JP4491104B2 - Method for producing carbonyl compound - Google Patents

Description

【０００８】
（式中、Ｒ１及びＲ２は、互いに独立して水素原子、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換のヘテロ環残基を表し、Ｒ１とＲ２が同時に水素原子を表すことはない。また、Ｒ１とＲ２は結合して、それらが結合している炭素原子と共に非金属原子からなる置換または非置換の環を形成していても良い。Ｒ３、Ｒ４及びＲ５は、互いに独立して置換または非置換のアルキル基、置換または非置換のアリール基を表す。また、Ｒ３、Ｒ４及びＲ５の任意の２つの置換基は結合して、それらが結合している炭素原子と共に非金属原子からなる置換または非置換の環を形成してもよい。Ｘはハロゲン原子を表す。）
（２） 一般式（Ｉ）におけるＲ１及びＲ２のうち少なくとも１つが、置換又は非置換の窒素原子及び／又は硫黄原子を含有するヘテロ環残基を置換基として有する、アルキル基、アリール基又はヘテロ環残基である前記（１）に記載のカルボニル化合物の製造方法。
（３） 一般式（Ｉ）におけるＲ１及びＲ２のうち少なくとも１つが、置換又は非置換のアミノ基を置換基として有する、アルキル基、アリール基又はヘテロ環残基である前記（１）に記載のカルボニル化合物の製造方法。
（４） 一般式（Ｉ）におけるＲ１及びＲ２のうち少なくとも１つが、置換又は非置換のインドリニル残基を置換基として有するアルキル基である前記（１）に記載のカルボニル化合物の製造方法。
【０００９】
本発明は、出発物質である一般式（Ｉ）で表されるニトロ化合物を、一般式（ＩＩ）で表されるシリル化合物と反応させる。このとき、シリルニトロナート化合物の如き中間体が生成していると思われる。この中間体に過酸化水素を反応させることにより、一般式(III）で表されるカルボニル化合物が得られる。本発明は、温和な条件で反応が進行し、また分子内にアミノ基や含窒素環、チオエーテルが存在する場合や、一級ニトロアルカン類等の基質からアルデヒド類を製造する場合でも、酸化や加水分解といった副反応が起こらないため目的のカルボニル化合物を高収率且つ高純度で得ることができる。
【００１０】
【発明の実施の形態】
以下に本発明について、詳細に説明する。
本発明の方法で使用されるニトロ化合物は、上記した通りの一般式（Ｉ）で表わされるが、一般式（Ｉ）におけるＲ１及びＲ２は、互いに独立して水素原子、置換または非置換のアルキル基、置換または非置換のアリール基、置換または非置換のヘテロ環残基を表す。具体的には水素原子；メチル、エチル、イソプロピル、ｔ−ブチル、シクロペンチル、シクロヘキシル等の直鎖、分岐または環状のアルキル基；フェニル、ナフチル、フェナントリル等のアリール基；フリル、ピリジル、キノリル、イソキノリル、クマリニル、ベンゾチアゾリル、イミダゾリル、オキサゾリル、モルホリニル、ピラゾリジニル等のヘテロ環残基が挙げられる。好ましくは、炭素数１〜１０の置換または非置換アルキル基、置換または非置換フェニル基、置換または非置換の含窒素ヘテロ環残基であり、より好ましくは炭素数１〜６の置換または非置換アルキル基、置換または非置換フェニル基である。但し、Ｒ１とＲ２が同時に水素原子である場合を除く。
【００１１】
上記アルキル基、アリール基、ヘテロ環残基に置換する基は、一置換でも多置換でもよく、多置換の場合は各々の置換基は同一でも異なってもよい。また、置換基は反応に関与しない部位であればどこに置換していてもよい。置換基は塩基、一般式（ＩＩ）で表されるシリル化合物および過酸化水素と反応しないものであるか、あるいはシリル化合物と反応しうるものでも後処理により加水分解して元の置換基に戻るものであれば何でもよい。例えば、シアノ基；アミノ、ジメチルアミノ、アニリノ等の置換または非置換アミノ基；アセチルアミノ、ベンゾイルアミノ等のアシルアミノ基；エチルスルホニルアミノ、フェニルスルホニルアミノ等のスルホニルアミノ基；スルファモイル、Ｎ−フェニルスルファモイル、Ｎ，Ｎ−ジメチルスルファモイル等の置換または非置換スルファモイル基；カルバモイル、Ｎ−フェニルカルバモイル、Ｎ，Ｎ−ジエチルカルバモイル等の置換または非置換カルバモイル基；メトキシカルボニルアミノ、フェノキシカルボニルアミノ等のウレタン基；ウレイド、Ｎ−エチルウレイド、Ｎ，Ｎ−ジフェニルウレイド等の置換または非置換ウレイド基；ピリジル、ジピリジル、ピリミジニル、ピリダジニル、キノリル、イソキノリル、ピラゾリル、イミダゾリル、テトラゾリル、３−フェニルピペリジル、モルホリニル、インドリル、１−メチルインドリル、インドリニル、１−エチルインドリニル等の置換または非置換含窒素ヘテロ環残基；メチルチオエチル、エチルチオプロピル等のアルキルチオアルキル基；フェニルチオメチル、ナフチルチオエチル等のアリールチオアルキル基；チエニル、テトラヒドロチエニル、２−メチルチエニル等の置換または非置換含硫黄ヘテロ環残基；チアゾリジニル、チアゾリル、２−メチルチアゾリニル等の置換または非置換含窒素・含硫黄ヘテロ環残基が挙げられる。
【００１２】
これらの更なる置換基の中で好ましくは、シアノ基、置換または非置換のアミノ基、アルキルチオアルキル基、アリールチオアルキル基、置換または非置換のピリジル、イミダゾリル、インドリル、インドリニル、チアゾリジニル、チアゾリル等の窒素原子及び／又は硫黄原子を含有するヘテロ環残基であり、より好ましくは、置換または非置換のアミノ基およびインドリニル、チアゾリジニル等の窒素原子及び／又は硫黄原子を含有するヘテロ環残基であり、特に好ましくは置換または非置換インドリニル残基である。
これらの更なる置換基は、上記アルキル基、アリール基、ヘテロ環残基に直接置換していても、または連結基を介して結合していてもよい。連結基としては、好ましくはメチレン、エチレン、ブチレン等のアルキレン基；１，４−フェニレン基、１，５−ナフチレン基等のアリーレン基；ピリミジン−２，４−ジイル基、１，３，５−トリアジン−２，４−ジイル基等の２価のヘテロ環残基が挙げられる。また、これらの連結基は置換基を有していてもよい。
【００１３】
また、Ｒ１とＲ２は互いに結合して、ニトロ基が結合している炭素原子と共に非金属原子からなる置換または非置換の環を形成していても良く、具体例としてはシクロプロパン、シクロペンタン、シクロヘキサン等の脂肪族環；エチルシクロペンタン、ジメチルアミノシクロヘキサン等の置換脂肪族環；ピペリジン、ピラゾリン、ピロリジン等のヘテロ環；１−メチルピペリジン、１−ベンジルピロリジン、１−ナフチル−２−ピラゾリン等の置換ヘテロ環が挙げられる。
【００１４】
尚、本発明の方法で使用されるニトロ化合物は、ニトロオレフィン化合物から還元または付加反応で簡単に合成することができる（例えば、Ｃａｎ．Ｊ．Ｃｈｅｍ．，５０，pp.１２９２（１９７２）、Ｓｙｎｔｈ．ｃｏｍｍｕｎ．，１２（５）， pp.１０９３（１９８２）、Ｓｙｎｔｈ．ｃｏｍｍｕｎ．，１５（２）， pp.１５１（１９８５）、Ｓｙｎｔｈ．ｃｏｍｍｕｎ．，１８（１）， pp.２１（１９８８）、Ｔｅｔｒａｈｅｄｒｏｎ， ５１（１７）， pp.４９９７（１９９５）、Ｔｅｔｒａｈｅｄｒｏｎ，４３（５）， pp.８１３（１９８７）、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７０， pp.１４７（１９４８）、Ｊ．Ｏｒｇ．Ｃｈｅｍ．ＵＳＳＲ（Ｅｎｇｌ．Ｔｒａｎｓｌ．），９， pp.１０８７（１９７３）、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，２７， pp.１９８（１９７９）、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２６， pp.１３４８（１９６１）等参照。）。
【００１５】
また、更にその前駆体であるニトロオレフィン化合物についても、従来から知られている方法で簡単に合成することができる（例えば、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２５，pp.４７（１９６０）、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１５，pp.８（１９５０）、Ｔｅｔｒａｈｅｄｒｏｎ、２８， pp.６６３（１９７２），Ｊ．Ｃｈｅｍ．Ｓｏｃ．， pp.１４７，（１９６１）、Ｏｒｇ．Ｓｙｎｔｈ．，ＩＶ， pp.５７３（１９６３）、Ｓｙｎｔｈｅｓｉｓ，１９８５（５）， pp.５１５等参照）。
【００１６】
本発明の方法で使用されるシリル化合物は、上記一般式（ＩＩ）で表わされるものであるが、一般式（ＩＩ）中のＲ３、Ｒ４及びＲ５の具体例としては、メチル、エチル、ｔ−ブチル、シクロペンチル、シクロヘキシル等の直鎖、分岐または環状アルキル基；フェニルプロピル、メトキシエチル、２−クロロプロピル、ベンジル、３−ジメチルアミノメチル等の置換アルキル基；フェニル、ナフチル等のアリール基；トリル、キノリル、クロロフェニル、１−メチルピロリジニル、１−メチルピペリジル等の置換アリール基が挙げられる。
【００１７】
これらＲ３、Ｒ４及びＲ５の組み合わせとしては、いずれもメチル、エチル、イソプロピルあるいはフェニルを表す組み合わせ、１つがｔ−ブチルを表し、他の２つがメチルあるいはフェニルを表す組み合わせ、２つがメチルを表し、他の１つがフェニル、ビニル、クロロメチルあるいはオクタデシルを表す組み合わせ、２つがフェニルを表し、他の１つがメチルを表す組み合わせ等が挙げられ、好ましくはいずれもメチル、エチルあるいはイソプロピルを表す組み合わせ、１つがｔ−ブチルを表し、他の２つがメチルあるいはフェニルを表す組み合わせ、２つがメチルを表し、他の１つがフェニルを表す組み合わせであり、より好ましくはいずれもメチル、エチルあるいはイソプロピルを表す組み合わせ、１つがｔ−ブチルを表し、他の２つがメチルを表す組み合わせである。
【００１８】
また、Ｒ３、Ｒ４及びＲ５の中の任意の２つの置換基は結合して、それらが結合している珪素原子と共に非金属原子からなる置換または非置換の環を形成してもよく、具体例としてはシクロプロパン、シクロペンタン、シクロヘキサン等の脂肪族環；エチルシクロペンタン、ジメチルアミノシクロヘキサン等の置換脂肪族環；ピペリジン、ピラゾリン、ピロリジン等のヘテロ環；１−メチルピペリジン、１−ベンジルピロリジン、１−ナフチル−２−ピラゾリン等の置換ヘテロ環が挙げられる。
Ｘは塩素、臭素、ヨウ素等のハロゲン原子を表し、好ましくは塩素及び臭素である。
【００１９】
尚、上記シリル化合物は市販品を容易に入手することが可能であるし、また、従来知られている方法を用いて容易に合成することもできる（例えば、ＡｃｔａＣｈｅｍ．Ｓｃａｎｄ．，５ ， pp.１１７３（１９５１）、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７３， pp.２５０９（１９５１）、Ｊ．Ｏｒｇ．Ｃｈｅｍ．，３４， pp.６３８（１９６９）、Ｊ．Ｏｒｇａｎｏｍｅｔ．Ｃｈｅｍ．，１８８， pp.２５（１９８０）等参照）。
【００２０】
以下に一般式（ＩＩ）及び一般式(III）で表される化合物の具体例を列挙するが、本発明はこれらの化合物に限定されるものではない。
【００２１】
【化３】

【００２２】
【化４】

【００２３】
【化５】

【００２４】
ニトロ化合物とシリル化合物の反応においては、通常塩基性条件下で行なう。本発明で用いられる塩基は、水素化ナトリウム、水素化リチウム、水素化カリウム、ナトリウムアミド、ブチルリチウム、ピリジン、ジメチルアミノピリジン、イミダゾール、トリエチルアミン（ＴＥＡ）、ジイソプロピルエチルアミン（ＤＩＰＥＡ ）、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ ）、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）等が挙げられ、好ましくはトリエチルアミン（ＴＥＡ）、ジイソプロピルエチルアミン（ＤＩＰＥＡ ）、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ ）、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）等の有機塩基であり、より好ましくは１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ ）、及び、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）である。
【００２５】
本発明の方法においては、通常ニトロ化合物とシリル化合物の反応の際に上記した塩基を存在させるが、その際の塩基の使用量はニトロ化合物１モルに対し、通常１．０〜１０モル量、好ましくは１．０〜５．０モル量、より好ましくは１．２〜２．０モル量であるのが望ましい。
【００２６】
また、シリル化合物の使用量はニトロ化合物１モルに対し、通常１．０〜１０モル量、好ましくは２．０〜５．０モル量であるのが望ましい。
【００２７】
本発明においては、反応溶媒は使用しなくでもよいが、必要に応じて溶媒を使用しても良い。溶媒は基本的にシリル化合物や過酸化水素と反応しない溶媒なら何でも良く、例えば、アニゾール、トルエン、アセトニトリル、キシレン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、１，４−ジオキサン、テトラヒドロフラン等を使用しても良い。望ましくはＮ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、１，４−ジオキサン、テトラヒドロフラン、アセトニトリル等の水溶性溶媒である。
【００２８】
本発明において、ニトロ化合物とシリル化合物の反応（シリル化反応）の際の反応温度は−５０〜１５０℃、好ましくは−２０〜１００℃、より好ましくは−１０〜３０℃の範囲であるのが望ましい。これらの反応は通常１０時間以内で終了し、多くの場合は１〜２時間で終了する。尚、反応終了は、原料のニトロ化合物の消失で確認することができ、この確認は、薄層クロマトグラフィー（ＴＬＣ）または高速液体クロマトグラフィー（ＨＰＬＣ）で行なうことができる。
【００２９】
原料の消失を確認した後、過酸化水素を添加しその生成物と反応させるが、シリルニトロナート化合物と考えられる中間体を単離せずに、そのまま一貫法で過酸化水素処理を行うことが可能である。
【００３０】
過酸化水素の使用量はニトロ化合物１モルに対し、好ましくは１．０〜１０モル量、より好ましくは１．０〜５．０モル量、更に好ましくは１．２〜２．０モル量の範囲で実施するのが好ましい。
過酸化水素での処理の温度は−２０〜１００℃、好ましくは−１０〜５０℃、より好ましくは０〜３０℃の範囲であるのが望ましい。これらの反応は通常３時間以内で終了し、多くの場合は０.５〜１時間で終了する。
【００３１】
反応終了後、目的物であるカルボニル化合物の精製方法としては、通常行われる方法、例えば再結晶、減圧蒸留、シリカゲルを用いたカラム精製、水蒸気蒸留等が挙げられる。多くの場合は貧溶媒の添加によって結晶化し、適当な溶媒で再結晶または再結晶をしなくても高純度な目的物を得ることが可能である。
【００３２】
【実施例】
以下、本発明を実施例に基づいて具体的に説明するが、本発明は、これに限定されるものではない。
実施例１ ３−［５−（２−オキソプロピル）インドリニル］−プロピルベンゾエート（Ａ−２）の合成
３−［５−（２−ニトロプロピル）インドリニル］−プロピルベンゾエート（Ａ−１）１００．０ｇ（０．２７モル）を２００ｍｌのアセトニトリルに溶解し、内温０〜２０℃で１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ ）８２．０ｇ（０．５４モル）を添加した。次いで、塩化トリメチルシリル８８．０ｇ（０．８１モル）を３０分かけて滴下した後、０〜２０℃で１時間攪拌した。反応液を１０℃以下に冷却した後、３０％過酸化水素水４５．０ｇ（０．４０モル）を滴下し、引き続き０〜２０℃で１時間反応した。反応終了後、反応液に５００ｍｌの水を添加し、酢酸エチルエステル５００ｍｌで計２回抽出した。有機層を飽和重曹水、飽和食塩水で洗浄した後、無水芒硝で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムで精製し、目的物（Ａ−２） の微黄色粉末７４．２ｇ（収率８１．５％）を得た。ＨＰＬＣ分析（カラム ＹＭＣ Ａ−３１２、検出ＵＶ２７０ｎｍ、流量１．０ｍｌ／ｍｉｎ、溶離液 アセトニトリル／水＝７０：３０ トリエチルアミン０．２％、酢酸０．２％添加）の結果、純度は９７．８％であった。
【００３３】
実施例２ ３−［５−（２−オキソプロピル）−７−シアノインドリニル］−プロピルベンゾエート（Ａ−４）の合成
３−［５−（２−ニトロプロピル）−７−シアノインドリニル］−プロピルベンゾエート（Ａ−３） ８０．０ｇ（０．２０モル）をＮ，Ｎ−ジメチルホルムアミド３２０ｍｌに溶解し、内温０〜１０℃で１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）４８．０ｇ（０．３２モル）を添加した。次いで塩化トリエチルシリル９２．０ｇ（０．６１モル）を３０分かけて滴下した後、０〜１０℃で１時間攪拌した。反応液を５℃以下に冷却した後、３０％過酸化水素水３５．７ｇ（０．３１モル）を滴下し、引き続き０〜１０℃で１時間反応した。反応液を１７００ｍｌの水中に添加晶析し、得られた粗製物を更に酢酸エチルとヘキサンから再結晶し、目的物（Ａ−４）の微黄色粉末６０．３ｇ（収率８２．０％）を得た。ＨＰＬＣ分析（カラム ＹＭＣ Ａ−３１２、検出ＵＶ２７０ｎｍ、流量１．０ｍｌ／ｍｉｎ、溶離液 アセトニトリル／水＝７０／３０ トリエチルアミン０．２％、酢酸０．２％添加）の結果、純度は９６．８％であった。
【００３４】
実施例３ ６−（４−メトキシフェニル）−４−メチルヘキサン−３−オン（Ａ−６）の合成
１−メトキシ−４−（３−メチル−４−ニトロヘキシル）ベンゼン（Ａ−５） ２５．１ｇ（０．１０モル）をＮ，Ｎ−ジメチルホルムアミド１００ｍｌに溶解し、内温０〜１０℃で１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）２４．０ｇ（０．１６モル）を添加した。次いで塩化トリエチルシリル４６．０ｇ（０．３１モル）を３０分かけて滴下した後、０〜１０℃で１時間攪拌した。反応液を５℃以下に冷却した後、３０％過酸化水素水１８．８ｇ（０．１７モル）を滴下し、引き続き０〜１０℃で１時間反応した。反応液を８００ｍｌの水中に添加し、酢酸エチル５００ｍｌで抽出した。亜硫酸ナトリウム水溶液、重曹水、飽和食塩水で洗浄した後、無水芒硝で乾燥した。減圧下溶媒を留去し、目的物（Ａ−６）２０．９ｇ（収率９５．０％）を得た。ＨＰＬＣ分析（カラム ＹＭＣ Ａ−３１２、検出ＵＶ２５４ｎｍ、流量１．０ｍｌ／ｍｉｎ、溶離液 アセトニトリル／水＝７０／３０ トリエチルアミン０．２％、酢酸０．２％添加）の結果、純度は９８．１％であった。
【００３５】
実施例４ ３，７−ジメチル−１−（５−メチル−６−オキソ−６−フェニルヘキシル）−３，７−ジヒドロプリン−２，６−ジオン（Ａ−８）の合成
３，７−ジメチル−１−（５−メチル−６−ニトロ−６−フェニルヘキシル）−３，７−ジヒドロプリン−２，６−ジオン（Ａ−７） ４０．０ｇ（０．１０モル）をＮ，Ｎ−ジメチルホルムアミド１００ｍｌに溶解し、内温０〜１０℃で１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）２４．０ｇ（０．１６モル）を添加した。次いで塩化トリエチルシリル４６．０ｇ（０．３１モル）を３０分かけて滴下した後、０〜１０℃で１時間攪拌した。反応液を５℃以下に冷却した後、３０％過酸化水素水１８．８ｇ（０．１７モル）を滴下し、引き続き０〜１０℃で１時間反応した。反応液を１０００ｍｌの水中に添加し、０〜５℃で５時間攪拌した後、生成した結晶を濾過し、目的物（Ａ−８）３４．３ｇ（収率９３．１％）を得た。ＨＰＬＣ分析（カラム ＹＭＣ Ａ−３１２、検出ＵＶ２５４ｎｍ、流量１．０ｍｌ／ｍｉｎ、溶離液 アセトニトリル／水＝６０／４０ トリエチルアミン０．２％、酢酸０．２％添加）の結果、純度は９６．３％であった。
以下に、前述のＡ−１〜Ａ−８の化合物の構造を示す。
【００３６】
【化６】

【００３７】
実施例５〜実施例２１
ニトロ化合物、シリル化合物及び塩基を、下記表−１に記載される通り変更した以外は、実施例１に記載される方法と同様にカルボニル化合物を合成した。その結果得られたカルボニル化合物の収率と純度を下記表−１に示す。
【００３８】
【表１】

【００３９】
【表２】

【００４０】
【表３】

【００４１】
【表４】

【００４２】
以下の５種のＮｅｆ反応（強塩基と強酸での処理方法、塩基−過酸化水素法、過酸酸化法、硝酸二アンモニウムセリウム（ＣＡＮ）酸化法および重金属酸化物による酸化法）を用いて実施例２の化合物を合成し、本発明との比較を行った。以下に、その結果を述べる。
比較例１ 強塩基と強酸での処理方法（ Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１７，pp.５８１（１９５２）記載の方法）
２００ｍｌの四つ口フラスコにエタノール１５ｍｌを入れ、氷冷、窒素気流下、ナトリウム０.４６ｇ（０.０２モル）を添加し、３０分間攪拌した。３−［５−（２−ニトロプロピル）−７−シアノインドリニル］−プロピルベンゾエート（Ａ−３）４．０ｇ（０．０１モル）をエタノール４０ｍｌに溶解し、内温０〜５℃で反応液に滴下し、同温のまま１時間攪拌した。次にこの反応液を、０〜５℃で１ｍｏｌ／Ｌの塩酸１２０ｍｌ（０．１２モル）と１００ｍｌのエタノールの混合液中に滴下し、同温で１時間反応した。重曹で中和した後、酢酸エチルで抽出し、乾燥、濃縮した。得られたオイルを実施例２と同条件でＨＰＬＣ分析し、またＮＭＲ、ＭＳによる構造解析を行った。その結果、目的物は生成されず、原料の残存および副生物（Ａ−２６）の生成（３８．７％）が確認された。
【００４３】
比較例２ 塩基−過酸化水素法（Ｓｙｎｔｈｅｓｉｓ，１９８８，pp．９１５、Ｓｙｎｔｈｅｓｉｓ，１９８６，pp.１０２４ 記載の方法）
氷冷下、３−[５−（２−ニトロプロピル）−７−シアノインドリニル]−プロピルベンゾエート（Ａ−３） ４．０ｇ（０．０１モル）をメタノール５０ｍｌに溶解し、内温０〜５℃で３０％過酸化水素水２０．０ｇ（０．１８モル）を滴下した。炭酸カリウム８．０ｇを添加し、室温まで昇温して、そのまま１０時間反応した。反応液を２ｍｏｌ／Ｌの塩酸で中和し、酢酸エチルで抽出し、洗浄、乾燥、濃縮した。得られたオイルを実施例２と同条件でＨＰＬＣ分析した結果、目的物のＨＰＬＣ含有率は５３．２％であり、原料の残存と多数の副生物の生成が確認された。このうち主な副生物（含有率１４．３％）をＨＰＬＣ分取し、ＮＭＲ、ＭＳによる構造解析を行ったところ、（Ａ−２７）の構造であることが判明した。
【００４４】
比較例３ 過酸酸化法（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，２８(４４)， pp.５３６１（１９８７）記載の方法）
３−［５−（２−ニトロプロピル）−７−シアノインドリニル］−プロピルベンゾエート（Ａ−３）４．０ｇ（０．０１モル）をジクロロメタン３０ｍｌに溶解し、氷冷、窒素気流下、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）１．８ｇ(０．０１２モル)を添加した。次いで塩化トリメチルシリル２．２ｇ（０．０２モル）を滴下した後、０〜５℃で３０分間攪拌した。 ｍ−クロロ過安息香酸２．５ｇ（０．０１４モル）をジクロロメタン３０ｍｌに溶解したものを滴下し、更に０℃〜室温の範囲で２時間反応した。反応終了後、１ｍｏｌ／Ｌの亜硫酸ソーダ水溶液６０ｍｌ、１ｍｏｌ／Ｌの塩酸６０ｍｌ、飽和重曹水４０ｍｌで順次洗浄し、乾燥、濃縮した。得られたオイルを実施例２と同条件でＨＰＬＣ分析した結果、目的物のＨＰＬＣ含有率は３．３％であり、原料の残存と多数の副生物が確認された。カラム等での精製は困難であった。主な副生物をＨＰＬＣ分取し、ＮＭＲ、ＭＳによる機器解析を行ったところ、（Ａ−２８）、（Ａ−２９）の構造であることが判明した。
【００４５】
比較例４ ＣＡＮ酸化法（Ｓｙｎｔｈｅｓｉｓ，１９８０，pp.４４ 記載の方法）
３−［５−（２−ニトロプロピル）−７−シアノインドリニル］−プロピルベンゾエート（Ａ−３）４．０ｇ（０．０１モル）をジメチルホルムアミド３０ｍｌに溶解し、氷冷、窒素気流下、１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（ＤＢＵ）２．３ｇ（０．０１５モル）を添加した。次いで塩化トリメチルシリル３．３ｇ（０．０３モル）を滴下した後、０〜５℃で３時間攪拌した。次に硝酸二アンモニウムセリウム（ＣＡＮ）８．５ｇ（０．０１６モル）を水２０ｍｌに溶解した水溶液を滴下し、０℃〜室温で２時間反応した。反応終了後、１ｍｏｌ／Ｌの亜硫酸ソーダ水溶液６０ｍｌ、１ｍｏｌ／Ｌの塩酸６０ｍｌ、飽和重曹水４０ｍｌで順次洗浄し、乾燥、濃縮した。得られたオイルを実施例２と同条件でＨＰＬＣ分析した結果、目的物のＨＰＬＣ含有率は３１．１％であり、原料の残存（８．２％）と多数の副生物が確認された。カラム等での精製は困難であった。主な副生物をＨＰＬＣ分取し、ＮＭＲ、ＭＳによる機器解析を行ったところ、それぞれ（Ａ−２７）、（Ａ−２８）、（Ａ−２９）の構造であることが判明した。
【００４６】
比較例５ 重金属酸化物による酸化法（ Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２７， pp.３６９９（１９６２） 記載の方法）
氷冷下、３−[５−（２−ニトロプロピル）−７−シアノインドリニル]−プロピルベンゾエート（Ａ−３）４．０ｇ（０．０１モル）をアセトン４０ｍｌに溶解し、０℃で０．１ｍｏｌ／Ｌの水酸化カリウム水溶液１００ｍｌを添加した。次に同温で０．２ｍｏｌ／Ｌの過マンガン酸カリウム水溶液５ｍｌ（０．０１モル）を滴下した。０〜１０℃で２時間攪拌した後、酢酸エチルで抽出し、乾燥、濃縮した。得られたオイルを実施例２と同条件でＨＰＬＣ分析し、またＮＭＲ、ＭＳによる構造解析を行った。その結果、目的物は生成されず、副生物（Ａ−２８）が８２．９％、（Ａ−３０）が９．４％生成していることが判明した。
比較例１〜５の結果を下記表−２に示した。尚、副生物の構造は、下記（Ａ−２６）〜（Ａ−３０）に示される通りである。
【００４７】
【表５】

【００４８】
【化７】

【００４９】
表−２から明らかなように、強塩基／強酸を用いる方法（比較例1）及び重金属酸化物を用いる方法（比較例５）では、全く目的のカルボニル化合物を得ることが出来ず、またシリル化合物を使用しない比較例２や、塩基、シリル化合物は使用するものの過酸化水素を使用せずに過酸化水素以外のもので酸化させた比較例3及び４でも、原料が残存し、副反応により不純物が大量に生成するために、収率が非常に低いことが判る。それに対し、塩基、シリル化合物及び過酸化水素を組み合わせた本発明の方法においては、従来技術とは比較にならないほどの高収率、高純度で目的のカルボニル化合物が得られることが判る。
【００５０】
【発明の効果】
本発明によれば、目的物であるカルボニル化合物を緩和な反応条件で、分子内にアミノ基、含窒素環、チオエーテルおよび含硫黄環を有する場合や、一級ニトロアルカン類等の基質からアルデヒド類を製造する場合でも副生物を生成せず、高収率且つ高純度に合成することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a carbonyl compound which is an important intermediate in the fields of pharmaceuticals, agricultural chemicals, dyes and electrophotographic materials.
[0002]
[Prior art]
Numerous methods have been developed for synthesizing carbonyl compounds. For example, a method for converting a nitro group into a carbonyl group (Nef reaction) is known. This method includes, for example, a treatment method with a strong base and a strong acid (J. Am. Chem. Soc., 99 pp. 3861 (1977), J. Org. Chem., 17, pp. 581 (1952)), ozone oxidation. (J. Org. Chem., 39, pp. 259 (1974)), Lewis acid treatment method such as titanium trichloride (J. Am. Chem. Soc., 93. pp. 5309 (1971), J. Med). Chem., 9, pp. 52 (1966)), oxidation method using heavy metal oxide (J. Org. Chem., 27, pp. 3699 (1962), J. Chem. Soc. Perkin Transl., 1997 (3). ), 207, J. Chem. Soc. Chem. Commun., 1982 (11), pp. 635, Russian Patent (SU) 829628, Tetrahedron Le. t., 22 (52), pp. 5235 (1987)), electrode reaction method (Synthesis, 1986 (9), pp. 766, Synthesis, 1983 (9), pp. 763)), acid-hydrogen peroxide method (J. Org. Chem. USSR (Engl. Transl.), 15, pp. 2204 (1979)), base-hydrogen peroxide method (Synthesis, 1988 (11), pp. 915) and the like.
[0003]
However, these methods have several drawbacks. For example, in the treatment method with strong base and strong acid, acid-hydrogen peroxide method and base-hydrogen peroxide method, reaction conditions are so severe that functional groups such as ester, amide, and cyano groups coexist in the molecule. Side reactions such as hydrolysis occur, adversely affecting yield and quality. In addition, the ozone oxidation method and the electrode reaction method require expensive equipment, and in the Lewis acid treatment method and the oxidation method using heavy metal oxides, the treatment of the heavy metal residue generated is a big problem.
[0004]
On the other hand, a peracid oxidation method in which a nitro compound is reacted with a trimethylsilyl compound in the presence of a base and then treated with m-chloroperbenzoic acid (Tetrahedron Lett., 28 (44), pp. 5361 (1987)), or in the presence of a base. A method (Synthesis, 1980, pp. 44) in which a nitro compound is reacted with a trimethylsilyl compound and oxidized with diammonium cerium nitrate (CAN) has been reported. However, in the above reaction, when an amino group, a nitrogen-containing ring, a thioether or a sulfur-containing ring is present, or a primary nitroalkane or the like (when either R1 or R2 is a hydrogen atom in the general formula (I)) is a substrate. In the production of aldehydes, side reactions occur, and thus cannot be used for substrates having these substituents.
[0005]
[Problems to be solved by the invention]
The object of the present invention is to provide a by-product even in the case of having an amino group, a nitrogen-containing ring, a thioether and a sulfur-containing ring in the molecule under mild reaction conditions, or in the case of producing an aldehyde from a substrate such as a primary nitroalkane. It is an object of the present invention to provide a method for producing a carbonyl compound with high yield and high purity without being produced.
[0006]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above object, the present inventor has found that the above object is achieved by the following production method.
That is, the present invention has the following configuration.
(1) A general feature of reacting a nitro compound represented by the following general formula (I) with a silyl compound represented by the following general formula (II) and then reacting the product with hydrogen peroxide A method for producing a carbonyl compound represented by the formula (III).
[0007]
[Chemical formula 2]

[0008]
(In the formula, R1 and R2 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, and R1 and R2 are simultaneously hydrogenated. R1 and R2 may be bonded to each other to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the carbon atom to which R1 and R2 are bonded.R3, R4 and R5 Represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group independently of each other, and any two substituents of R3, R4 and R5 are bonded to each other to form a carbon to which they are bonded. A substituted or unsubstituted ring composed of a nonmetallic atom may be formed together with an atom, and X represents a halogen atom.)
(2) An alkyl group, an aryl group, or a hetero group in which at least one of R1 and R2 in the general formula (I) has a heterocyclic residue containing a substituted or unsubstituted nitrogen atom and / or a sulfur atom as a substituent. The manufacturing method of the carbonyl compound as described in said (1) which is a ring residue.
(3) The at least one of R1 and R2 in the general formula (I) is an alkyl group, an aryl group, or a heterocyclic residue having a substituted or unsubstituted amino group as a substituent. A method for producing a carbonyl compound.
(4) The method for producing a carbonyl compound according to (1), wherein at least one of R1 and R2 in the general formula (I) is an alkyl group having a substituted or unsubstituted indolinyl residue as a substituent.
[0009]
In the present invention, a nitro compound represented by general formula (I) as a starting material is reacted with a silyl compound represented by general formula (II). At this time, it seems that an intermediate such as a silylnitronate compound is formed. By reacting this intermediate with hydrogen peroxide, a carbonyl compound represented by the general formula (III) is obtained. In the present invention, the reaction proceeds under mild conditions, and even when an amino group, a nitrogen-containing ring, or a thioether is present in the molecule, or when an aldehyde is produced from a substrate such as a primary nitroalkane, Since side reactions such as decomposition do not occur, the target carbonyl compound can be obtained in high yield and high purity.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described in detail below.
The nitro compound used in the method of the present invention is represented by the general formula (I) as described above, and R1 and R2 in the general formula (I) are each independently a hydrogen atom, substituted or unsubstituted alkyl. Represents a group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue. Specifically, hydrogen atom; linear, branched or cyclic alkyl group such as methyl, ethyl, isopropyl, t-butyl, cyclopentyl, cyclohexyl, etc .; aryl group such as phenyl, naphthyl, phenanthryl; furyl, pyridyl, quinolyl, isoquinolyl, Examples include heterocyclic residues such as coumarinyl, benzothiazolyl, imidazolyl, oxazolyl, morpholinyl, pyrazolidinyl and the like. Preferably, it is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group, a substituted or unsubstituted nitrogen-containing heterocyclic residue, and more preferably a substituted or unsubstituted group having 1 to 6 carbon atoms. An alkyl group, a substituted or unsubstituted phenyl group; However, the case where R1 and R2 are hydrogen atoms at the same time is excluded.
[0011]
The group substituted on the alkyl group, aryl group or heterocyclic residue may be mono-substituted or poly-substituted, and in the case of poly-substitution, each substituent may be the same or different. Further, the substituent may be substituted anywhere as long as it does not participate in the reaction. Substituents that do not react with the base, the silyl compound represented by the general formula (II) and hydrogen peroxide, or those that can react with the silyl compound are hydrolyzed to return to the original substituent by post-treatment. Anything can be used. For example, cyano group; substituted or unsubstituted amino group such as amino, dimethylamino and anilino; acylamino group such as acetylamino and benzoylamino; sulfonylamino group such as ethylsulfonylamino and phenylsulfonylamino; sulfamoyl and N-phenylsulfa Substituted or unsubstituted sulfamoyl groups such as moyl, N, N-dimethylsulfamoyl; substituted or unsubstituted carbamoyl groups such as carbamoyl, N-phenylcarbamoyl, N, N-diethylcarbamoyl; methoxycarbonylamino, phenoxycarbonylamino, etc. Urethane group; substituted or unsubstituted ureido group such as ureido, N-ethylureido, N, N-diphenylureido; pyridyl, dipyridyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, pyrazolyl, imi Substituted or unsubstituted nitrogen-containing heterocyclic residues such as zolyl, tetrazolyl, 3-phenylpiperidyl, morpholinyl, indolyl, 1-methylindolyl, indolinyl and 1-ethylindolinyl; alkylthioalkyl groups such as methylthioethyl and ethylthiopropyl Arylthioalkyl groups such as phenylthiomethyl and naphthylthioethyl; substituted or unsubstituted sulfur-containing heterocyclic residues such as thienyl, tetrahydrothienyl and 2-methylthienyl; substitutions such as thiazolidinyl, thiazolyl and 2-methylthiazolinyl Or an unsubstituted nitrogen-containing sulfur-containing heterocyclic residue is mentioned.
[0012]
Among these further substituents, preferably cyano group, substituted or unsubstituted amino group, alkylthioalkyl group, arylthioalkyl group, substituted or unsubstituted pyridyl, imidazolyl, indolyl, indolinyl, thiazolidinyl, thiazolyl, etc. A heterocyclic residue containing a nitrogen atom and / or a sulfur atom, more preferably a substituted or unsubstituted amino group and a heterocyclic residue containing a nitrogen atom and / or a sulfur atom such as indolinyl and thiazolidinyl Particularly preferred are substituted or unsubstituted indolinyl residues.
These further substituents may be substituted directly on the alkyl group, aryl group, heterocyclic residue or may be bonded via a linking group. The linking group is preferably an alkylene group such as methylene, ethylene or butylene; an arylene group such as 1,4-phenylene group or 1,5-naphthylene group; a pyrimidine-2,4-diyl group, 1,3,5- And divalent heterocyclic residues such as triazine-2,4-diyl group. Further, these linking groups may have a substituent.
[0013]
R1 and R2 may be bonded to each other to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the carbon atom to which the nitro group is bonded. Specific examples include cyclopropane, cyclopentane, Aliphatic rings such as cyclohexane; Substituted aliphatic rings such as ethylcyclopentane and dimethylaminocyclohexane; Heterocycles such as piperidine, pyrazoline and pyrrolidine; 1-methylpiperidine, 1-benzylpyrrolidine, 1-naphthyl-2-pyrazoline and the like Examples include substituted heterocycles.
[0014]
The nitro compound used in the method of the present invention can be easily synthesized from a nitroolefin compound by reduction or addition reaction (for example, Can. J. Chem., 50, pp. 1292 (1972), Synth). Comm., 12 (5), pp. 1093 (1982), Synth. Commun., 15 (2), pp. 151 (1985), Synth. Commun., 18 (1), pp. 21 (1988), Tetrahedron, 51 (17), pp. 4997 (1995), Tetrahedron, 43 (5), pp. 813 (1987), J. Am. Chem. Soc., 70, pp. 147 (1948), J. Org. Chem.USSR (Engl.Transl.), 9, pp.1087 (1973), Chem.Pharm.Bul. ., 27, pp.198 (1979), J.Org.Chem., 26, pp.1348 (1961), etc. See.).
[0015]
Furthermore, the precursor nitroolefin compound can also be easily synthesized by a conventionally known method (for example, J. Org. Chem., 25, pp. 47 (1960), J. Org. Org.Chem., 15, pp. 8 (1950), Tetrahedron, 28, pp. 663 (1972), J. Chem. Soc., Pp. 147, (1961), Org. Synth., IV, pp. 573 (1963), Synthesis, 1985 (5), pp. 515, etc.).
[0016]
The silyl compound used in the method of the present invention is represented by the above general formula (II). Specific examples of R3, R4 and R5 in the general formula (II) include methyl, ethyl, t- Linear, branched or cyclic alkyl groups such as butyl, cyclopentyl and cyclohexyl; substituted alkyl groups such as phenylpropyl, methoxyethyl, 2-chloropropyl, benzyl and 3-dimethylaminomethyl; aryl groups such as phenyl and naphthyl; tolyl, Examples thereof include substituted aryl groups such as quinolyl, chlorophenyl, 1-methylpyrrolidinyl, and 1-methylpiperidyl.
[0017]
As combinations of these R3, R4 and R5, all represent methyl, ethyl, isopropyl or phenyl, one represents t-butyl, the other two represent methyl or phenyl, two represent methyl, and others A combination in which one of them represents phenyl, vinyl, chloromethyl or octadecyl, two represents a phenyl, and the other represents a methyl, etc., preferably a combination in which all represent methyl, ethyl or isopropyl, A combination in which -butyl is represented and the other two represent methyl or phenyl, two represents methyl, and the other represents phenyl, more preferably a combination in which both represent methyl, ethyl or isopropyl, and one represents t -Represents butyl, the other two There is a combination of methyl.
[0018]
Further, any two substituents in R3, R4 and R5 may be bonded to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the silicon atom to which they are bonded. As aliphatic rings such as cyclopropane, cyclopentane and cyclohexane; substituted aliphatic rings such as ethylcyclopentane and dimethylaminocyclohexane; heterocycles such as piperidine, pyrazoline and pyrrolidine; 1-methylpiperidine, 1-benzylpyrrolidine, 1 -Substituted heterocycles such as naphthyl-2-pyrazolin.
X represents a halogen atom such as chlorine, bromine or iodine, preferably chlorine or bromine.
[0019]
In addition, the said silyl compound can obtain a commercial item easily, and can also synthesize | combine easily using a conventionally well-known method (for example, ActaChem.Scan., 5, pp.). 1173 (1951), J. Am. Chem. Soc., 73, pp. 2509 (1951), J. Org. Chem., 34, pp. 638 (1969), J. Organomet. Chem., 188, pp. 25 (1980) etc.).
[0020]
Specific examples of the compounds represented by formulas (II) and (III) are listed below, but the present invention is not limited to these compounds.
[0021]
[Chemical 3]

[0022]
[Formula 4]

[0023]
[Chemical formula 5]

[0024]
The reaction between the nitro compound and the silyl compound is usually carried out under basic conditions. The base used in the present invention is sodium hydride, lithium hydride, potassium hydride, sodium amide, butyl lithium, pyridine, dimethylaminopyridine, imidazole, triethylamine (TEA), diisopropylethylamine (DIPEA), 1,4-diazabicyclo. [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and the like, preferably triethylamine (TEA), diisopropylethylamine (DIPEA), Organic bases such as 1,4-diazabicyclo [2.2.2] octane (DABCO 3) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), more preferably 1,4 -Diazabicyclo [2.2.2] octane (DABCO) And, it is a 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).
[0025]
In the method of the present invention, the above-mentioned base is usually present during the reaction of the nitro compound and the silyl compound, and the amount of the base used is usually 1.0 to 10 moles per 1 mole of the nitro compound. Preferably it is 1.0-5.0 mol amount, More preferably, it is 1.2-2.0 mol amount.
[0026]
The amount of the silyl compound used is usually 1.0 to 10 mol, preferably 2.0 to 5.0 mol, per 1 mol of the nitro compound.
[0027]
In the present invention, the reaction solvent may not be used, but a solvent may be used as necessary. The solvent can be basically any solvent that does not react with silyl compounds or hydrogen peroxide, such as anisole, toluene, acetonitrile, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, tetrahydrofuran. Etc. may be used. Desirable are water-soluble solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,4-dioxane, tetrahydrofuran, and acetonitrile.
[0028]
In the present invention, the reaction temperature in the reaction of the nitro compound and the silyl compound (silylation reaction) is −50 to 150 ° C., preferably −20 to 100 ° C., more preferably −10 to 30 ° C. desirable. These reactions are usually completed within 10 hours, and in many cases are completed within 1 to 2 hours. The completion of the reaction can be confirmed by disappearance of the starting nitro compound, and this confirmation can be performed by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
[0029]
After confirming the disappearance of the raw materials, hydrogen peroxide is added and reacted with the product, but it is possible to perform the hydrogen peroxide treatment in an integrated manner as it is without isolating an intermediate that is considered to be a silylnitronate compound. It is.
[0030]
The amount of hydrogen peroxide used is preferably 1.0 to 10 moles, more preferably 1.0 to 5.0 moles, and still more preferably 1.2 to 2.0 moles per mole of nitro compound. It is preferable to carry out in a range.
The temperature of the treatment with hydrogen peroxide is −20 to 100 ° C., preferably −10 to 50 ° C., more preferably 0 to 30 ° C. These reactions are usually completed within 3 hours, and in many cases are completed within 0.5 to 1 hour.
[0031]
Examples of the purification method of the target carbonyl compound after completion of the reaction include commonly used methods such as recrystallization, vacuum distillation, column purification using silica gel, and steam distillation. In many cases, it can be crystallized by adding a poor solvent, and a high-purity target product can be obtained without recrystallization or recrystallization with an appropriate solvent.
[0032]
【Example】
EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to this.
Example 1 Synthesis of 3- [5- (2-oxopropyl) indolinyl] -propylbenzoate (A-2)
3- [5- (2-nitropropyl) indolinyl] -propylbenzoate (A-1) 100.0 g (0.27 mol) was dissolved in 200 ml of acetonitrile, and 1,4-diazabicyclo was dissolved at an internal temperature of 0 to 20 ° C. [2.2.2] 82.0 g (0.54 mol) of octane (DABCO) was added. Next, 88.0 g (0.81 mol) of trimethylsilyl chloride was added dropwise over 30 minutes, followed by stirring at 0 to 20 ° C. for 1 hour. After cooling the reaction solution to 10 ° C. or lower, 45.0 g (0.40 mol) of 30% hydrogen peroxide solution was added dropwise, and subsequently reacted at 0 to 20 ° C. for 1 hour. After completion of the reaction, 500 ml of water was added to the reaction solution, and extracted twice with 500 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column to obtain 74.2 g (yield: 81.5%) of the slightly yellow powder of the target product (A-2). As a result of HPLC analysis (column YMC A-312, detection UV 270 nm, flow rate 1.0 ml / min, eluent acetonitrile / water = 70: 30 triethylamine 0.2%, acetic acid 0.2% added), the purity was 97.8%. Met.
[0033]
Example 2 Synthesis of 3- [5- (2-oxopropyl) -7-cyanoindolinyl] -propylbenzoate (A-4)
3- [5- (2-nitropropyl) -7-cyanoindolinyl] -propylbenzoate (A-3) 80.0 g (0.20 mol) was dissolved in 320 ml of N, N-dimethylformamide, and the internal temperature was 0. At 10 ° C., 48.0 g (0.32 mol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added. Subsequently, 92.0 g (0.61 mol) of triethylsilyl chloride was added dropwise over 30 minutes, followed by stirring at 0 to 10 ° C. for 1 hour. After cooling the reaction solution to 5 ° C. or less, 35.7 g (0.31 mol) of 30% hydrogen peroxide solution was added dropwise, and subsequently reacted at 0 to 10 ° C. for 1 hour. The reaction solution was added and crystallized in 1700 ml of water, and the resulting crude product was further recrystallized from ethyl acetate and hexane to give 60.3 g (yield: 82.0%) of the slightly yellow powder of the target product (A-4). Got. As a result of HPLC analysis (column YMC A-312, detection UV 270 nm, flow rate 1.0 ml / min, eluent acetonitrile / water = 70/30 triethylamine 0.2%, acetic acid 0.2% added), the purity was 96.8%. Met.
[0034]
Example 3 Synthesis of 6- (4-methoxyphenyl) -4-methylhexane-3-one (A-6)
25.1 g (0.10 mol) of 1-methoxy-4- (3-methyl-4-nitrohexyl) benzene (A-5) was dissolved in 100 ml of N, N-dimethylformamide, and the internal temperature was 0 to 10 ° C. 14.0-Diazabicyclo [5.4.0] undec-7-ene (DBU) 24.0 g (0.16 mol) was added. Next, 46.0 g (0.31 mol) of triethylsilyl chloride was added dropwise over 30 minutes, followed by stirring at 0 to 10 ° C. for 1 hour. After cooling the reaction solution to 5 ° C. or less, 18.8 g (0.17 mol) of 30% hydrogen peroxide solution was added dropwise, and subsequently reacted at 0 to 10 ° C. for 1 hour. The reaction solution was added to 800 ml of water and extracted with 500 ml of ethyl acetate. The extract was washed with an aqueous sodium sulfite solution, an aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 20.9 g (yield 95.0%) of the desired product (A-6). As a result of HPLC analysis (column YMC A-312, detection UV 254 nm, flow rate 1.0 ml / min, eluent acetonitrile / water = 70/30 triethylamine 0.2%, acetic acid 0.2% added), the purity was 98.1%. Met.
[0035]
Example 4 Synthesis of 3,7-dimethyl-1- (5-methyl-6-oxo-6-phenylhexyl) -3,7-dihydropurine-2,6-dione (A-8)
40.0 g (0.10 mol) of 3,7-dimethyl-1- (5-methyl-6-nitro-6-phenylhexyl) -3,7-dihydropurine-2,6-dione (A-7) It was dissolved in 100 ml of N, N-dimethylformamide, and 24.0 g (0.16 mol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added at an internal temperature of 0 to 10 ° C. . Next, 46.0 g (0.31 mol) of triethylsilyl chloride was added dropwise over 30 minutes, followed by stirring at 0 to 10 ° C. for 1 hour. After cooling the reaction solution to 5 ° C. or less, 18.8 g (0.17 mol) of 30% hydrogen peroxide solution was added dropwise, and subsequently reacted at 0 to 10 ° C. for 1 hour. The reaction solution was added to 1000 ml of water and stirred at 0 to 5 ° C. for 5 hours, and then the produced crystals were filtered to obtain 34.3 g (yield 93.1%) of the desired product (A-8). As a result of HPLC analysis (column YMC A-312, detection UV 254 nm, flow rate 1.0 ml / min, eluent acetonitrile / water = 60/40 0.2% triethylamine, 0.2% acetic acid added), the purity was 96.3%. Met.
The structures of the aforementioned compounds A-1 to A-8 are shown below.
[0036]
[Chemical 6]

[0037]
Examples 5 to 21
A carbonyl compound was synthesized in the same manner as described in Example 1, except that the nitro compound, silyl compound and base were changed as described in Table 1 below. The yield and purity of the carbonyl compound obtained as a result are shown in Table 1 below.
[0038]
[Table 1]

[0039]
[Table 2]

[0040]
[Table 3]

[0041]
[Table 4]

[0042]
Implemented using the following 5 types of Nef reaction (treatment method with strong base and strong acid, base-hydrogen peroxide method, peracid oxidation method, diammonium cerium nitrate (CAN) oxidation method and oxidation method with heavy metal oxide) The compound of Example 2 was synthesized and compared with the present invention. The results are described below.
Comparative Example 1 Treatment with Strong Base and Strong Acid (Method described in J. Org. Chem., 17, pp. 581 (1952))
In a 200 ml four-necked flask, 15 ml of ethanol was added, 0.46 g (0.02 mol) of sodium was added under ice cooling and nitrogen stream, and the mixture was stirred for 30 minutes. 4.0 g (0.01 mol) of 3- [5- (2-nitropropyl) -7-cyanoindolinyl] -propylbenzoate (A-3) was dissolved in 40 ml of ethanol and reacted at an internal temperature of 0 to 5 ° C. The solution was added dropwise to the solution and stirred at the same temperature for 1 hour. Next, this reaction solution was dropped into a mixed solution of 1 mol / L hydrochloric acid 120 ml (0.12 mol) and 100 ml ethanol at 0 to 5 ° C., and reacted at the same temperature for 1 hour. The mixture was neutralized with sodium bicarbonate, extracted with ethyl acetate, dried and concentrated. The obtained oil was subjected to HPLC analysis under the same conditions as in Example 2, and structural analysis by NMR and MS was performed. As a result, the target product was not produced, and it was confirmed that the raw material remained and by-product (A-26) was produced (38.7%).
[0043]
Comparative Example 2 Base-hydrogen peroxide method (method described in Synthesis, 1988, pp. 915, Synthesis, 1986, pp. 1024)
Under ice-cooling, 4.0 g (0.01 mol) of 3- [5- (2-nitropropyl) -7-cyanoindolinyl] -propylbenzoate (A-3) was dissolved in 50 ml of methanol. At 5 ° C., 20.0 g (0.18 mol) of 30% aqueous hydrogen peroxide was added dropwise. Potassium carbonate 8.0g was added, it heated up to room temperature, and it reacted for 10 hours as it was. The reaction solution was neutralized with 2 mol / L hydrochloric acid, extracted with ethyl acetate, washed, dried and concentrated. The obtained oil was subjected to HPLC analysis under the same conditions as in Example 2. As a result, the HPLC content of the target product was 53.2%, and it was confirmed that the raw material remained and many by-products were produced. Of these, main by-products (content: 14.3%) were collected by HPLC, and subjected to structural analysis by NMR and MS. As a result, it was found that the structure was (A-27).
[0044]
Comparative Example 3 Peracid oxidation method (method described in Tetrahedron Lett., 28 (44), pp. 5361 (1987))
4.0 g (0.01 mol) of 3- [5- (2-nitropropyl) -7-cyanoindolinyl] -propylbenzoate (A-3) was dissolved in 30 ml of dichloromethane, and the mixture was cooled with ice under a nitrogen stream. , 8-diazabicyclo [5.4.0] undec-7-ene (DBU) 1.8 g (0.012 mol) was added. Subsequently, after adding dropwise trimethylsilyl chloride 2.2g (0.02mol), it stirred at 0-5 degreeC for 30 minutes. A solution prepared by dissolving 2.5 g (0.014 mol) of m-chloroperbenzoic acid in 30 ml of dichloromethane was dropped, and the reaction was further carried out in the range of 0 ° C. to room temperature for 2 hours. After completion of the reaction, the mixture was washed successively with 60 ml of 1 mol / L sodium sulfite aqueous solution, 60 ml of 1 mol / L hydrochloric acid and 40 ml of saturated aqueous sodium hydrogen carbonate, dried and concentrated. The obtained oil was subjected to HPLC analysis under the same conditions as in Example 2. As a result, the HPLC content of the target product was 3.3%, and the remaining raw materials and many by-products were confirmed. Purification using a column or the like was difficult. Main by-products were collected by HPLC and subjected to instrumental analysis by NMR and MS. As a result, it was found that the structures were (A-28) and (A-29).
[0045]
Comparative Example 4 CAN oxidation method (method described in Synthesis, 1980, pp. 44)
4.0 g (0.01 mol) of 3- [5- (2-nitropropyl) -7-cyanoindolinyl] -propylbenzoate (A-3) was dissolved in 30 ml of dimethylformamide, ice-cooled under a nitrogen stream, 2.3 g (0.015 mol) of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was added. Next, 3.3 g (0.03 mol) of trimethylsilyl chloride was dropped, and the mixture was stirred at 0 to 5 ° C. for 3 hours. Next, an aqueous solution in which 8.5 g (0.016 mol) of diammonium cerium nitrate (CAN) was dissolved in 20 ml of water was added dropwise and reacted at 0 ° C. to room temperature for 2 hours. After completion of the reaction, the mixture was washed successively with 60 ml of 1 mol / L sodium sulfite aqueous solution, 60 ml of 1 mol / L hydrochloric acid and 40 ml of saturated aqueous sodium hydrogen carbonate, dried and concentrated. The obtained oil was subjected to HPLC analysis under the same conditions as in Example 2. As a result, the HPLC content of the target product was 31.1%, and the remaining raw material (8.2%) and many by-products were confirmed. Purification using a column or the like was difficult. Main by-products were collected by HPLC and subjected to instrumental analysis by NMR and MS. As a result, they were found to have the structures (A-27), (A-28), and (A-29), respectively.
[0046]
Comparative Example 5 Oxidation Method Using Heavy Metal Oxide (Method described in J. Org. Chem., 27, pp. 3699 (1962))
Under ice cooling, 4.0 g (0.01 mol) of 3- [5- (2-nitropropyl) -7-cyanoindolinyl] -propylbenzoate (A-3) was dissolved in 40 ml of acetone, and 0 ° C. was added at 0 ° C. 100 ml of a 1 mol / L potassium hydroxide aqueous solution was added. Next, 5 ml (0.01 mol) of a 0.2 mol / L potassium permanganate aqueous solution was added dropwise at the same temperature. The mixture was stirred at 0 to 10 ° C. for 2 hours, extracted with ethyl acetate, dried and concentrated. The obtained oil was subjected to HPLC analysis under the same conditions as in Example 2, and structural analysis by NMR and MS was performed. As a result, it was found that the target product was not produced, and 82.9% by-product (A-28) and 9.4% (A-30) were produced.
The results of Comparative Examples 1 to 5 are shown in Table 2 below. The structure of the by-product is as shown in the following (A-26) to (A-30).
[0047]
[Table 5]

[0048]
[Chemical 7]

[0049]
As is apparent from Table 2, the method using a strong base / strong acid (Comparative Example 1) and the method using a heavy metal oxide (Comparative Example 5) do not give the desired carbonyl compound at all, and the silyl compound In Comparative Example 2 where no base is used, and in Comparative Examples 3 and 4 where base and silyl compounds are used but hydrogen peroxide is not used but oxidized with something other than hydrogen peroxide, the raw material remains and impurities are caused by side reactions. It can be seen that the yield is very low due to the large amount of produced. In contrast, in the method of the present invention in which a base, a silyl compound, and hydrogen peroxide are combined, it can be seen that the target carbonyl compound can be obtained in a high yield and purity that is incomparable to the prior art.
[0050]
【The invention's effect】
According to the present invention, when a target carbonyl compound has an amino group, a nitrogen-containing ring, a thioether and a sulfur-containing ring in a molecule under mild reaction conditions, or an aldehyde is obtained from a substrate such as a primary nitroalkane. Even when it is produced, no by-product is produced, and it can be synthesized in high yield and high purity.

Claims (4)

A nitro compound represented by the following general formula (I) and a silyl compound represented by the following general formula (II) are reacted, and then the product and hydrogen peroxide are reacted. The manufacturing method of the carbonyl compound represented by this.

(In the formula, R1 and R2 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, and R1 and R2 are simultaneously hydrogenated. R1 and R2 may be bonded to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the carbon atom to which the nitro group is bonded, R3, R4 and R5 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group independently of each other, and any two substituents of R3, R4 and R5 are bonded to each other. A substituted or unsubstituted ring composed of a non-metal atom may be formed together with a silicon atom, and X represents a halogen atom.) An alkyl group, an aryl group or a heterocyclic residue, wherein at least one of R1 and R2 in formula (I) has a heterocyclic residue containing a substituted or unsubstituted nitrogen atom and / or sulfur atom as a substituent. The method for producing a carbonyl compound according to claim 1. The production of a carbonyl compound according to claim 1, wherein at least one of R1 and R2 in formula (I) is an alkyl group, an aryl group or a heterocyclic residue having a substituted or unsubstituted amino group as a substituent. Method. The method for producing a carbonyl compound according to claim 1, wherein at least one of R1 and R2 in the general formula (I) is an alkyl group having a substituted or unsubstituted indolinyl residue as a substituent.