JP4255247B2 - N-acylindolecarboxylic acid esters and method for producing indolecarboxylic acids - Google Patents

Description

［式中、Ｒ_１ＯＣＯ−基は ４〜７位のいずれかにあり、Ｒ_１は、炭素数１〜４のアルキル基を表し、Ｒ_２は、水素、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルキル基、炭素数２〜４のアルケニル基、ベンジル基またはフェニル基を表す］で表わされるＮ−アシルインドールカルボン酸エステル類を製造するにあたり、一般式（２）
【化９】

［式中、Ｒ_１は、炭素数１〜４のアルキル基を表し、Ｒ_２は、水素、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルキル基、炭素数２〜４のアルケニル基、ベンジル基またはフェニル基を表す］
で表わされるＮ−アシル−Ｎ−ヒドロキシアミノ安息香酸エステル類を反応溶媒の存在又は不存在下、貴金属触媒として白金族元素及び／または白金族元素を含む化合物を用い、一般式（４）
【化１０】

［式中、Ｒ_３は炭素数１〜４のアルキル基またはフェニル基を表わす］で示されるビニルエステル類と反応させることにより、高純度のＮ−アシルインドールカルボン酸エステル類を製造できることおよび一般式（２）で表わされるＮ−アシル−Ｎ−ヒドロキシアミノ安息香酸エステル類を反応溶媒の存在又は不存在下、貴金属触媒として白金族元素及び／または白金族元素を含む化合物を用い、一般式（４）で示されるビニルエステル類と反応させることにより、一般式（１）で表わされるＮ−アシルインドールカルボン酸エステル類とし、さらに加水分解することにより一般式（５）
【化１１】

［式中、ＨＯＣＯ−基は ４〜７位のいずれかにある。］で表わされるインドールカルボン酸類が高純度で得られることを見出し、本発明を完成した。
【０００７】
【発明の実施の形態】
以下、本発明について更に詳細に説明する。
本発明におけるＮ−アシル−Ｎ−ヒドロキシアミノ安息香酸エステル類は、例えば、ニトロ安息香酸エステル類から米国特許公報３６９４５０９号、Ｊ．Ｉｎｄｉａｎ Ｃｈｅｍ．Ｓｏｃ．，Ｖｏｌ．４６，Ｎｏ．９，１９６９等の公知の方法によってヒドロキシルアミン化、アシル化することにより製造することができる。
【０００８】
本発明において、一般式（２）
【化１２】

で表わされるＮ−アシル−Ｎ−ヒドロキシアミノ安息香酸エステル類におけるＲ_１としては、炭素数１〜４のアルキル基を、Ｒ_２としては水素、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、炭素数１〜４のハロアルキル基、炭素数２〜４のアルケニル基、ベンジル基またはフェニル基であり、Ｒ_１としてさらに具体的には、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、−ＣＯＲ_２としてはホルミル基、アセチル基、クロロアセチル基、プロピオニル基、β−クロロプロピオニル基、ブチリル基、イソブチリル基、アクリロイル基、ベンゾイル基等が挙げられ、これらのなかでも、Ｒ_１がメチル基またはエチル基、−ＣＯＲ_２がアセチル基、メトキシカルボニル基、エトキシカルボニル基またはベンゾイル基であることが好ましい。
【０００９】
本発明において必要に応じて用いられる助触媒としては、一般式（３）
Ｍ₃Ｘ_ｎ （３）
[式中、Ｍ_２は金属原子を表わし、Ｘはハロゲン原子を表わす。ｎは１〜２の整数表わす。]で表わされる金属ハロゲン化物であり、例えば、Ｌｉ、Ｍｇ、Ｃａ、Ｆｅ、Ｃｏ、Ｍｎ、Ｎｉ、Ｃｕ、Ａｇ、Ｚｎ等のハロゲン化物が挙げられ、中でもＣｕ、Ｚｎのハロゲン化物が好ましく、一般式（２）で表わされるＮ−アシル−Ｎ−ヒドロキシアミノ安息香酸エステル類に対して通常、１〜２００モル％、好ましくは１０〜５０モル％用いられる。
【００１０】
本発明における、一般式（４）
【化１３】

で示されるビニルエステル類において、Ｒ_３は炭素数１〜４のアルキル基またはフェニル基を示し、具体的には、酢酸ビニル、プロピオン酸ビニル、酪酸ビニル、２−メチルプロピオン酸ビニル、安息香酸ビニルが挙げられ、なかでも酢酸ビニルが好ましい。
【００１１】
本発明における貴金属触媒としては、一般式（５）
Ｍ_１ ^a［Ｍ₂Ｌ_ｍ］^b （５）
［式中、ｂは０〜−２の整数であり、電荷を表す。Ｌはリガンドを示し、ｍは０〜４の整数であり、ｍが２〜４の場合同一であっても異なっていてもよい。 ａ+ｂ＝０であり、Ｍ_１はｂが−１または−２の時、対イオンを表す。Ｍ₂は白金族元素を表わす。］
で表され、これらの触媒は単独または組み合わせて用いることができ、例えば、担体に担持されていてもよいＰｄ原子またはＰｔ原子、Ｌｉ_２ＰｄＣｌ_４、Ｎａ_２ＰｄＣｌ_４、（ＮＨ_４）_２ＰｄＣｌ_４、ＰｄＣｌ_２、Ｐｄ（ＯＣＯＣＨ_３）_２、Ｐｄ（ＣＨ_３ＣＯＣＨＣＯＣＨ_３）_２、ＰｔＣｌ_２、Ｎａ_２ＰｔＣｌ_４等が挙げられ、特に担体に担持されていてもよいＰｄ原子、Ｌｉ_２ＰｄＣｌ_４、Ｎａ_２ＰｄＣｌ_４、（ＮＨ_４）_２ＰｄＣｌ_４、ＰｄＣｌ_２、Ｐｄ（ＯＣＯＣＨ_３）_２が好ましい。
【００１２】
本発明において必要に応じて用いられる閉環反応溶媒としては、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、ペンタン、ヘキサン、ヘプタン等の脂肪族炭化水素類、ジクロロメタン、１，２−ジクロロエタン等のハロゲン化炭化水素類、ジエチルエーテル、ジ−ｎ−プロピルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、テトラヒドロフラン、ジオキサン等の脂肪族および環状エーテル類、ギ酸メチル、ギ酸エチル、酢酸メチル、酢酸エチル、酢酸ｎ−ブチル、酢酸イソブチル、酢酸ビニル等のエステル類、アセトニトリル、プロピオニトリル、ブチロニトリル、ベンゾニトリル等のニトリル類、アセトン、ジエチルケトン、ジイソプロピルケトン、メチルエチルケトン、メチルイソブチルケトン等のケトン類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、１−メチル−２−ピロリジノン等のアミド類等が挙げられ、その中でもヘプタン、トルエン、クロロベンゼン、酢酸ビニル、酢酸エチル、ジイソプロピルエーテルが好ましく、さらには酢酸ビニルがより好ましく、その使用量は、一般式（２）で表わされるＮ−アシル−Ｎ−ヒドロキシアミノ安息香酸エステル類に対して通常、３〜１００モル％、好ましくは５〜５０モル％である。
【００１３】
本発明における閉環反応時の温度は、通常、０〜１２０℃の間で行われ、好ましくは、２０〜７５℃、更に好ましくは、５０〜７５℃で行われる。還元反応時の圧力は、通常、常圧で行われるが、加圧条件下や減圧条件下や脱水条件下で行うこともできる。
【００１４】
本発明の一般式（１）で表されるＮ−アシルインドールカルボン酸エステルとしてはＮ−アセチル−５−メトキシカルボニルインドール、Ｎ−アセチル−５−エトキシカルボニルインドール、Ｎ−アセチル−５−イソプロポキシカルボニルインドール、Ｎ−ベンゾイル−５−メトキシカルボニルインドール、Ｎ−ベンゾイル−５−エトキシカルボニルインドール、Ｎ−ベンゾイル−５−エトキシカルボニルインドール、Ｎ−ホルミル−５−メトキシカルボニルインドール、Ｎ−ホルミル−５−エトキシカルボニルインドール、Ｎ−メトキシカルボニル−５−エトキシカルボニルインドール、Ｎ−エトキシカルボニル−５−メトキシカルボニルインドール等が挙げられる。
【００１５】
一般式（１）で表されるＮ−アシルインドールカルボン酸エステル類は、金属水酸化物を作用させることで容易に加水分解してインドールカルボン酸が合成される。
【００１６】
加水分解おける金属水酸化物としてはアルカリ金属の水酸化物、アルカリ土類金属の水酸化物等が挙げられる。例えば、アルカリ金属の水酸化物としては水酸化リチウム、水酸化ナトリウム、水酸化カリウム等が挙げられ、例えば、アルカリ土類金属の水酸化物としては水酸化カルシウム、水酸化バリウム等が挙げられる。これらの中でも水酸化ナトリウム、水酸化カリウム、水酸化カルシウムが好ましい。その使用量は、一般式（１）で表されるＮ−アシルインドールカルボン酸エステル類に対して、通常２モル当量以上であり、好ましくは２〜１０当量である。
【００１７】
加水分解反応に使用できる溶媒としては水単独であっても水と有機溶媒の併用であっても使用可能である。本反応における水の使用量は、一般式（１）で表されるＮ−アシルインドールカルボン酸エステル類に対して１〜１００重量倍が適用できるが、溶媒の使用量が多いと反応における容積効率が悪く工業的製造法としては不適当であるため、一般式（１）で表されるＮ−アシルインドールカルボン酸エステル類に対して３〜２０重量倍が好適である。
【００１８】
加水分解反応において必要に応じて用いる有機溶媒は、一般式（１）で表されるＮ−アシルインドールカルボン酸エステル類を溶解させ、不活性であるものならば特に限定されないが、メタノール、エタノール、イソプロピルアルコール等のアルコール類、トルエン、キシレン等の芳香族炭化水素、或いはメチル−ｔｅｒｔ−ブチルエーテル、ジイソプロピルエーテル等のエーテル類等を選ぶことができる。これらの有機溶媒のうち、水と均一溶液とならない有機溶媒の場合には、Ｎ−アシルインドールカルボン酸エステル類を溶解するが、一方、加水分解反応で得られたインドールカルボン酸塩は水に溶解するので、加水分解反応中はもとより加水分解反応後も、水と有機溶媒を分液するだけで、容易に目的物を分離することができる。本加水分解反応における有機溶媒の使用量は、一般式（１）で表されるＮ−アシルインドールカルボン酸エステル類に対して１〜５重量倍が好適である。
【００１９】
本発明の加水分解反応における反応温度は０℃以上で可能であるが、反応をよりスムーズに行うためには２０〜７０℃が好適である。本発明の反応における反応時間は特に限定されないが通常２〜３０時間の範囲が好適である。
【００２０】
加水分解反応で得られるインドールカルボン酸塩を分液、中和すれば高純度のインドールカルボン酸を得ることができる。
【００２１】
【発明の効果】
本発明の方法によれば、工業的に用いられており安価な Ｐｄ／ＣやＰｄＣｌ_２等を閉環反応の触媒として使用することができる。さらに金属ハロゲン化物を助触媒として用いることにより、高価な貴金属触媒の使用量を、貴金属触媒のみの場合の通常１モル％以上に対して、０．５モル％以下まで、組み合わせによっては０．０５モル％以下まで大幅に削減することができる。このようにして高純度のＮ−アシルインドールカルボン酸エステル類及びインドールカルボン酸類を、工業的に有利に製造することができる。
【００２２】
次に、本発明の詳細を以下の実施例にて示すが、本発明はこれらに限定されるものではない。
【実施例１】
反応容器に塩化パラジウム２．５ｍｇ（０．０１４ミリモル）、塩化亜鉛１．１５ｇ（８．４４ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル７．５ｇ（３３．６ミリモル）及び酢酸ビニル４３．４ｇ（５０４ミリモル）を仕込み、気相部を窒素で置換した後、５５℃で７時間攪拌した。
この時点において反応液をＨＰＬＣにて分析したところ、Ｎ−アセチル−５−エトキシカルボニルインドール：９６．９％、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル未検出であった。
この反応液を冷却後ろ過し、ろ液および洗液を水で洗浄した後、有機層を濃縮乾固して、純度９７．４％のＮ−アセチル−５−エトキシカルボニルインドール７．３８ｇを得た。（収率９５．０％）
なお、得られたＮ−アセチル−５−エトキシカルボニルインドールは新規物質であり、その物性値は以下のとおりであった。
融点９８．３〜９８．８℃ 元素分析結果 Ｃ６７．６５（計算値６７．５２）；Ｈ５．６９（計算値５．６７）；Ｎ５．９４（計算値６．０６） ＮＭＲ−スペクトル（３００ＭＨｚ，ＣＤＣｌ_３）：１．４２ｐｐｍ（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ）；２．６３ｐｐｍ（３Ｈ，ｓ）；４．４０ｐｐｍ（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ）；６．６９ｐｐｍ（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）；７．４６ｐｐｍ（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ）；８．０２ｐｐｍ（１Ｈ，ｄｄ，Ｊ＝１．７Ｈｚ，８．７Ｈｚ）；８．２８ｐｐｍ（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ）；８．４５ｐｐｍ（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ）
【００２３】
【実施例２】
反応容器に塩化パラジウム０．２０ｍｇ（０．００１１ミリモル）、塩化亜鉛３５９ｍｇ（２．６３ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル２．５０ｇ（１１．２ミリモル）及び酢酸ビニル１４．４５ｇ（１６７．８ミリモル）を仕込み、気相部を窒素で置換した後、５５℃で２４時間攪拌した後、実施例１と同様の処理を行い、純度９６．１％のＮ−アセチル−５−エトキシカルボニルインドール２．３２ｇを得た。（収率８９．５％）
【００２４】
【実施例３】
反応容器に塩化パラジウム３．７ｍｇ（０．０２１ミリモル）、塩化第一銅１０４．２ｍｇ（１．０５ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル９４０ｍｇ（４．２１ミリモル）及び酢酸ビニル５．４４ｇ（６３．２ミリモル）を仕込み、還流温度（７２〜７４℃程度）で４時間攪拌した後、実施例１と同様の処理を行い、純度９７．１％のＮ−アセチル−５−エトキシカルボニルインドール９３６ｍｇを得た。（収率９３．４％）
【００２５】
【参考例１】
反応容器に塩化パラジウム０．６３ｇ（３．６ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル７．９４ｇ（３５．６ミリモル）及び酢酸ビニル４５．９ｇ（５３３ミリモル）を仕込み、還流温度（７２〜７４℃程度）で２１時間反応後、実施例１と同様の処理を行い、純度８４．０％のＮ−アセチル−５−エトキシカルボニルインドール８．４４ｇを得た。（収率８６．２％）
【００２６】
【実施例４】
反応容器に塩化パラジウム０．３６ｍｇ（０．００２ミリモル）、塩化亜鉛１６１．６ｍｇ（１．１８６ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル１．０００ｇ（４．４８ミリモル）、酢酸ビニル０．５８ｇ（６．７ミリモル）及びトルエン５．２８ｇを仕込み、気相部を窒素で置換した後、５５℃で１６時間攪拌した後、実施例１と同様の処理を行い、純度９６．２％のＮ−アセチル−５−エトキシカルボニルインドール１．００ｇを得た。（収率９２．８％）
【００２７】
【参考例２】
反応容器に塩化白金１０．２ｍｇ（０．０３８ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル３４．３ｍｇ（０．１５４ミリモル）、酢酸ビニル０．３１ｇ（３．６ミリモル）を仕込み、７２℃で２時間攪拌したものにつき、分析したところＮ−アセチル−５−エトキシカルボニルインドールの純度は９０．０％であった。
【００２８】
実施例 ５〜１１
反応容器に、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸エチル１．００ｇ（４．４８ミリモル）、酢酸ビニル５．８ｇ（６７ミリモル）及びそれ以外は、下記の表１〜２に記載の貴金属触媒および助触媒を仕込み、反応温度５５℃において下記の表１〜２に記載の条件にて反応した反応液ついてＨＰＬＣにより、Ｎ−アセチル−５−エトキシカルボニルインドールの純度について分析した。
【００２９】
【表１】
表１

表１における貴金属触媒Ａ〜Ｄは以下のとおり
Ａ：ＰｄＣｌ_２
Ｂ：５％Ｐｄ−Ｃ
Ｃ：Ｐｄ（ＯＡｃ）_２
Ｄ：（ＮＨ_４）_２ＰｄＣｌ_４
【００３０】
【実施例１２】
反応容器に水分５０．６５％含有５％Ｐｄ／Ｃ １５．８ｍｇ（０．００３７ミリモル）、塩化亜鉛４８９ｍｇ（３．５９ミリモル）、ｐ−（Ｎ−アセチル−Ｎ−ヒドロキシ）アミノ安息香酸メチル３．００ｇ（１４．３ミリモル）、酢酸ビニル３６．９８ｇ（４３０ミリモル）を仕込み、気相部を窒素で置換した後、５５℃で８時間攪拌した。冷却後、酢酸エチルを加えて反応により析出した有機物の結晶を溶解、濾過により無機固形分を除去した。ろ液及び洗液を水で洗浄した後、酢酸エチル層を濃縮乾固し、純度９７．６％のＮ−アセチル−５−メトキシカルボニルインドール３．０８ｇを得た。（収率９６．５％）
【００３１】
実施例１３
反応容器に反応容器に水分５０．６５％含有５％Ｐｄ／Ｃ ６２．６ｍｇ（０．０１４５ミリモル）、塩化亜鉛１２５ｍｇ（０．９１７ミリモル）、ｐ−（Ｎ−ベンゾイル−Ｎ−ヒドロキシ）アミノ安息香酸エチル１．０２ｇ（３．５８ミリモル）、酢酸ビニル４．６４ｇ（５４．９ミリモル）を仕込み、５５℃で２時間保温・攪拌した後、実施例１と同様の処理を行い、純度９４．７％のＮ−ベンゾイル−５−エトキシカルボニルインドール１．０７ｇを得た。（収率９６．７％）
【００３２】
実施例１４
反応容器に実施例１で得たＮ−アセチル−５−エトキシカルボニルインドール ４．５０ｇ (１９．５ｍｍｏｌ) と １％ＮａＯＨ水溶液 ３１１ｇ (７７．８ｍｍｏｌ) を仕込み、窒素雰囲気下で攪拌しながら６０℃に昇温した。６時間後、冷却し１８％ＨＣｌ水溶液 １６．９ｇ (８３．６ｍｍｏｌ) を加えてｐＨ ３．０とした。反応液にメチルｔ−ブチルエーテルを加えて抽出した後、水で洗浄した。油分をエバポレータで濃縮して、純度 ９５．９％の褐色結晶のインドール−５−カルボン酸３．１２ｇを得た。（収率は９５．４％ 融点２０６〜２０７℃）
【００３１】
実施例１５
反応容器に実施例１で得たＮ−アセチル−５−エトキシカルボニルインドール １．９０ｇ (８．２２ｍｍｏｌ) 、メタノール １．９ｇ及び１０％ＮａＯＨ水溶液 ７．９０ｇ (１９．８ｍｍｏｌ) を仕込み、５０℃で４時間攪拌した。冷却後、減圧濃縮してメタノールを除去後、６２．５％硫酸水溶液 １．５５ｇ (９．８８ｍｍｏｌ) を加えた。 析出した結晶を濾過・水洗浄後乾燥することにより純度 ９５．９％のインドール−５−カルボン酸１．３３ｇを得た。（収率９６．５％）
【００３２】
実施例１６
反応容器に実施例１４で得たＮ−アセチル−５−メトキシカルボニルインドール ２１７ｍｇ (１．０ｍｍｏｌ) と ５％ＮａＯＨ水溶液 １．９２ｇ (２．４ｍｍｏｌ) を仕込み、６０℃で２時間攪拌した。冷却後、メチルｔ−ブチルエーテルにて不純物を抽出除去した。 分液後の水層に１８％ＨＣｌ水溶液 ０．４９ｇ (２．４ｍｍｏｌ) を加えた。 析出した結晶をメチルｔ−ブチルエーテルに溶解、ろ過により不溶分を除去した後、ろ液及び洗液を水で洗浄後、油層を濃縮乾固して、純度 ９４．７％のインドール−５−カルボン酸１４４ｍｇを得た。（収率８４．７％）[0001]
[Industrial application fields]
The present invention relates to a method for producing N-acylindolecarboxylic acid esters and indolecarboxylic acids useful as raw materials for pharmaceuticals, agricultural chemicals and electronic materials.
[0002]
[Prior art]
Since indoles have higher reactivity at the 2nd and 3rd positions of the indole ring than the 4th to 7th positions, it is possible to synthesize a compound having a substituent at the 4th to 7th positions while the 2nd and 3rd positions remain unsubstituted. Generally difficult.
As a method for producing N-acylindolecarboxylic acid esters represented by the general formula (1) as an object of the present invention, 2-ethenylacetanilides are converted to 10 mol% palladium chloride in Japanese Patent Application Laid-Open No. 3-24056. Has been proposed to obtain N-acetylmethoxycarbonylindoles by reacting in the presence of equimolar cuprous chloride and alcohol in an oxygen atmosphere. However, this method requires o-bromoacetanilides having an alkoxycarbonyl group which is more expensive than nitrobenzoic acid esters which are raw materials of the present invention as raw materials for ethenylacetanilides, and ethylene gas is used. In addition to being a high-pressure reaction, a large amount of catalyst is required also in the ring-closing process, which is problematic as an industrial production means.
[0003]
In addition, as a method for producing a similar compound, in Japanese Patent Publication No. 3-12058, N-acylindole is prepared by reacting vinyl esters with N-hydroxy-N-acylanilides in the presence of a mercury catalyst and a palladium catalyst. It shows how to get the kind. However, this method uses expensive Li ₂ PdCl ₄ in a large amount of 1 to 3 mol% in order to complete the reaction, and has a problem as an industrial production means.
[0004]
Examples of the method for producing indole carboxylic acids having no substitution at the 2-position and the 3-position include J.OC. 20, 1458-1460 (1955), J.C. Amer. Chem. Soc. 71, 761-766 (1949) describes a method of synthesizing cyanoindoles by hydrolysis.
However, this method is not preferable as an industrial production method because a large amount of copper cyanide is required for introducing a cyano group and a cyanide detoxification treatment is required in the post-treatment. In addition, J. et al. Chem. Technol. Biotechnol. 36 (12), 562-564, (1986), 2-bromo-4-methoxycarbonylaniline is reacted with ethylene under high pressure conditions in the presence of palladium acetate to give 4-methoxycarbonyl-2-vinylaniline. After tosylation, ring closure is performed using an equimolar palladium catalyst, and hydrolysis is performed to obtain indolecarboxylic acid. However, this method has problems as industrial production means such as high-pressure reaction using ethylene gas and use of a large amount of Pd catalyst.
[0005]
[Problems to be solved by the invention]
The problem to be solved by the present invention is to solve these problems and to provide a method for producing N-acylindolecarboxylic acid esters and indolecarboxylic acids with high purity and industrially advantageously. Is.
[0006]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have
The following general formula (1)
[Chemical 8]

_Wherein, R 1 OCO- groups located in one of the 4-7-position, _{R 1} represents an alkyl group having 1 to 4 carbon atoms, _{R 2} is hydrogen, an alkyl group having 1 to 4 carbon atoms, In the production of N-acyl indole carboxylic acid esters represented by C 1-4 alkoxy group, C 1-4 haloalkyl group, C 2-4 alkenyl group, benzyl group or phenyl group]. And general formula (2)
[Chemical 9]

[Wherein, R ₁ represents an alkyl group having 1 to 4 carbon atoms, and R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a haloalkyl having 1 to 4 carbon atoms. Group, an alkenyl group having 2 to 4 carbon atoms, a benzyl group or a phenyl group]
A platinum group element and / or a compound containing a platinum group element is used as a noble metal catalyst in the presence or absence of a reaction solvent for N-acyl-N-hydroxyaminobenzoates represented by the general formula (4)
[Chemical Formula 10]

[In the formula, R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group] By reacting with a vinyl ester represented by the formula, high-purity N-acyl indole carboxylic acid esters can be produced, and the general formula Using a compound containing a platinum group element and / or a platinum group element as a noble metal catalyst in the presence or absence of a reaction solvent, N-acyl-N-hydroxyaminobenzoates represented by (2) are represented by the general formula (4 ) To give N-acylindolecarboxylic acid esters represented by the general formula (1), and further hydrolyzing the general formula (5).
Embedded image

[Wherein the HOCO- group is in any of the 4-7 positions. The indole carboxylic acids represented by the above have been obtained with high purity, and the present invention has been completed.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
N-acyl-N-hydroxyaminobenzoic acid esters in the present invention are disclosed in, for example, nitrobenzoic acid esters from US Pat. Indian Chem. Soc. , Vol. 46, no. It can be produced by hydroxylamination and acylation by a known method such as 9,1969.
[0008]
In the present invention, the general formula (2)
Embedded image

R ₁ in the N-acyl-N-hydroxyaminobenzoates represented by formula (1) is an alkyl group having 1 to 4 carbon atoms, R ₂ is hydrogen, an alkyl group having 1 to 4 carbon atoms, An alkoxy group having 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyl group, or a phenyl group, and more specifically, for example, R ₁ is, for example, a methyl group, an ethyl group, or n-propyl. Group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, —COR ₂ as formyl group, acetyl group, chloroacetyl group, propionyl group, β-chloropropionyl group, butyryl group, isobutyryl group, acryloyl group, benzoyl group and the like, among these, R ₁ is a methyl group or an ethyl group, -COR ₂ is acetyl group, methemoglobin Aryloxycarbonyl group is preferably an ethoxycarbonyl group or a benzoyl group.
[0009]
The cocatalyst used as necessary in the present invention is represented by the general formula (3)
M ₃ X _n (3)
[Wherein, M ₂ represents a metal atom, and X represents a halogen atom. n represents an integer of 1 to 2. ], For example, halides such as Li, Mg, Ca, Fe, Co, Mn, Ni, Cu, Ag, Zn, etc. Among them, halides of Cu and Zn are preferable. The amount of N-acyl-N-hydroxyaminobenzoate represented by the formula (2) is usually 1 to 200 mol%, preferably 10 to 50 mol%.
[0010]
In the present invention, the general formula (4)
Embedded image

R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group, specifically vinyl acetate, vinyl propionate, vinyl butyrate, vinyl 2-methylpropionate, vinyl benzoate. Among them, vinyl acetate is preferable.
[0011]
As the noble metal catalyst in the present invention, the general formula (5)
^{_{M 1 a [M 2 L m}} ] b (5)
[In formula, b is an integer of 0-2, and represents an electric charge. L represents a ligand, m is an integer of 0 to 4, and when m is 2 to 4, they may be the same or different. a + b = 0, and M ₁ represents a counter ion when b is −1 or −2. M ₂ represents a platinum group element. ]
These catalysts can be used alone or in combination, for example, Pd atom or Pt atom which may be supported on a support, Li ₂ PdCl ₄ , Na ₂ PdCl ₄ , (NH ₄ ) ₂ PdCl ₄ , PdCl ₂ , Pd (OCOCH ₃ ) ₂ , Pd (CH ₃ COCHCOCH ₃ ) ₂ , PtCl ₂ , Na ₂ PtCl _{4, and the} like, and in particular, a Pd atom, Li ₂ PdCl ₄ , Na which may be supported on the support ₂ PdCl ₄ , (NH ₄ ) ₂ PdCl ₄ , PdCl ₂ , Pd (OCOCH ₃ ) ₂ are preferred.
[0012]
Examples of the ring-closing reaction solvent used as necessary in the present invention include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, and fats such as pentane, hexane and heptane. Hydrocarbons, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, aliphatic and cyclic ethers such as diethyl ether, di-n-propyl ether, methyl-tert-butyl ether, tetrahydrofuran and dioxane, methyl formate , Esters such as ethyl formate, methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate, nitriles such as acetonitrile, propionitrile, butyronitrile, benzonitrile, acetone, diethyl ketone, diisopropyl ketone, methyl Examples include ketones such as tilketone and methyl isobutyl ketone, and amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone. Among them, heptane, toluene, chlorobenzene, vinyl acetate , Ethyl acetate, and diisopropyl ether are preferable, and vinyl acetate is more preferable. The amount used is usually 3 to 100 with respect to the N-acyl-N-hydroxyaminobenzoates represented by the general formula (2). It is mol%, preferably 5 to 50 mol%.
[0013]
In the present invention, the temperature during the ring-closing reaction is usually between 0 to 120 ° C, preferably 20 to 75 ° C, more preferably 50 to 75 ° C. The pressure during the reduction reaction is usually carried out at normal pressure, but can also be carried out under pressure, reduced pressure or dehydration.
[0014]
Examples of the N-acylindolecarboxylic acid ester represented by the general formula (1) of the present invention include N-acetyl-5-methoxycarbonylindole, N-acetyl-5-ethoxycarbonylindole, and N-acetyl-5-isopropoxycarbonyl. Indole, N-benzoyl-5-methoxycarbonylindole, N-benzoyl-5-ethoxycarbonylindole, N-benzoyl-5-ethoxycarbonylindole, N-formyl-5-methoxycarbonylindole, N-formyl-5-ethoxycarbonyl Indole, N-methoxycarbonyl-5-ethoxycarbonylindole, N-ethoxycarbonyl-5-methoxycarbonylindole and the like can be mentioned.
[0015]
The N-acyl indole carboxylic acid ester represented by the general formula (1) is easily hydrolyzed by the action of a metal hydroxide to synthesize an indole carboxylic acid.
[0016]
Examples of the metal hydroxide that can be hydrolyzed include alkali metal hydroxides and alkaline earth metal hydroxides. Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples of the alkaline earth metal hydroxide include calcium hydroxide and barium hydroxide. Among these, sodium hydroxide, potassium hydroxide, and calcium hydroxide are preferable. The usage-amount is 2 mol equivalent or more normally with respect to N-acyl indole carboxylic acid ester represented by General formula (1), Preferably it is 2-10 equivalent.
[0017]
As a solvent that can be used for the hydrolysis reaction, water alone or a combination of water and an organic solvent can be used. The amount of water used in this reaction can be 1 to 100 times the weight of the N-acylindolecarboxylic acid ester represented by the general formula (1), but the volumetric efficiency in the reaction is large when the amount of solvent used is large. However, it is unsuitable as an industrial production method, and is preferably 3 to 20 times by weight with respect to the N-acylindolecarboxylic acid esters represented by the general formula (1).
[0018]
The organic solvent used as necessary in the hydrolysis reaction is not particularly limited as long as it dissolves the N-acylindolecarboxylic acid ester represented by the general formula (1) and is inactive, but methanol, ethanol, Alcohols such as isopropyl alcohol, aromatic hydrocarbons such as toluene and xylene, or ethers such as methyl-tert-butyl ether and diisopropyl ether can be selected. Among these organic solvents, in the case of an organic solvent that does not form a homogeneous solution with water, N-acylindolecarboxylic acid esters are dissolved, whereas indolecarboxylate obtained by the hydrolysis reaction is dissolved in water. Therefore, the target product can be easily separated by simply separating water and the organic solvent not only during the hydrolysis reaction but also after the hydrolysis reaction. The amount of the organic solvent used in the hydrolysis reaction is preferably 1 to 5 times the weight of the N-acylindolecarboxylic acid ester represented by the general formula (1).
[0019]
The reaction temperature in the hydrolysis reaction of the present invention can be 0 ° C. or higher, but 20 to 70 ° C. is suitable for performing the reaction more smoothly. The reaction time in the reaction of the present invention is not particularly limited, but a range of usually 2 to 30 hours is preferable.
[0020]
If the indole carboxylate obtained by the hydrolysis reaction is separated and neutralized, highly pure indole carboxylic acid can be obtained.
[0021]
【The invention's effect】
According to the method of the present invention, inexpensive Pd / C, PdCl _{2 and the} like that are industrially used can be used as a catalyst for the ring closure reaction. Furthermore, by using a metal halide as a co-catalyst, the amount of expensive noble metal catalyst used can be reduced to 0.5 mol% or less with respect to 1 mol% or more in the case of only the noble metal catalyst, depending on the combination. It can be greatly reduced to less than mol%. In this way, high-purity N-acyl indole carboxylic acid esters and indole carboxylic acids can be produced industrially advantageously.
[0022]
Next, although the detail of this invention is shown in the following examples, this invention is not limited to these.
[Example 1]
In a reaction vessel, 2.5 mg (0.014 mmol) of palladium chloride, 1.15 g (8.44 mmol) of zinc chloride, 7.5 g (33.6 mmol) of ethyl p- (N-acetyl-N-hydroxy) aminobenzoate. ) And 43.4 g (504 mmol) of vinyl acetate, and the gas phase portion was replaced with nitrogen, followed by stirring at 55 ° C. for 7 hours.
When the reaction liquid was analyzed by HPLC at this time, N-acetyl-5-ethoxycarbonylindole: 96.9%, ethyl p- (N-acetyl-N-hydroxy) aminobenzoate was not detected.
The reaction solution was cooled and filtered, and the filtrate and washings were washed with water, and then the organic layer was concentrated to dryness to obtain 7.38 g of N-acetyl-5-ethoxycarbonylindole having a purity of 97.4%. It was. (Yield 95.0%)
The obtained N-acetyl-5-ethoxycarbonylindole was a novel substance, and the physical properties thereof were as follows.
Melting point: 98.3 to 98.8 ° C. Elemental analysis result C67.65 (calculated value 67.52); H5.69 (calculated value 5.67); N5.94 (calculated value 6.06) NMR spectrum (300 MHz, CDCl ₃ ): 1.42 ppm (3H, t, J = 7.1 Hz); 2.63 ppm (3H, s); 4.40 ppm (2H, q, J = 7.1 Hz); 6.69 ppm (1H, d) , J = 3.7 Hz); 7.46 ppm (1H, d, J = 3.7 Hz); 8.02 ppm (1H, dd, J = 1.7 Hz, 8.7 Hz); 8.28 ppm (1H, d, J = 1.5 Hz); 8.45 ppm (1H, d, J = 8.7 Hz)
[0023]
[Example 2]
In a reaction vessel, 0.20 mg (0.0011 mmol) of palladium chloride, 359 mg (2.63 mmol) of zinc chloride, 2.50 g (11.2 mmol) of ethyl p- (N-acetyl-N-hydroxy) aminobenzoate and After charging 14.45 g (167.8 mmol) of vinyl acetate and replacing the gas phase with nitrogen, the mixture was stirred at 55 ° C. for 24 hours, and then treated in the same manner as in Example 1 to obtain N of purity 96.1%. -2.32 g of acetyl-5-ethoxycarbonylindole was obtained. (Yield 89.5%)
[0024]
[Example 3]
In a reaction vessel, 3.7 mg (0.021 mmol) of palladium chloride, 104.2 mg (1.05 mmol) of cuprous chloride, 940 mg (4.21 mmol) of ethyl p- (N-acetyl-N-hydroxy) aminobenzoate. ) And 5.44 g (63.2 mmol) of vinyl acetate, and the mixture was stirred at reflux temperature (about 72 to 74 ° C.) for 4 hours, and then treated in the same manner as in Example 1 to obtain N— with a purity of 97.1%. 936 mg of acetyl-5-ethoxycarbonylindole was obtained. (Yield 93.4%)
[0025]
[ Reference Example 1 ]
In a reaction vessel, 0.63 g (3.6 mmol) of palladium chloride, 7.94 g (35.6 mmol) of ethyl p- (N-acetyl-N-hydroxy) aminobenzoate and 45.9 g (533 mmol) of vinyl acetate were added. After charging and reacting at reflux temperature (about 72 to 74 ° C.) for 21 hours, the same treatment as in Example 1 was performed to obtain 8.44 g of N-acetyl-5-ethoxycarbonylindole having a purity of 84.0%. (Yield 86.2%)
[0026]
[Example 4 ]
In a reaction vessel, palladium chloride 0.36 mg (0.002 mmol), zinc chloride 161.6 mg (1.186 mmol), ethyl p- (N-acetyl-N-hydroxy) aminobenzoate 1.000 g (4.48 mmol). ), 0.58 g (6.7 mmol) of vinyl acetate and 5.28 g of toluene were charged, and after replacing the gas phase with nitrogen, the mixture was stirred at 55 ° C. for 16 hours, and then the same treatment as in Example 1 was performed. 1.00 g of N-acetyl-5-ethoxycarbonylindole having a purity of 96.2% was obtained. (Yield 92.8%)
[0027]
[ Reference Example 2 ]
In a reaction vessel, platinum chloride 10.2 mg (0.038 mmol), ethyl p- (N-acetyl-N-hydroxy) aminobenzoate 34.3 mg (0.154 mmol), vinyl acetate 0.31 g (3.6 mmol) ) And stirred at 72 ° C. for 2 hours and analyzed, the purity of N-acetyl-5-ethoxycarbonylindole was 90.0%.
[0028]
Examples 5 to 11
In a reaction vessel, 1.00 g (4.48 mmol) of ethyl p- (N-acetyl-N-hydroxy) aminobenzoate, 5.8 g (67 mmol) of vinyl acetate and the others are shown in Tables 1-2 below. The purity of N-acetyl-5-ethoxycarbonylindole was analyzed by HPLC for the reaction solution prepared by charging the described noble metal catalyst and cocatalyst and reacting under the conditions described in Tables 1 and 2 below at a reaction temperature of 55 ° C.
[0029]
[Table 1]
Table 1

The noble metal catalysts A to D in Table 1 are as follows: A: PdCl ₂
B: 5% Pd-C
C: Pd (OAc) ₂
D: (NH ₄ ) ₂ PdCl ₄
[0030]
[Example 12]
15.8 mg (0.0037 mmol) of 5% Pd / C containing 50.65% water, 489 mg (3.59 mmol) of zinc chloride, methyl p- (N-acetyl-N-hydroxy) aminobenzoate 3 0.000 g (14.3 mmol) and 36.98 g (430 mmol) of vinyl acetate were charged, and the gas phase portion was replaced with nitrogen, followed by stirring at 55 ° C. for 8 hours. After cooling, ethyl acetate was added to dissolve the organic crystals precipitated by the reaction, and the inorganic solid content was removed by filtration. The filtrate and washings were washed with water, and then the ethyl acetate layer was concentrated to dryness to obtain 3.08 g of N-acetyl-5-methoxycarbonylindole having a purity of 97.6%. (Yield 96.5%)
[0031]
Example 13
52.6% (0.0145 mmol) of 5% Pd / C containing 50.65% water in the reaction vessel, 125 mg (0.917 mmol) of zinc chloride, p- (N-benzoyl-N-hydroxy) aminobenzoic acid 1.02 g (3.58 mmol) of ethyl acid and 4.64 g (54.9 mmol) of vinyl acetate were charged, and the mixture was heated and stirred at 55 ° C. for 2 hours, and then treated in the same manner as in Example 1 to obtain a purity of 94. 1.07 g of 7% N-benzoyl-5-ethoxycarbonylindole was obtained. (Yield 96.7%)
[0032]
Example 14
The reaction vessel was charged with 4.50 g (19.5 mmol) of N-acetyl-5-ethoxycarbonylindole obtained in Example 1 and 311 g (77.8 mmol) of 1% NaOH aqueous solution and stirred at 60 ° C. under a nitrogen atmosphere. The temperature rose. After 6 hours, the mixture was cooled and 16.9 g (83.6 mmol) of an 18% aqueous HCl solution was added to adjust the pH to 3.0. Methyl t-butyl ether was added to the reaction solution for extraction, followed by washing with water. The oil was concentrated by an evaporator to obtain 3.12 g of brown crystal indole-5-carboxylic acid having a purity of 95.9%. (The yield is 95.4%, melting point 206-207 ° C.)
[0031]
Example 15
The reaction vessel was charged with 1.90 g (8.22 mmol) of N-acetyl-5-ethoxycarbonylindole obtained in Example 1, 1.9 g of methanol, and 7.90 g (19.8 mmol) of 10% aqueous NaOH solution at 50 ° C. Stir for 4 hours. After cooling and concentration under reduced pressure to remove methanol, 1.55 g (9.88 mmol) of 62.5% aqueous sulfuric acid solution was added. The precipitated crystals were filtered, washed with water and dried to obtain 1.33 g of indole-5-carboxylic acid having a purity of 95.9%. (Yield 96.5%)
[0032]
Example 16
A reaction vessel was charged with 217 mg (1.0 mmol) of N-acetyl-5-methoxycarbonylindole obtained in Example 14 and 1.92 g (2.4 mmol) of 5% aqueous NaOH solution, and stirred at 60 ° C. for 2 hours. After cooling, impurities were extracted and removed with methyl t-butyl ether. 0.49 g (2.4 mmol) of an 18% aqueous HCl solution was added to the aqueous layer after separation. The precipitated crystals are dissolved in methyl t-butyl ether, and insolubles are removed by filtration. The filtrate and washings are washed with water, and the oil layer is concentrated to dryness to give 94.7% purity indole-5-carboxyl. 144 mg of acid was obtained. (Yield 84.7%)

Claims (3)

The following general formula (1)

[Wherein, the R ₁ OCO— group is in any of positions 4 to 7, R ₁ represents an alkyl group having 1 to 4 carbon atoms, R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, In the production of N-acyl indole carboxylic acid esters represented by C 1-4 alkoxy group, C 1-4 haloalkyl group, C 2-4 alkenyl group, benzyl group or phenyl group]. And general formula (2)

[Wherein, R ₁ represents an alkyl group having 1 to 4 carbon atoms, and R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a haloalkyl having 1 to 4 carbon atoms. Group, an alkenyl group having 2 to 4 carbon atoms, a benzyl group or a phenyl group]
N-acyl-N-hydroxyaminobenzoates represented by the formula: Pd element as a noble metal catalyst in the presence or absence of a reaction solvent, Pd element supported on a support, Pd-containing compound supported on a support, At least one selected from Li ₂ PdCl ₄ , Na ₂ PdCl ₄ , (NH ₄ ) ₂ PdCl _4, PdCl ₂ , Pd (OCOCH ₃ ) ₂ and at least one selected from a halide of Cu or Zn as a co-catalyst In combination with general formula (4)

[Wherein R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group], and a method for producing an N-acyl indole carboxylic acid ester characterized by reacting with vinyl esters. General formula (2)

[Wherein, R ₁ represents an alkyl group having 1 to 4 carbon atoms, and R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a haloalkyl having 1 to 4 carbon atoms. Group, an alkenyl group having 2 to 4 carbon atoms, a benzyl group or a phenyl group]
N-acyl-N-hydroxyaminobenzoates represented by the formula: Pd element as a noble metal catalyst in the presence or absence of a reaction solvent, Pd element supported on a support, Pd-containing compound supported on a support, _{li 2 PdCl 4, Na 2 PdCl} 4, (NH 4) 2 PdCl 4, PdCl 2, Pd (OCOCH 3) and at least one selected from _2, at least one selected from the halides of Cu or Zn as a cocatalyst In combination with general formula (4)

[Wherein R ₃ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group] and is reacted with a vinyl ester represented by the general formula (1)

[Wherein, the R ₁ OCO— group is in any of positions 4 to 7, R ₁ represents an alkyl group having 1 to 4 carbon atoms, R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, An N-acyl indole carboxylic acid ester represented by a C 1-4 alkoxy group, a C 1-4 haloalkyl group, a C 2-4 alkenyl group, a benzyl group or a phenyl group. General formula (5) characterized by decomposing

[Wherein the HOCO- group is in any of the 4-7 positions. ] The manufacturing method of indolecarboxylic acid represented by this. Cocatalyst _CuCl, CuCl 2, at least one kind of method for producing N- acyl indole carboxylic acid esters according to claim 1, wherein and the manufacturing method of the indole carboxylic acids according to claim 2, wherein is selected from ZnCl _2.