the reaction solution, a solvent such as water is added, and the precipitated acetylazlactone compound (11) can be subjected to solid-liquid separation. The reaction solution can also be used for the reaction for producing N-arylcarbonyl-α-acetylaspartic acid monoester (12) without isolating the product.
[0037]
The reaction for producing N-arylcarbonyl-α-acetylaspartic acid monoester (12) from acetylazlactone compound (11) is carried out with 0.5 to 2.0 water per 1.0 mol of acetylazlactone compound (11). Mol, preferably 0.8 to 1.2 mol, more preferably 1.0 mol. The reaction temperature is room temperature to 100 ° C, preferably 50 to 90 ° C, more preferably 60 to 80 ° C. This reaction solution can be used as it is for the reaction for producing the lactone compound (3). On the other hand, the desired N-arylcarbonyl-α-acetylaspartic acid monoester represented by the formula (12) may be taken out by subjecting the reaction solution to operations such as concentration, extraction and solid-liquid separation.
[0038]
The reaction for producing the lactone compound (3) and the ketocarboxylic acid (9) from the N-arylcarbonyl-α-acetylaspartic acid monoester (12) is performed by converting the N-arylcarbonyl-α-acetylaspartic acid monoester (12) to an acidic compound. Reacts in the presence of There is no restriction | limiting in particular in the usage-amount of an acidic compound, and what is necessary is just to consider considering the fluidity | liquidity of a reaction liquid, volumetric efficiency, a yield, etc. The reaction temperature is 50 to 200 ° C, preferably 100 to 180 ° C, more preferably 130 to 150 ° C. The reaction solution is concentrated, water is added, and the precipitated lactone compound (3) can be separated by solid-liquid separation. When the separated mother liquor obtained by solid-liquid separation of the lactone compound (3) is allowed to stand, crystals precipitate, and the ketocarboxylic acid (9) can be taken out by solid-liquid separation. This reaction solution can be used as it is or in a reaction to produce 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6).
[0039]
The reaction for producing the ketocarboxylic acid ester (8) from the ketocarboxylic acid (9) is carried out in an amount of 0.001 to 5 mol, preferably 0.01 to 2 mol, of an acidic compound such as sulfuric acid and hydrochloric acid with respect to 1.0 mol of the reaction substrate. More preferably, 0.1 to 0.5 mol and 3 to 100 mol of lower alcohol, preferably 5 to 50 mol, more preferably 7 to 30 mol are used. The reaction temperature is 40 ° C to 70 ° C, preferably 60 ° C to 70 ° C. The reaction solution is concentrated, dispersed in water, toluene, etc., extracted with a solvent, and the extracted layer is concentrated to precipitate the ketocarboxylic acid ester (8) crystal, which can be solid-liquid separated. The reaction solution can be concentrated and used in a reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7).
[0040]
The reaction to produce 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7) from 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6) 0.001 to 5 mol, preferably 0.01 to 2 mol, more preferably 0.1 to 0.5 mol and lower alcohol 3 to 100 mol, preferably 0.1 to 0.5 mol, such as sulfuric acid and hydrochloric acid, relative to 0 mol 5 to 50 mol, more preferably 7 to 30 mol is used. The reaction temperature is 40 ° C to 70 ° C, preferably 60 ° C to 70 ° C. The reaction solution is concentrated, dispersed in water, toluene, etc., extracted with a solvent, and the extracted layer is concentrated to isolate 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7). .
[0041]
The reaction for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7) from the lactone compound (3) and the ketocarboxylic acid (9) production reaction solution is carried out with respect to 1.0 mol of the reaction substrate. 0.001 to 5 mol, preferably 0.01 to 2 mol, more preferably 0.1 to 0.5 mol, and lower alcohol 3 to 100 mol, preferably 5 to 50 mol, of an acidic compound such as sulfuric acid and hydrochloric acid. More preferably, 7 to 30 mol is used. The reaction temperature is 40 ° C to 70 ° C, preferably 60 ° C to 70 ° C. The reaction solution is concentrated, dispersed in water, toluene or the like and extracted with a solvent to obtain a mixture of 2- (5-methyl-2-aryl-4-oxazolyl) acetate (7) and ketocarboxylate (8). I can do it. Using 0.01 to 2 mol, preferably 0.1 to 1.0 mol, more preferably 0.2 to 0.8 mol of phosphorus oxychloride with respect to 1.0 mol of this mixture, the reaction temperature is 50 to 120. The ketocarboxylic acid ester (8) is converted to 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (7) by reacting at 0 ° C., preferably 80 to 120 ° C., more preferably 90 to 110 ° C. I can do it. 2- (5-Methyl-2-aryl-4-oxazolyl) acetic acid ester (7) is obtained by dispersing this reaction liquid in water, toluene or the like, and extracting and concentrating the solvent.
[0042]
The reaction for producing the ketocarboxylic acid (9) from the lactone compound (3) can be obtained by dispersing the lactone compound in water and considering the fluidity, volumetric efficiency, and yield without any limitation on the amount of water. 0.5 to 10 mol, preferably 0.00.9 to 2 mol, more preferably 1.0 to 1.5 mol of alkali (for example, sodium hydroxide) is used per 1.0 mol of lactone compound (3). . The reaction temperature is room temperature to 100 ° C, preferably 40 to 80 ° C, more preferably 50 to 70 ° C. The reaction solution is acidified with sulfuric acid or the like, and the precipitated crystals are separated into solid and liquid to obtain ketocarboxylic acid (9).
[0043]
The reaction for producing the ketocarboxylic acid compound (9) from the acetyl azlactone compound (4) and the diacetyl azlactone compound (5) is carried out by dispersing the acetyl azlactone compound (4) and the diacetyl azlactone compound (5) in water. . The amount of water at this time can be set to an appropriate amount in consideration of fluidity, volumetric efficiency, and yield. Hydrolysis may be performed in the presence of an acidic compound such as sulfuric acid, hydrochloric acid, and acetic acid. The reaction temperature is preferably 0 to 100 ° C, preferably 40 to 90 ° C, more preferably 60 to 80 ° C. The ketocarboxylic acid compound (9) can be obtained by cooling the reaction solution and solid-liquid separating the precipitated crystals.
[0044]
The reaction to produce the acetyl azlactone compound (4) from the ketocarboxylic acid (9) involves dispersing the ketocarboxylic acid (9) in an aromatic hydrocarbon such as acetic acid or toluene.・ Can be selected considering the yield. Acetic anhydride is used in an amount of 0.5 to 20 mol, preferably 1.0 to 10 mol, more preferably 1.5 to 8 mol, per 1.0 mol of ketocarboxylic acid (9). An acid such as P-toluenesulfonic acid is used in the range of 0.0001 to 10.0 weight with respect to 1.0 weight of ketocarboxylic acid (9) depending on the acid used. The reaction temperature is room temperature to 120 ° C, preferably 50 to 100 ° C, more preferably 60 to 80 ° C. The reaction solution is concentrated, water is added, and the precipitated crystals are solid-liquid separated to obtain the acetylazlactone compound (4). It can also be used for the reaction which produces | generates 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid (6), without isolating a product by concentrating a reaction liquid.
[0045]
EXAMPLES Next, although an Example demonstrates this invention in detail, the Example described here is for demonstrating this invention, and should not be understood to limit this invention.
[0046]
【Example】
Example 1
Synthesis of N-benzoylaspartic acid (1) from L-aspartic acid
66.6 g of L-aspartic acid was dispersed in 320 g of water. While stirring the slurry, a 48% aqueous sodium hydroxide solution was added dropwise at 20 to 30 ° C. to adjust the pH in the system to 9.5 to 10.0. While stirring this solution, 70.3 g of benzoyl chloride was added at 20 to 30 ° C. over 3 hours while maintaining the pH in the system at 9.5 to 10.5. After stirring at 20-30 ° C. for 1 hour at a pH of 9.5 to 10.5 at the system, the reaction solution was dispersed in a 12 wt% hydrochloric acid aqueous solution (306.3 g) at 40 to 45 ° C. The slurry was cooled to 20-25 ° C. and filtered, and the crystals were washed with 200 g of water. The obtained crystals were dried to obtain 114.0 g of N-benzoylaspartic acid (1). Yield 96%
mp 180.5-182.0 ℃ (dec.)
MS ESI (neg) m / z 236 [MH]
IR (KBr) ν = 3323 (NH), 2940 (OH), 1706 (C = O), 1649 (C = O, amide)
¹ H-NMR (DMSO, ppm) δ = 2.78, 2.91 (2H, ABX system, J _AB = 16.6 Hz, J _AX = 5.8 Hz, J _BX = 7.8 Hz, CH ₂ ), 4.80 (1H, q, J _AX = 5.8 Hz, J _BX = 7.8 Hz, CH), 7.83-7.86 (5H, aromatic H), 8.73 (1H, d, J = 7.8 Hz, NH), 12.56 (2H, br, CO ₂ H)
[0047]
(Example 2)
Synthesis of N-benzoylaspartic anhydride (2) from N-benzoylaspartic acid (1)
103.4 g of N-benzoylaspartic acid (1) was dispersed in a mixed solution of 206.8 g of acetic acid and 229.4 g of acetic anhydride. The mixture was stirred at 87 to 89 ° C. for 4 hours, cooled to 6 ° C., filtered, and the crystals were washed with 101.8 g of t-butyl-methyl ether. The obtained crystals were dried to obtain 88.9 g of N-benzoylaspartic anhydride (2). Yield 93%
Formula (2) N-benzoyl-L-aspartic anhydride
mp 198.6-204.6 ℃ (dec.)
MS (APCI) m / z 220 [M + H], 252 [M + H + MeOH]
IR (KBr) ν = 3328 (NH), 1864 (C = O), 1784 (C = O)
¹ H-NMR (DMSO-d ₆ , ppm) δ = 3.02, 3.32 (2H, ABX system, J _AB = 18.6 Hz, J _AX = 10.0 Hz, J _BX = 5.8 Hz, CH ₂ ), 4.83 (1H, J _AX = 10.0 Hz, J _BX = 5.8 Hz, CH), 7.4-7.9 (5H, arom H), 9.49 (1H, d, J = 7.0 Hz, NH)
[0048]
(Example 3)
Synthesis of N-benzoylaspartic acid monomethyl ester (10) from N-benzoylaspartic acid (1)
95.0 g of N-benzoylaspartic acid (1) was dispersed in a mixed solution of 190.0 g of acetic acid and 212.4 g of acetic anhydride. The mixture was stirred at 87 to 89 ° C for 4 hours, cooled to 65 to 70 ° C, and methanol was added over 3 hours. Furthermore, the mixture was stirred for 6 hours in the same temperature range to obtain a uniform solution. Then, after concentration under reduced pressure to remove the solvent, recrystallization from ethyl acetate gave 45.0 g of N-benzoylaspartic acid monomethyl ester (10). Yield 45%
mp 121-122 ℃ (AcOEt)
MS (ESI) m / z 250 [MH]
IR (KBr) ν (cm ^-1 ) = 3331 (NH), 3170 (OH), 1759 (C = O), 1722 (C = O, ester), 1675 (C = O, amide)
¹ H-NMR (CDCl _Three , ppm) δ = 3.04, 3.18 (2H, ABX system, J _AB = 17.6 Hz, J _AX = 4.4 Hz, J _BX = 4.5 Hz, CH ₂ ), 3.78 (3H, s, CO ₂ CH _Three ), 5.07 (1H, J _AX = 4.4 Hz, J _BX = 4.5 Hz, CH), 7.26 (1H, s, NH), 7.4-7.8 (5H, arom H), 9.1 (1H, br, CO ₂ H)
[0049]
(Example 4)
Synthesis of acetylazlactone compound (11) from N-benzoylaspartic acid monomethyl ester (10)
To 132.2 g of N-benzoylaspartic acid monomethyl ester (10), 537.2 g of acetic anhydride was added and stirring was started. While cooling to below 20 ° C, 362.1 g of triethylamine and 6.4 g of DMAP were added. After stirring at room temperature for 1 hour, the mixture was heated to 90 ° C and reacted for 2 hours. The reaction mixture was dispersed in 5266 g of water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then treated with activated carbon and concentrated under reduced pressure to obtain 94.2 g of an acetylazlactone compound (11). Yield 65%
mp 100-101 ℃ (i-PrOH)
MS (APCI) m / z 276 [M + H]
IR (KBr) ν (cm ^-1 ) = 1793 (C = O, lactone), 1741 (C = O, ester), 1646 (C = N)
¹ H-NMR (CDCl _Three , ppm) δ = 1.83 (3H, s, COCH _Three ,), 3.10 (1H, d, J = 18 Hz, CH ₂ ), 3.73 (1H, d, J = 18 Hz, CH ₂ ), 3.84 (3H, s, CO ₂ CH _Three ), 7.2-8.0 (5H, m, arom H)
[0050]
(Example 5)
Synthesis of lactone compound (3) from acetyl azlactone compound (11)
Acetic acid 262.4 g and water 4.6 g were added to 47.1 g of acetyl azlactone compound (11), and the reaction was carried out in an autoclave at 130 to 150 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with ethyl acetate. The obtained crude crystals were recrystallized from methanol to obtain 5.6 g of a lactone compound (3). Yield 15%
mp 172-173 ° C (CH _Three OH)
MS (APCI) m / z 218 [M + H], 235 [M + NH _Four ]
IR (KBr) ν (cm ^-1 ) = 3311 (NH), 1725 (C = O, lactone), 1698 (C = O, amide)
¹ H-NMR (CDCl _Three , ppm) δ = 1.52 (3H, d, CH _Three , J = 6.6 Hz), 5.27 (1H, q, CH, J = 6.6 Hz), 6.17 (1H, s, = CH-), 7.5-7.8 (5H, m, arom H), 11.0 (1H, br, NH)
[0051]
(Example 6)
Synthesis of N-benzoyl-α-acetylaspartic acid monomethyl ester (12) from acetyl azlactone compound (11)
0.55 g of acetyl azlactone compound (11) was added to a mixed solution of 3.1 g of acetic acid and 0.36 g of water and heated at 70-80 ° C. for 6 hours with stirring. The reaction solution was concentrated under reduced pressure. 0.6 g of the concentrated residue was dissolved in 20 g of chloroform, washed with 40 g of water twice, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 0.5 g of the concentrated residue was recrystallized with a mixed solvent of 3.0 ml of ethyl acetate and 3.8 ml of n-hexane to obtain 0.25 g of N-benzoyl-α-acetylaspartic acid monomethyl ester (12). Yield 43%
mp 115.9-118.9 ° C (AcOEt / hexane.)
MS (APCI) m / z 294 [M + H]
IR (KBr) ν (cm ^-1 ) = 3352 (NH), 3165 (OH), 1774 (C = O), 1741 (C = O)
¹ H-NMR (CDCl _Three , ppm) δ = 2.20 (3H, s, COCH _Three ,), 3.57 (1H, d, J = 18 Hz, CH ₂ ), 3.76 (1H, d, J = 18 Hz, CH ₂ ), 3.79 (3H, s, CO ₂ CH _Three ), 7.4-7.8 (5H, m, arom H)
[0052]
(Example 7)
Synthesis of acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic acid (1)
To a mixed solution of 114.5 g of acetic acid and 123.2 g of acetic anhydride, 60.3 g of the formula N-benzoylaspartic acid (1) was added with stirring and reacted at 98 ° C. for 2 hours. Next, 28.0 g of 2,3-lutidine was added and reacted at 90 ° C. for 2 hours and at 114 ° C. for 2 hours, followed by concentration under reduced pressure to remove the solvent. Extraction was performed by adding 100 ml of water and 100 ml of chloroform to the concentrated residue, and then the organic layer was washed with 100 ml of water. The organic layer was washed with 5% hydrochloric acid, activated carbon treatment, 2N aqueous sodium hydroxide solution, 2N hydrochloric acid and water, then dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to obtain 22.3 g of a concentrated residue. 1.0 g of the concentrated residue was purified by column chromatography to obtain 0.3 g of acetyl azlactone compound (4) and 0.2 g of diacetyl azlactone compound formula (5).
Acetyl azlactone compound (4)
mp 92.0-93.0 ℃ (hexane)
MS (APCI) m / z 218 [M + H], 250 [M + H + MeOH]
IR (KBr) ν (cm ^-1 ) = 1789 (C = O), 1650 (C = N)
¹ H-NMR (CDCl _Three , ppm) δ = 1.91 (3H, s, COCH _Three ), 2.93, 3.06 (2H, ABX system, J _AB = 18.7 Hz, J _AX = 8.2 Hz, J _BX = 2.0 Hz, CH ₂ ), 4.62 (1H, q, J _AX = 8.2 Hz, J _BX = 2.0 Hz, CH), 7.4-8.0 (5H, arom H)
Diacetyl azlactone compound (5)
mp 90.7-91.7 ° C (hexane)
MS (APCI) m / z 260 [M + H]
IR (KBr) ν (cm ^-1 ) = 1789 (C = O), 1716 (C = O), 1647 (C = N)
¹ H-NMR (CDCl _Three , ppm) δ = 1.74 (3H, s, COCH _Three ), 2.27 (3H, s, OCOCH _Three ), 2.89 (1H, d, J = 18 Hz), 3.65 (1H, d, J = 18 Hz), 7.4-8.1 (5H, arom H)
[0053]
(Example 8)
Synthesis of lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic acid (1)
450 ml of toluene, 92.0 g of acetic anhydride, 107.0 g of N-benzoylaspartic acid (1) and 27.0 g of sodium acetate were placed in a 1000 ml four-necked Kolben equipped with a stirrer, and reacted at 90-100 ° C. for 4 hours. The HPLC analysis of the reaction solution revealed that the area ratio was 44.8% for the lactone compound (3), 41.9% for the acetyl azlactone compound (4), 12.0% for the diacetyl azlactone compound (5), and the N-benzoylaspartic acid starting material was 0.1% or less. The reaction was complete. The reaction solution was concentrated to 80 ° C./35 Torr (4.655 kPa). 150 ml of water was added to the concentrated solution under ice cooling, and the precipitated crystals were filtered and dried to obtain 85.0 g of crystals. When the obtained crystals were analyzed by HPLC, the composition ratio was 35.2% lactone compound (3), 51.8% acetyl azlactone compound (4), and 13.0% diacetyl azlactone compound (5).
[0054]
Example 9
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) from N-benzoylaspartic acid (1)
450 ml of toluene, 92.0 g of acetic anhydride, 107.0 g of N-benzoylaspartic acid (1), and 27.0 g of sodium acetate were placed in a 1000 ml four-necked Kolben equipped with a stirrer and reacted at 90-100 ° C. for 4 hours. The HPLC analysis of the reaction solution revealed that the area ratio was 44.8% for the lactone compound (3), 41.9% for the acetyl azlactone compound (4), 12.0% for the diacetyl azlactone compound (5), and the N-benzoylaspartic acid starting material was 0.1% or less. The reaction was complete. The reaction solution was concentrated to 80 ° C./35 Torr (4.655 kPa), and 439.0 g of toluene, acetic acid, and acetic anhydride were recovered. To the concentrated residue, 100 g of 98% sulfuric acid was added dropwise at 70 to 110 ° C, and then reacted at 125 ° C for 3 hours. HPLC analysis of the reaction solution contained 93.5% of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6). Disperse the reaction liquid in 480 g of water at 20-30 ° C., add 83.3 g of 48% aqueous sodium hydroxide solution, filter the precipitated crystals, wash with water, and dry, 2- (5-methyl-2-phenyl-4-oxazolyl) Acetic acid (6) 89.1g was obtained. Yield 90.9%
mp 102 ° C (CH _Three CN / H ₂ O)
MS (ESI) m / z 216 [MH]
IR (KBr) ν (cm ^-1 ) = 3430 (OH), 2924 (OH), 1712 (C = O), 1650 (C = N)
¹ H-NMR (CDCl _Three , ppm) δ = 2.35 (3H, s, CH _Three ), 3.64 (2H, s, CH ₂ ), 7.4-7.5 (3H, m, arom H), 7.9-8.0 (2H, arom H), 9.22 (1H, br, OH)
[0055]
(Example 10)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) from N-benzoylaspartic acid (1)
450 ml of toluene, 92.0 g of acetic anhydride, 107.0 g of N-benzoylaspartic acid (1), and 27.0 g of sodium acetate were placed in a 1000 ml four-necked Kolben equipped with a stirrer and reacted at 90-100 ° C. for 4 hours. The HPLC analysis of the reaction solution revealed that the area ratio was 44.8% for the lactone compound (3), 41.9% for the acetyl azlactone compound (4), 12.0% for the diacetyl azlactone compound (5), and the N-benzoylaspartic acid starting material was 0.1% or less. The reaction was complete. This reaction solution was concentrated to 80 ° C. and 35 Torr (4.655 kPa), and 439.0 g of toluene, acetic acid and acetic anhydride were recovered. To the concentrated residue, 100 g of 98% sulfuric acid was added dropwise at 70 to 110 ° C, and then reacted at 125 ° C for 3 hours. HPLC analysis of the reaction solution contained 93.5% of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6). The reaction solution was cooled to 50 ° C., 430 g of methanol was added, and the mixture was reacted at 65 to 68 ° C. for 3 hours. When the reaction solution was analyzed by HPLC, the area ratio was 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) 90.1%, 2- (5-methyl-2-phenyl-4-oxazolyl) Acetic acid (6) was 4.7%. This esterification reaction solution was concentrated to 50 Torr (6.65 kPa) at 60 ° C. to recover 341.2 g of methanol. 200 ml of toluene, 500 ml of water and 142.8 g of sodium hydrogen carbonate were placed in a 1000 ml four-necked Kolben equipped with a stirrer, and the above esterified concentrate was added dropwise at 20-30 ° C. with stirring. After the dropping, the content liquid was transferred to a separatory funnel and separated to obtain 257.6 g of a toluene extraction layer and 704.8 g of an aqueous layer. The toluene extraction layer was concentrated to 80 ° C./5 Torr (0.665 kPa) to obtain 80.1 g of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7). Yield 76.8%
MS (ACPI) m / z 232 [M + H]
IR (KBr) ν (cm ^-1 ) = 1744 (C = O), 1644 (C = N)
¹ H-NMR (CDCl _Three , ppm) δ = 2.36 (3H, s, CH _Three ), 3.57 (2H, s, CH ₂ ), 3.73 (3H, s, CO ₂ CH _Three ), 7.4-7.5 (3H, m, arom H), 7.9-8.0 (2H, arom H)
[0056]
Example 11
Synthesis of N-benzoylaspartic acid (1) to lactone compound (3) and ketocarboxylic acid (9)
64.5 g of N-benzoylaspartic acid was added to 114.5 g of acetic acid, 100 g of acetic anhydride and 20.0 g of sodium acetate, and reacted at 114 ° C. for 2 hours. The reaction mixture was analyzed by HPLC. The area ratio was 33.5% for the lactone compound (3), 43.1% for the acetyl azlactone compound (4), and 20.6% for the diacetyl azlactone compound (5). The reaction solution was cooled to 85 ° C, 13.0 g of water was added, and the mixture was reacted at 85 ° C for 7 hours. The reaction mixture was analyzed by HPLC. The area ratio was ketocarboxylic acid (9) 19.5% and lactone compound (3) 76.0%. The reaction solution was concentrated under reduced pressure to 70 ° C./50 Torr (6.65 kPa), 50.0 g of water was added at 60 ° C. and cooled to 10 ° C., and the precipitated crystals were filtered, washed with water, and dried to obtain 35.5 g of a lactone compound (3). . Yield 68.7%
When the lactone crystallization mother liquor was allowed to stand overnight, more crystals were precipitated. This was filtered, washed with water and dried to obtain 9.4 g of a ketocarboxylic acid compound (9). Yield 16.8%
mp 129-130 ℃
MS (APCI) m / z 236 [M + H]
IR (KBr) ν (cm ^-1 ) = 3298 (NH), 3053 (OH), 1725 (C = O), 1696 (C = O)
¹ H-NMR (CDCl _Three , ppm) δ = 2.15 (3H, s, COCH _Three ), 2.60, 2.89 (2H, ABX system, J _AB = 16.6 Hz, J _AX = 6.4 Hz, J _BX = 7.1 Hz, CH ₂ ), 4.71 (1H, q, J _AX = 6.4 Hz, J _BX = 7.1 Hz, CH), 7.4-7.9 (5H, arom H), 8.92 (NH, d, J = 7.5 Hz), 12.4 (1H, br, CO ₂ H)
[0057]
Example 12
Synthesis of ketocarboxylic acid methyl ester (8) and 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) mixture from N-benzoylaspartic acid (1) and isolation of ketocarboxylic acid methyl ester (8)
A 1000 ml four-necked Kolben equipped with a stirrer was charged with 183.2 g of acetic acid, 197.1 g of acetic anhydride, 91.2 g of N-benzoylaspartic acid (1) and 24.0 g of sodium acetate, and reacted at 90-100 ° C. for 4 hours. The HPLC analysis of the reaction solution revealed that the area ratio was 29.2% for the lactone compound (3), 46.1% for the acetyl azlactone compound (4), 20.0% for the diacetyl azlactone compound (5), and the N-benzoylaspartic acid starting material was 0.1% or less. The reaction was complete. The reaction solution was concentrated to 70 ° C./15 Torr (1.995 kPa) to recover 321.1 g of acetic acid / acetic anhydride. To this concentrate, 185 g of 98% sulfuric acid and 420.0 g of methanol were added at 40-60 ° C., and then reacted at 65 ° C. for 14 hours. The reaction mixture was analyzed by HPLC. The area ratio was ketocarboxylic acid methyl ester (8) 63.3% and 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) 27.5%. The reaction solution was concentrated to 45 ° C./170 Torr (22.61 kPa), and the concentrate was dispersed at 20 to 25 ° C. in 1400.0 g of water, 300 ml of toluene and 235.0 g of sodium hydrogen carbonate. This dispersion was transferred to a separating funnel to obtain 318.7 g of a toluene layer and 2013.2 g of an aqueous layer. The aqueous layer was further extracted with 200 ml of toluene to obtain 178.3 g of a toluene secondary extraction layer. The obtained toluene layer was washed with 200 ml of water and concentrated under reduced pressure to distill off 450 ml of toluene. The concentrated liquid was cooled to 5 ° C., and the precipitated crystals were filtered, washed with toluene, and dried under reduced pressure to obtain 29.6 g of ketocarboxylic acid methyl ester (8). Yield 34.2%
mp 63-69 ℃
MS (APCI) m / z 250 [M + H]
IR (KBr) ν (cm ^-1 ) = 3285 (NH), 1739 (C = O), 1724 (C = O), 1641 (C = O)
¹ H-NMR (CDCl _Three , ppm) δ = 2.31 (3H, s, COCH _Three ), 2.91, 3.12 (2H, ABX system, J _AB = 17.2 Hz, J _AX = 4.4 Hz, J _BX = 4.6 Hz, CH ₂ ), 3.71 (3H, s, CO ₂ CH _Three ), 4.96 (1H, q, J _AX = 4.4 Hz, J _BX = 4.6 Hz, CH), 7.4-7.9 (5H, arom H)
[0058]
(Example 13)
Isolation of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) from the mother liquor of Example 12
450 ml of toluene and 30.0 g of phosphorus oxychloride were added to the separation mother liquor of ketocarboxylic acid methyl ester of Example 12, and reacted at 105 ° C. for 7 hours. The reaction solution was analyzed by HPLC, and the area ratio was 2- (5-methyl-2-phenyl- 4-oxazolyl) acetic acid methyl ester (7) 84.1% and ketocarboxylic acid methyl ester (8) 1.8%. This reaction solution was dispersed at 30 to 25 ° C. in 300.0 g of water and 65.0 g of sodium hydrogen carbonate. The toluene layer was separated and concentrated under reduced pressure to 90 ° C./3 Torr (0.399 kPa) to obtain 43.2 g of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7). Yield 48.6%
[0059]
(Example 14)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) from N-benzoylaspartic acid (1)
A 1000 ml four-necked Kolben equipped with a stirrer was charged with 183.2 g of acetic acid, 197.1 g of acetic anhydride, 91.2 g of N-benzoylaspartic acid (1) and 24.0 g of sodium acetate, and reacted at 90-100 ° C. for 4 hours. The HPLC analysis of the reaction solution revealed that the area ratio was 29.2% for the lactone compound (3), 46.1% for the acetyl azlactone compound (4), 20.0% for the diacetyl azlactone compound (5), and the N-benzoylaspartic acid starting material was 0.1% or less. The reaction was complete. The reaction solution was concentrated to 70 ° C./15 Torr (1.995 kPa) to recover 321.0 g of acetic acid / acetic anhydride. To this concentrate, 185 g of 98% sulfuric acid and 420.0 g of methanol were added at 40-60 ° C., and then reacted at 65 ° C. for 14 hours. The reaction mixture was analyzed by HPLC. The area ratio was ketocarboxylic acid methyl ester (8) 63.3% and 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) 27.5%. The reaction solution was concentrated to 45 ° C./170 Torr (22.61 kPa), and the concentrate was dispersed at 20-25 ° C. in 1400.0 g of water, 300 ml of toluene, and 235.0 g of sodium hydrogen carbonate. This dispersion was separated to obtain 319.0 g of a toluene layer. The aqueous layer was further extracted with 200 ml of toluene to obtain 178.3 g of a toluene secondary extraction layer. The obtained toluene layers were mixed, heated to 110 ° C., and 40 ml of toluene was distilled off. After adding 60.0 g of phosphorus oxychloride and reacting at 105 ° C. for 7 hours, HPLC analysis of the reaction solution revealed that the area ratio was 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) 91.0%, ketocarbon Acid methyl ester (8) was not detected. The reaction solution was dispersed at 20 to 25 ° C. in 350.0 g of water, 65.0 g of sodium hydrogen carbonate and 43.0 g of sodium carbonate. The precipitated inorganic salt was filtered and washed with 100 ml of toluene, and the obtained filtrate was separated to obtain 501.1 g of a toluene layer. The toluene layer was concentrated under reduced pressure to 90 ° C. and 3 Torr (0.399 kPa) to obtain 72.0 g of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7). Yield 81.0%
[0060]
(Example 15)
Synthesis of acetylazlactone compound (4) from ketocarboxylic acid compound (9)
To 15.0 g of acetic acid and 20.0 g of acetic anhydride were added 0.1 g of p-toluenesulfonic acid and 7.1 g of ketocarboxylic acid, and the mixture was reacted at 70 ° C. for 1.5 hours. As a result of HPLC analysis of the reaction solution, the areas were 94.9% of the acetylazlactone compound (4) and 1.2% of the ketocarboxylic acid compound (9). The reaction solution was concentrated under reduced pressure to 70 ° C./15 Torr (1.995 kPa), 50 ml of water was added, and the precipitated crystals were filtered, washed with water and dried to obtain 6.0 g of an acetylazlactone compound (4). Yield 91.5%
[0061]
(Example 16)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) from lactone compound (3)
5.0 g of lactone compound (3) was added to 5.0 g of 98% sulfuric acid and reacted at 70 ° C. for 4 hours. The reaction mixture was analyzed by HPLC. The area ratio of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) of formula (6) was 100%, and the lactone compound (3) was not detected.
[0062]
(Example 17)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) from acetylazlactone compound (4)
5.0 g of acetyl azlactone compound (4) was added to 5.0 g of 98% sulfuric acid and reacted at 120 ° C. for 3 hours. The reaction mixture was analyzed by HPLC. The area ratio was 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) 100%, and no acetylazlactone compound (4) was detected.
[0063]
(Example 18)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) from diacetylazlactone compound (5)
5.0 g of diacetyl azlactone compound (5) was added to 5.0 g of 98% sulfuric acid and reacted at 120 ° C. for 3 hours. The reaction mixture was analyzed by HPLC. The area ratio was 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) 100% and the diacetylazlactone compound (5) was not detected.
[0064]
Example 19
Synthesis of ketocarboxylic acid methyl ester (8) from acetyl azlactone compound (4) 5.0 g of acetyl azlactone compound (4) was added to 10.0 g of methanol and 10.0 g of 98% sulfuric acid, and reacted at 65 ° C. for 24 hours. The reaction mixture was analyzed by HPLC. The area ratio was 97.5% ketocarboxylic acid methyl ester (8), and no acetylazlactone compound (4) was detected.
[0065]
(Example 20)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
To 0.2 g of N-benzoylaspartic anhydride (2), 0.3 g of acetic anhydride and 1.2 ml of toluene were added 0.05 g of N-methylmorpholine and 0.01 g of dimethylaminopyridine, and the mixture was reacted at 70 ° C. for 1 hour. The reaction mixture was analyzed by HPLC to find that the area ratio was lactone compound (3) 14.4%, acetyl azlactone compound (4) 22.0%, and diacetyl azlactone compound (5) 27.7%.
[0066]
(Example 21)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
N-benzoylaspartic anhydride 0.1 g, acetic anhydride 0.2 g and dimethylaminopyridine 0.01 g were added and reacted at 115 ° C. for 1 hour. When the reaction solution was analyzed by HPLC, the area ratio was lactone compound (3) 6.7%, acetyl azlactone compound (4) 30.6%, and diacetyl azlactone compound (5) 47.3%.
[0067]
(Example 22)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
N-benzoylaspartic anhydride 0.1 g, acetic anhydride 0.3 g and 2.3-lutidine 0.05 g were added and reacted at 115 ° C. for 1 hour. When the HPLC analysis of the reaction solution, the area ratio is lactone compound (3) 3.0%, acetyl azlactone compound (4) 27.2%, diacetyl azlactone compound (5) 24.3%, N-benzoylaspartic anhydride (2) 38.8% Met.
[0068]
(Example 23)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
N-benzoylaspartic anhydride (2) 0.1 g, acetic anhydride 0.4 g, and pyridine 0.05 g were added and reacted at 70 ° C. for 1 hour. The reaction mixture was analyzed by HPLC. The area ratio was 2.5% for the lactone compound (3), 47.2% for the acetylazlactone compound (4), and 24.9% for the diacetylazlactone compound (5).
[0069]
(Example 24)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
N-benzoylaspartic anhydride 1.0 g, acetic anhydride 4.5 g, acetic acid 4.3 g, and triethylamine 1.0 g were added and reacted at 70 ° C. for 2 hours. When the reaction solution was analyzed by HPLC, the area ratio was 2.0% for the lactone compound (3), 37.5% for the acetylazlactone compound (4), and 42.2% for the diacetylazlactone compound (5).
[0070]
(Example 25)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
N-benzoylaspartic anhydride 1.0 g, acetic anhydride 2.0 g and triethylamine 0.4 g were added and reacted at 90 ° C. for 2 hours. When the reaction solution was analyzed by HPLC, the area ratio was lactone compound (3) 2.8%, acetyl azlactone compound (4) 16.8%, and diacetyl azlactone compound (5) 35.2%.
[0071]
(Example 26)
Synthesis of a mixture containing lactone compound (3), acetyl azlactone compound (4) and diacetyl azlactone compound (5) from N-benzoylaspartic anhydride (2)
100 ml of toluene was added to 21.9 g of N-benzoylaspartic anhydride (2), 10.2 g of acetic anhydride and 6.0 g of sodium acetate, and reacted at 95 ° C. for 12 hours. When the reaction solution was analyzed by HPLC, the area ratio was 45.0% for the lactone compound (3), 41.9% for the acetyl azlactone compound (4), and 12.1% for the diacetyl azlactone compound (5). The reaction solution was concentrated to 35 Torr (4.655 kPa) at 90 ° C, 50 ml of water was added to the concentrated residue at room temperature, and the precipitated crystals were filtered, washed with water, and dried under reduced pressure to mix the compounds of formulas (3), (4), and (5) 19.3 g of crystals were obtained. When the obtained crystals were analyzed by HPLC, the composition ratio was 35.2% lactone compound (3), 51.8% acetyl azlactone compound (4), and 13.0% diacetyl azlactone compound (5). Yield 87.1%
[0072]
(Example 27)
Synthesis of ketocarboxylic acid compound (9) from lactone (3)
To 5 ml of 10% NaOH aqueous solution, 0.1 g of lactone compound (3) was added and reacted at 60 ° C. for 1 hour. When 1.5 g of concentrated sulfuric acid was added to the reaction solution and the reaction solution was subjected to HPLC analysis, the area ratio was 100% of the ketocarboxylic acid compound (9).
[0073]
(Example 28)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) from 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6)
4- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) 45.0 g, methanol 200 g, and sulfuric acid 1.0 g were added and reacted at 65-68 ° C. for 3 hours. After the reaction, the mixture was concentrated to 40 ° C. and 15 Torr (1.995 kPa). The concentrated solution was dispersed in 50 g of water, 1.7 g of sodium bicarbonate and 200 ml of toluene at room temperature, and the toluene layer was separated. The toluene layer was dried over magnesium sulfate and concentrated to obtain 44.7 g of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7). Yield 93.3%
[0074]
(Example 29)
Synthesis of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7) from 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6)
2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid (6) 45.0 g and 10% HCl-methanol 220 g were added and reacted at 65-68 ° C. for 3 hours. After the reaction, the mixture was concentrated to 40 ° C. and 15 Torr (1.995 kPa). The concentrated solution was dispersed in 50 g of water and 200 ml of toluene at room temperature, and the toluene layer was separated. The toluene layer was dried over magnesium sulfate and concentrated to obtain 45.6 g of 2- (5-methyl-2-phenyl-4-oxazolyl) acetic acid methyl ester (7). Yield 95.3%
[0075]
(Example 30)
Synthesis of N- (4-methylphenyl) aspartic acid from L-aspartic acid
26.6 g of L-aspartic acid was dispersed in 128 g of water. While stirring the slurry, a 48% aqueous sodium hydroxide solution was added dropwise at 20 to 30 ° C. to adjust the pH in the system to 9.5 to 10.0. While stirring this solution, 30.9 g of p-toluoyl chloride was added at 20 to 30 ° C. over 3 hours while maintaining the pH in the system at 9.5 to 10.5. The mixture was stirred at 20-30 ° C. for 1 hour while maintaining the pH in the system at 9.5-10.5, and then the reaction solution was dispersed in a 12 wt% hydrochloric acid aqueous solution (122.5 g) at 40-45 ° C. The slurry was cooled to 20-25 ° C. and filtered, and the crystals were washed with 100 g of water. The obtained crystals were dried to obtain 46.6 g of N- (4-methylphenyl) aspartic acid. Yield 93%
[0076]
(Example 31)
Synthesis of 2- [2- (4-methylphenyl) -4-methyloxazolyl] acetic acid methyl ester from N- (4-methylphenyl) aspartic acid (1)
A 1000 ml four-necked Kolben equipped with a stirrer was charged with 50 ml of toluene, 10.2 g of acetic anhydride, 12.6 g of N- (4-toluoyl) aspartic acid and 3.0 g of sodium acetate, and reacted at 90-100 ° C. for 4 hours. When the reaction mixture was analyzed by HPLC, the area ratio was 24.0% for the lactone compound, 52.9% for the acetyl azlactone compound, 10.0% for the diacetyl azlactone compound, and 0.1% or less for the starting N- (4-methylphenyl) aspartic acid, and the reaction was completed. It was. This reaction solution was concentrated to 80 ° C. and 35 Torr (5.655 kPa), and 11.1 g of 98% sulfuric acid was added dropwise to the concentrated residue at 70 to 110 ° C., followed by reaction at 125 ° C. for 3 hours. HPLC analysis of the reaction solution contained 90.5% 2- [2- (4-methylphenyl) -4-methyloxazolyl] acetic acid. The reaction solution was cooled to 50 ° C., 46.0 g of methanol was added, and the mixture was reacted at 65 to 68 ° C. for 3 hours. HPLC analysis of the reaction mixture revealed that the area ratio was 2- [2- (4-methylphenyl) -4-methyloxazolyl] acetic acid methyl ester 90.0%, 2- [2- (4-methylphenyl) -4-methyl Oxazolyl] acetic acid was 5.1%. The esterification reaction solution was concentrated to 50 Torr (6.65 kPa) at 60 ° C. To a 1000 ml four-necked Kolben equipped with a stirrer, 22 ml of toluene, 55 ml of water and 15.7 g of sodium hydrogen carbonate were added, and the above esterified concentrate was added dropwise at 10 to 15 ° C. with stirring. After the dropping, the content liquid was transferred to a separating funnel and separated to obtain 35.7 g of a toluene extraction layer. The toluene extraction layer was concentrated to 80 ° C. and 5 Torr (0.655 kPa) to obtain 8.7 g of methyl 2- [2- (4-methylphenyl) -4-methyloxazolyl] acetate. Yield 71.0%
mp 62-63 ℃
MS (APCI) m / z 246 [M + H]
IR (KBr) ν (cm ^-1 ) = 1737 (C = O), 1653 (C = N)
¹ H-NMR (CDCl _Three , ppm) δ = 2.35 (3H, s, CH _Three ), 2.38 (3H, s, CH _Three ), 3.57 (2H, s, CH _Three ), 3.73 (3H, s, CH _Three ), 7.22 (2H, d, J = 8.1Hz, arom H), 7.86 (2H, d, J = 8.1Hz, arom H)
[0077]
(Comparative Example 1)
Synthesis of ketocarboxylic acid methyl ester (8) from N-benzoylaspartic acid monomethyl ester (10) (additional test of JP 2000-143643)
N-benzoylaspartic acid monomethyl ester (10) 1.0 g, acetic anhydride 1.6 g, toluene 4.5 g, N-methylmorpholine 20 mg and 5 mg of dimethylaminopyridine were added and reacted at 55-60 ° C. for 4 hours. The reaction solution was tar-like and HPLC analysis showed that the unreacted N-benzylaspartic acid monomethyl ester (10) was 33% in area ratio and the target ketocarboxylic acid methyl ester (8) was not detected.
[0078]
(Comparative Example 2)
Synthesis of ketocarboxylic acid methyl ester (8) from N-benzoylaspartic acid monomethyl ester (10) (see organic syntheses coll., Vol.4)
0.4 g of N-benzoylaspartic acid monomethyl ester (10), 1.0 g of acetic anhydride and 0.7 g of pyridine were added and reacted at 100 ° C. for 6 hours. The reaction mixture was tar-like and HPLC analysis showed that the unreacted N-benzylaspartic acid monomethyl ester was 23.2% (10) in area ratio and the target ketocarboxylic acid methyl ester (8) was not detected.

Claims (33)

Chemical formula (1)

By reacting N-arylcarbonylaspartic acid represented by the formula (wherein any of L-form, D-form and racemic form, Ar represents substituted aryl or unsubstituted aryl) with acetic anhydride, the chemical formula (2)

N-arylcarbonylaspartic anhydride represented by the formula (However, any of L-form, D-form, and racemate may be used, Ar represents substituted aryl or unsubstituted aryl), and the N-aryl By reacting carbonyl aspartic anhydride with acetic anhydride in the presence of a base, the chemical formula (3)

A lactone compound represented by the formula (4)

Acetyl azlactone compound represented by the chemical formula (5)

At least one novel lactone compound selected from the group consisting of diacetylazlactone compounds represented by the formula (1), and treating at least one of the lactone compounds with concentrated sulfuric acid to give a chemical formula (6)

2- (5-methyl-2-aryl-4-oxazolyl) acetic acid represented by the formula (2) is produced, and the 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid is esterified. Chemical formula (7)

A process for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (R represents a lower alkyl group).  The base is triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6 -Lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1-methylpiperidine, 4-dimethylaminopyridine, 1-methylmorpholine, potassium hydroxide, sodium hydroxide, potassium carbonate 2- (5-methyl-2-aryl-4) according to claim 1, characterized in that it is at least one selected from the group consisting of sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium acetate, and sodium acetate. -Method for producing oxazolyl) acetate.  The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate according to claim 2, wherein the base is sodium acetate. The 2- (5-methyl) according to claim 1, 2 or 3, wherein at least one selected from the group consisting of benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, monochlorobenzene and dichlorobenzene is used as a solvent. -2-Aryl-4-oxazolyl) acetic acid ester production method. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate according to claim 4 , wherein the solvent is toluene. Represented by chemical formula (2)

N-arylcarbonylaspartic anhydride (which may be any of L-form, D-form, and racemate, Ar represents substituted aryl or unsubstituted aryl) is reacted with acetic anhydride in the presence of a base, Chemical formula (3)

A lactone compound represented by the formula (4)

Acetyl azlactone compound represented by the chemical formula (5)

A method for producing a novel lactone compound, comprising producing at least one selected from diacetyl azlactone compounds represented by the formula: The base is triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6 -Lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1-methylpiperidine, 4-dimethylaminopyridine, 1-methylmorpholine, potassium hydroxide, sodium hydroxide, potassium carbonate The method for producing a novel lactone compound according to claim 6, which is at least one selected from the group consisting of sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium acetate, and sodium acetate. The method for producing a novel lactone compound according to claim 7 , wherein the base is sodium acetate. 9. The production of a novel lactone compound according to claim 6, 7 or 8, wherein at least one selected from the group consisting of benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, monochlorobenzene and dichlorobenzene is used as a solvent. Method. The method for producing a novel lactone compound according to claim 9 , wherein the solvent is toluene. Chemical formula (3)

A lactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (4)

Acetyl azlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (5)

Wherein at least one novel lactone compound selected from the group consisting of diacetylazlactone compounds (Ar represents substituted aryl or unsubstituted aryl) is treated with concentrated sulfuric acid (6)

A process for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid represented by the formula: The 2- (5-methyl-2-aryl) according to claim 11, wherein at least one selected from the group consisting of benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, monochlorobenzene and dichlorobenzene is used as a solvent. -4-Oxazolyl) Acetic acid production method. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid according to claim 12 , wherein the solvent is toluene. Chemical formula (5)

(Ar represents a substituted aryl or unsubstituted aryl, and the substituent is a halogen group (fluoro, chloro, bromo, iodo), an alkyl group (methyl, ethyl, propyl, butyl), a nitro group ) Diacetyl azlactone compound. Chemical formula (3)

A lactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl) is reacted with a lower alcohol in the presence of concentrated sulfuric acid (7)

A process for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester (R represents a lower alkyl group). The 2- (5-methyl-2-aryl) according to claim 15, wherein at least one selected from the group consisting of benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, monochlorobenzene and dichlorobenzene is used as a solvent. -4-Oxazolyl) acetate production method. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate according to claim 16 , wherein the solvent is toluene. Chemical formula (4)

An acetyl azlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), or a chemical formula (5)

Is reacted with a lower alcohol in the presence of concentrated sulfuric acid in the presence of concentrated sulfuric acid to give a chemical formula (8)

A ketocarboxylic acid ester represented by the formula (wherein L may be any of D, D and racemates, Ar represents a substituted aryl or unsubstituted aryl, and R represents a lower alkyl group), and the ketocarboxylic acid Chemical formula (7) characterized by cyclizing an ester under dehydrating conditions

A process for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate represented by the formula: The 2- (5-methyl-2-aryl) according to claim 18, wherein at least one selected from the group consisting of benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, monochlorobenzene, and dichlorobenzene is used as a solvent. -4-Oxazolyl) acetate production method. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate according to claim 19 , wherein the solvent is toluene. Chemical formula (3)

A lactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (4)

Acetyl azlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (5)

By reacting at least one novel lactone compound selected from diacetyl azlactone compounds represented by the formula (Ar represents substituted aryl or unsubstituted aryl) with a lower alcohol in the presence of concentrated sulfuric acid , 7)

2- (5-Methyl-2-aryl-4-oxazolyl) acetate (R represents a lower alkyl group) represented by the formula (8)

2- (5-methyl-), wherein a mixture of ketocarboxylic acid esters represented by the formula (R represents a lower alkyl group) is produced, and the ketocarboxylic acid ester contained in the mixture is cyclized under dehydrating conditions. 2-aryl-4-oxazolyl) acetic acid ester production method. The 2- (5-methyl-2-aryl) according to claim 21, wherein at least one selected from the group consisting of benzene, toluene, ethylbenzene, cumene, xylene, mesitylene, monochlorobenzene and dichlorobenzene is used as a solvent. -4-Oxazolyl) acetate production method. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate according to claim 22 , wherein the solvent is toluene. Chemical formula (3)

A lactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (4)

Acetyl azlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (5)

By hydrolyzing at least one novel lactone compound of the diacetylazlactone compound (Ar represents substituted aryl or unsubstituted aryl) represented by the formula (9)

A ketocarboxylic acid compound represented by the formula (wherein any of L-form, D-form and racemic form, Ar represents substituted aryl or unsubstituted aryl), and esterification of the ketocarboxylic acid compound According to chemical formula (8)

A ketocarboxylic acid ester represented by the formula (R represents a lower alkyl group), and the ketocarboxylic acid ester is cyclized under dehydration conditions (7)

A process for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetate represented by the formula: The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester according to claim 24, wherein the hydrolysis is performed under basic conditions. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester according to claim 25, wherein the hydrolysis is performed in an aqueous sodium hydroxide solution. The esterification is carried out in the presence of at least one acidic compound selected from the group consisting of concentrated sulfuric acid, hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and strongly acidic ion exchange resin. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester according to claim 24, 25 or 26, wherein 28. The method for producing 2- (5-methyl-2-aryl-4-oxazolyl) acetic acid ester according to claim 27, wherein the acidic compound is concentrated sulfuric acid. Chemical formula (3)

A lactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (4)

Acetyl azlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl), chemical formula (5)

Wherein at least one novel lactone compound of the diacetyl azlactone compound represented by the formula (Ar represents substituted aryl or unsubstituted aryl) is hydrolyzed:

A method for producing a ketocarboxylic acid compound represented by the formula (However, any of L-form, D-form and racemate may be used, and Ar represents substituted aryl or unsubstituted aryl). Chemical formula (10)

N-arylcarbonylaspartic acid monoester represented by the formula (wherein L may be any of D, D and racemates, Ar represents a substituted aryl or unsubstituted aryl, and R represents a lower alkyl group) Reaction with acetic anhydride in the presence of chemical formula (11)

The manufacturing method of the acetyl azlactone compound represented by these. Chemical formula (11)

The compound represented by the chemical formula (12) is characterized by hydrolyzing an acetylazlactone compound represented by the formula (Ar is substituted aryl or unsubstituted aryl, R represents a lower alkyl group):

The manufacturing method of N-aryl carbonyl- alpha-acetyl aspartic acid monoester represented by these. Chemical formula (11)

(Ar represents a substituted aryl or unsubstituted aryl, R represents a lower alkyl group, and the substituent is a halogen group (fluoro, chloro, bromo, iodo), an alkyl group (methyl, ethyl, propyl, butyl), or a nitro group ) A novel acetylazlactone compound represented by: Chemical formula (12)

(Ar represents a substituted aryl or unsubstituted aryl, R represents a lower alkyl group, and the substituent is a halogen group (fluoro, chloro, bromo, iodo), an alkyl group (methyl, ethyl, propyl, butyl), or a nitro group ) A novel N-arylcarbonyl-α-acetylaspartic acid monoester represented by the formula: