JP2004182602A - Method for producing nitrogen-containing heterocyclic derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an inexpensive saturated or unsaturated nitrogen-containing heterocyclic derivative substituted with a methylamino group by which industrial wastes are reduced as much as possible from an inexpensive raw material in high yield. <P>SOLUTION: A saturated or an unsaturated nitrogen-containing heterocyclic compound represented by general formula (1) or (2) (wherein, R<SP>1</SP>is a 1-4C alkyl group; R<SP>2</SP>is a 1-4C alkyl group, an allyl group, an aralkyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group or a sulfonyl group; l is 0-2; m is 1 or 2; and n is an integer of 4-6) is reacted with formaldehyde or paraformalhyde in the presence of a hydrogen or a hydrogen-producing source to thereby produce the nitrogen-containing heterocyclic derivative represented by general formula (3) or (4). The resultant heterocyclic derivative represented by general formula (3) or (4) is further subjected to hydrolysis or hydrogenolysis to thereby produce the saturated or unsaturated nitrogen-containing heterocyclic derivative represented by general formula (5) or (6). <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【０００９】
（ここで、Ｒ^１は炭素数１〜４のアルキル基、Ｒ^２は炭素数１〜４のアルキル基、アリル基、アラルキル基、アルコキシカルボニル基、ベンジルオキシカルボニル基、スルホニル基を示す。また、ｌは０〜２、ｍは１または２、ｎは４〜６の整数を意味する。）で表される飽和または不飽和の含窒素複素環化合物と、ホルムアルデヒドまたはパラホルムアルデヒドを水素または水素発生源の存在下で反応させることにより、一般式（３）または一般式（４）
【００１０】
【化７】

【００１１】
（ここで、Ｒ^１ 、Ｒ^２ 、ｌ、ｍ、ｎは前記と同様。）で表される飽和または不飽和の含窒素複素環誘導体を製造する方法である。ここで、一般式（１）または一般式（２）で表される化合物に光学活性体を用いることにより、光学活性な一般式（３）または一般式（４）で表される飽和または不飽和の含窒素複素環誘導体を製造することができる。
【００１２】
さらに、得られた一般式（３）または一般式（４）で表される化合物を加水分解または水素化分解することにより、一般式（５）または一般式（６）
【００１３】
【化８】

【００１４】
（ここで、Ｒ^１ 、Ｒ^２ 、ｍ、ｎは前記と同様。）で表される飽和または不飽和の含窒素複素環誘導体を製造することができる。ここで、一般式（１）、一般式（２）、一般式（３）、一般式（４）で表される化合物が何れも光学活性体であれば、得られる一般式（５）、一般式（６）で表される化合物も光学活性体である。
【００１５】
【発明の実施の形態】
本発明で原料として使用する一般式（１）で表される飽和または不飽和含窒素複素環化合物の具体例としては、３−アミノ−１−ベンジルピロリジン、３−アミノ−１−トルエンスルホニルピロリジン、３−アミノ−１−ベンジルオキシカルボニルピロリジン等のピロリジン誘導体、３−アミノメチル−１−ベンジルピロ−ル、３−アミノメチル−１−トルエンスルホニルピロール、３−アミノメチル−１−ベンジルオキシカルボニルピロール等のピロール誘導体、３−アミノ−１−ベンジルピペリジン、３−アミノ−１−エトキシカルボニルピペリジン、３−アミノ−１−ベンジルオキシカルボニルピペリジン等のピペリジン誘導体、４−アミノ−１−ベンジル−１，４−ジヒドロピリジン、４−アミノ−１−フェニル−１，４−ジヒドロピリジン、４−アミノ−１−ベンジルオキシカルボニル−１，４−ジヒドロピリジン等の１，４−ジヒドロピリジン誘導体、３−アミノ−１−ベンジルピリジン、３−アミノ−１−トルエンスルホニルピリジン、３−アミノ−１−ベンジルオキシカルボニルピリジン等のピリジン誘導体、３−アミノ−１−ベンジルヘキサメチレンイミン、３−アミノ−１−トルエンスルホニルヘキサメチレンイミン、３−アミノ−１−ベンジルオキシカルボニルヘキサメチレンイミン等のヘキサメチレンイミン誘導体である。
【００１６】
また、一般式（２）で表される飽和または不飽和含窒素複素環化合物の具体例としては、３−エチルアミノ−１−ベンジルピロリジン、３−エチルアミノ−１−トルエンスルホニルピロリジン、３−エチルアミノ−１−ベンジルオキシカルボニルピロリジン等のピロリジン誘導体、１−ベンジル−３−プロピルアミノメチルピロ−ル、３−エチルアミノメチル−１−トルエンスルホニルピロール等のピロール誘導体、３−エチルアミノ−１−ベンジルピペリジン、３−プロピルアミノ−１−トルエンスルホニルピペリジン、３−エチルアミノ−１−ベンジルオキシカルボニル−３−エチルアミノピペリジン等のピペリジン誘導体、１−ベンジル−４−エチルアミノ−１，４−ジヒドロピリジン、４−エチルアミノ−１−トルエンスルホニル−１，４−ジヒドロピリジン、１−ベンジルオキシカルボニル−４−ブチルアミノ−１，４−ジヒドロピリジン等の１，４−ジヒドロピリジン誘導体、１−ベンジル−３−エチルアミノピリジン、４−ブチルアミノ−１−トルエンスルホニルピリジン、１−ベンジルオキシカルボニル−４−メチルアミノピリジン等のピリジン誘導体、１−ベンジル−３−ブチルアミノヘキサメチレンイミン、３−ブチルアミノ−１−トルエンスルホニルヘキサメチレンイミン等のヘキサメチレンイミン誘導体である。
【００１７】
もう一方の原料であるホルムアルデヒドとしては、ホルマリンとして容易に入手できる水溶液が使用できる。水溶液濃度はいかなる割合でも使用できる。また、通常は安定剤としてメタノールが含有されている場合が多いが、これも使用することができる。また、ホルムアルデヒドの重合体であるパラホルムアルデヒド（パラホルム）も使用することができる。何れの形態のホルムアルデヒドを使用しても本発明を実施する上で問題はない。使用量は、メチル化に供するアミノ基の水素原子に対して０．８〜３．０当量、好ましくは１．０〜２．０当量、更に好ましくは１．１〜１．４当量である。この範囲であれば反応収率も高く、廃棄物も少ない。反応溶媒は反応に不活性であればいかなるものでも使用できるが、好ましくはメタノール、エタノール等のアルコール類や水であり、これらの混合物も使用できるが、特に好ましくは水である。反応濃度は操作できる範囲であればいかなる濃度でも実施できるが、生産性を考慮すると仕込み含窒素複素環化合物として１０〜４０ｗｔ％、好ましくは１５〜２５ｗｔ％である。反応方法は、溶媒中に含窒素複素環化合物とホルムアルデヒドまたはパラホルムアルデヒドを混合し、水素または水素発生源を共存させて反応させる。ここで、水素を共存させる場合には常圧、加圧の何れの系を選択することもできるが、好ましくは加圧系である。その場合、水素圧は０．２〜１．０ＭＰａが好ましい。オートクレーブに封じ込めて実施する場合には、水素が消費されるに従って水素圧は低下するので、その都度水素を追加加圧すればよい。また、水素発生源を共存させる場合には、蟻酸が好ましく使用できる。反応を水または含水溶液中で実施する場合には、水溶液として市販されている蟻酸も使用することができる。蟻酸使用量はメチル化に供するアミノ基の水素原子に対して０．９〜３．０当量、好ましくは０．９５〜１．５当量、更に好ましくは１．０〜１．２当量である。但し、含窒素複素環の中和にも使用されるので、更に中和分を加える必要がある。従って、蟻酸の使用量はアミノ基の水素原子と複素環に含有される窒素原子の合計に対して０．９〜３．０当量、好ましくは０．９５〜１．５当量、更に好ましくは１．０〜１．２当量である。この範囲であれば反応収率も高く、廃棄物量も少ない。蟻酸を使用した場合、反応が進行するに従って炭酸ガスが発生するので、反応容器は密閉せずに、通気状態を保てる装置が好ましい。反応温度は水素を使用した密閉装置を使用する場合には、３０〜１５０℃が好ましく、特に好ましくは５０〜１００℃である。また、蟻酸を使用する場合には、室温から溶媒の沸点が好ましいが、特に好ましくは５０〜８０℃である。反応時間は化合物によって異なり、通常は５〜２０時間であるが反応の進行を分析でチェックしながら終点を決めるのが好ましい。含窒素複素環化合物の反応生成物の単離法は通常の方法が採用できる。例えば、反応液を塩基性にしてから抽出する方法が採用できる。精製は、蒸留法、再結晶法またはカラム精製法が採用できる。
【００１８】
かくして一般式（３）または一般式（４）で表される化合物が得られる。
【００１９】
【化９】

【００２０】
（ここで、Ｒ^１ 、Ｒ^２ 、ｌ、ｍ、ｎは前記と同様。）で表される飽和または不飽和の含窒素複素環誘導体を水素化分解または加水分解する。Ｒ^２がアラルキル基、ベンジルオキシカルボニル基の場合は、水素化分解が好ましく適用できる。Ｒ^２がアルコキシカルボニル基、スルホニル基の場合は、加水分解が好ましく適用できる。
【００２１】
水素化分解触媒としてはパラジウムや白金を活性炭、アルミナ等に担時させたものが好ましい。これらの触媒は、乾燥状態のものでも、含水状態のものでも使用できる。
【００２２】
触媒使用量は基質に対して１〜５０ｗｔ％が好ましく、特に好ましくは５〜２０ｗｔ％である。この範囲であれば、反応速度も速く、操作性が良好である。
【００２３】
反応溶媒としては、メタノール、エタノール等のアルコール類、テトラヒドロフラン等のエーテル類、トルエン等の炭化水素類、または水が好ましく使用できるが、メタノール、エタノールが特に好ましい。
【００２４】
水素圧は常圧から５ＭＰａが好ましく、特に好ましくは常圧から２ＭＰａである。
【００２５】
反応温度は室温から１２０℃が好ましく、特に好ましくは５０〜９０℃である。この範囲であれば、反応速度も速く副反応も抑制される。
【００２６】
反応方法はオートクレーブに仕込んで所定温度で攪拌する方法が好ましく採用されるが、Ｒ^２がベンジルオキシカルボニル基の場合には、常圧で水素を流通しながら実施する方法が好ましい。
【００２７】
かくして、一般式（５）または一般式（６）で表される飽和または不飽和の含窒素複素環誘導体が得られる。
【００２８】
単離は通常の方法が採用できる。具体的には蒸留法、再結晶法、カラム分離法等が採用できる。
【００２９】
加水分解は塩酸、臭素酸、硫酸等の無機酸水溶液、あるいは水酸化ナトリウム水溶液等のアルカリ水溶液と加熱することで達成される。水溶液の濃度は無機酸やアルカリの種類によって異なるが、通常は５ｗｔ％から飽和水溶液を使用する。反応温度は無機酸やアルカリの濃度、種類によって異なるが、室温から還流温度であり、好ましくは５０〜還流温度である。反応時間は反応条件によって異なるが、通常は１〜７０時間である。かくして一般式（５）または一般式（６）で表される飽和または不飽和の含窒素複素環誘導体が得られる。
【００３０】
単離するのは通常の方法が採用できる。たとえば、反応後に得られた無機酸水溶液を水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム等のアルカリを加えて塩基性とした後、有機溶媒で抽出する方法が採用できる。あるいは、反応後に得られた無機酸水溶液をカチオン交換樹脂に通液し、ナトリウムイオンやカリウムイオンをイオン交換樹脂に吸着させ、溶出した一般式（５）または一般式（６）で表される飽和または不飽和の含窒素複素環誘導体を濃縮する方法が採用できる。
【００３１】
【実施例】
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれに限定するものではない。
【００３２】
実施例１
攪拌機、ジムロート、滴下ロート、温度計を装着した１リットル（以下、Ｌと略す。）の４口フラスコに、水２１５ｇ、（Ｓ）−３−アミノ−１−ベンジルピロリジン６１．７ｇ（０．３５モル、自製、光学純度 ９９．４％ｅｅ）、工業用９０％蟻酸３５．８ｇ（０．７０モル）、粉末パラホルムアルデヒド（純度９５％、工業用）２４．３ｇ（０．７７モル）を仕込み、室温中で攪拌した。攪拌しながら７０℃に昇温してから、工業用９０％蟻酸３７．６ｇ（０．７３モル）を約１時間で滴下し、更に５時間攪拌した。反応終了後、攪拌しながら室温まで冷却し、４８％水酸化ナトリウム水溶液７２．９ｇ（０．８８モル）を滴下して中和した後、トルエン１００ｇを添加した１時間攪拌した。静置後、トルエン層を分離し、水層に再度トルエン１００ｇを添加し、同様にしてトルエン層を分離した。両トルエン層を合わせ、エバポレータで濃縮した後、真空蒸留して１２２〜１２４℃／１３３Ｐａの留分として（Ｓ）−１−ベンジル−３−ジメチルアミノピロリジン６７．９ｇ（０．３３モル）を得た。収率は９５％であり、光学純度は９９．４％ｅｅ、化学純度は９９．５％であった。
【００３３】
実施例２
攪拌機、ジムロート、滴下ロート、温度計を装着した１Ｌの４口フラスコに、水２１５ｇ、３−アミノ−１−ベンジルピロリジン６１．７ｇ（０．３５モル、自製）、工業用９０％蟻酸３５．８ｇ（０．７０モル）、粉末パラホルムアルデヒド（純度９５％、工業用）２４．３ｇ（０．７７モル）を仕込み、室温中で攪拌した。攪拌しながら７０℃に昇温してから、工業用９０％蟻酸３７．６ｇ（０．７３モル）を約１時間で滴下し、更に５時間攪拌した。反応終了後、攪拌しながら室温まで冷却し、４８％水酸化ナトリウム水溶液７２．９ｇ（０．８８モル）を滴下して中和した後、トルエン１００ｇを添加した１時間攪拌した。静置後、トルエン層を分離し、水層に再度トルエン１００ｇを添加し、同様にしてトルエン層を分離した。両トルエン層を合わせ、エバポレータで濃縮して１−ベンジル−３−ジメチルアミノピロリジン７０．０ｇを含む濃縮液８３ｇを得た。
【００３４】
１Ｌオートクレーブに濃縮液８２ｇとメタノール５００ｍｌ、５％Ｐｄ／Ｃ（含水率５０％、イーエヌーキャット社製）１４ｇを仕込んだ後、水素圧４ＭＰａに調整し、８０℃で８時間反応した。反応終了後、Ｐｄ／Ｃを濾過してから濾液をエバポレータで濃縮し、３−ジメチルアミノピロリジンを３９．２ｇ含む濃縮液５２ｇを得た。収率はほぼ定量的であった。
【００３５】
実施例３
攪拌機、ジムロート、滴下ロート、温度計を装着した１００ｍｌの４口フラスコに、水１０ｇ、１−ベンジルオキシカルボニル−３−アミノピペリジン（Ａｌｄｒｉｃｈ社３−アミノピペリジンから自社で合成）２．３ｇ（０．０１モル）、工業用９０％蟻酸１．０ｇ（０．０２モル）、３０％ホルマリン水溶液（和光純薬）２．０ｇ（０．０２モル）を仕込み、室温中で攪拌した。攪拌しながら６０℃に昇温してから、工業用９０％蟻酸１．５ｇ（０．０３モル）を約２０分間で滴下し、更に５時間攪拌した。反応終了後、攪拌しながら室温まで冷却し、４８％水酸化ナトリウム水溶液３．３ｇ（０．０４モル）を滴下して中和した後、トルエン２０ｇで抽出し、１−ベンジルオキシカルボニル−３−ジメチルアミノピペリジンを得た。転化率はほぼ１００％で、ＧＣ分析で副生物は検出されなかった。
【００３６】
実施例４
攪拌機、ジムロート、滴下ロート、温度計を装着した１００ｍｌの４口フラスコに、水１０ｇ、１−ベンジル−３−ブチルアミノピロリジン（１−ベンジル−３−オキソピロリジンから自社で合成）２．３ｇ（０．０１モル）、工業用９０％蟻酸０．５ｇ（０．０１モル）、３０％ホルマリン水溶液（和光純薬）１．０ｇ（０．０１モル）を仕込み、実施例１と同様にして１−ベンジル−３−ブチルメチルアミノピロリジンの濃縮液２．８ｇを得た。純分２．４ｇであり、ほぼ定量的であった。ＧＣ分析でトルエン以外の副生物ピークは検出されなかった。
【００３７】
実施例５
１００ｍｌのオートクレーブに 実施例４で得た１−ベンジル−３−ブチルメチルアミノピロリジン濃縮液２．８ｇ、メタノール３０ｍｌ、５％Ｐｄ／Ｃ（５０％含水）０．３ｇ仕込み、水素圧２ＭＰａに調整して８０℃で５時間攪拌した。冷却後、オートクレーブから溶液を取り出し、Ｐｄ／Ｃをろ過で除いた後、濾液を濃縮して３−ブチルメチルアミノピロリジン濃縮液２．１ｇを得た。純分１．６ｇであり、ほぼ定量的に脱ベンジル化反応が進行していた。
【００３８】
実施例６
攪拌機、ジムロート、滴下ロート、温度計を装着した１００ｍｌの４口フラスコに、水１０ｇ、３−アミノ−１−エトキシカルボニルピロリジン（３−アミノピロリジンとクロル炭酸エチルから自社で合成）１．６ｇ（０．０１モル）、工業用９０％蟻酸１．０ｇ（０．０２モル）、３０％ホルマリン水溶液（和光純薬）２．０ｇ（０．０２モル）を仕込み、実施例１と同様にして１−エトキシカルボニル−３−ジメチルアミノピロリジンの濃縮液２．５ｇを得た。純分１．９ｇであり、ほぼ定量的であった。ＧＣ分析でトルエン以外の副生物ピークは検出されなかった。得られた濃縮液を３０％臭素酸水溶液２０ｇに加え、５時間加熱還流した。冷却後、反応液を２０％水酸化ナトリウム水溶液でｐＨを１３以上に調整してからクロロホルム５０ｍｌで抽出し、３−ジメチルアミノピロリジン溶液を得た。純分は１．０ｇであり、収率８８％であった。
【００３９】
【発明の効果】
本発明によれば、安価な試薬、穏和な条件で容易にメチルアミノ基で置換された含窒素複素環誘導体が製造できる。更に、原料に光学活性体を使用すれば、光学純度を低下させることなくメチルアミノ基で置換された光学活性含窒素複素環誘導体が製造できる。[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to a method for producing a nitrogen-containing heterocyclic derivative useful as a raw material for medicines and agricultural chemicals, in particular, a saturated or unsaturated nitrogen-containing heterocyclic derivative substituted with a methylamino group.
[0002]
[Prior art]
A method for producing a nitrogen-containing heterocyclic compound substituted with a methylamino group has been known for a long time. For example, (1) reacting a hydroxyl group of 1-benzyl-3-hydroxypyrrolidine with toluenesulfonyl chloride to produce 1-benzyl-3- (toluenesulfonoxy) pyrrolidine, and then reacting with dimethylamine to give 1-benzyl Method for producing -3-dimethylaminopyrrolidine (Patent Document 1), (2) Method for producing dimethylaminopyrrolidine derivative by reacting 3-substituted butane with primary amine and dimethylamine to cyclize (Patent Document 2) Etc. are known. As a general production method for methylating an amino group, a method of reacting with a methyl halide such as methyl iodide to carry out methylation is also known. These methods are all excellent methods, but (1) is a method in which a hydroxyl group is converted to toluenesulfonyl and then reacted with dimethylamine again, and the operation is complicated. (2) is a method of synthesizing a skeleton from trisubstituted butane, and cannot be said to be a simple method. In addition, methylation of an amino group by methyl iodide is high in both reactivity and workability, but methyl iodide is expensive, and the molecular weight of iodine is large, so the amount of raw materials used is large, which is excellent as a lab synthesis method. However, it is not suitable for industrial production. Each of the above production methods has problems as an industrial production method, and a method for producing an inexpensive nitrogen-containing heterocyclic compound substituted with a methylamino group is required.
[0003]
[Patent Document 1] JP-A-49-273 (page 14)
[0004]
[Patent Document 2] Japanese Patent Publication No. Hei 3-20391 (page 4)
[0005]
[Problems to be solved by the invention]
That is, an object of the present invention is to provide a method for producing a saturated or unsaturated nitrogen-containing heterocyclic compound substituted with an inexpensive methylamino group from an inexpensive raw material at a high yield and reducing industrial waste as much as possible. It is in.
[0006]
[Means for Solving the Problems]
The present inventors have earnestly studied a method for solving the above-mentioned problem, and as a result, have reached the present invention.
[0007]
The present invention relates to the general formula (1) or the general formula (2)
[0008]
Embedded image

[0009]
(Here, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms, an allyl group, an aralkyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, or a sulfonyl group. l represents 0 to 2, m represents 1 or 2, and n represents an integer of 4 to 6) and a saturated or unsaturated nitrogen-containing heterocyclic compound represented by the following formula: By reacting in the presence of the general formula (3) or (4)
[0010]
Embedded image

[0011]
(Here, R ¹ , R ² , l, m, and n are the same as described above.) This is a method for producing a saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the formula: Here, by using an optically active substance for the compound represented by the general formula (1) or the general formula (2), a saturated or unsaturated compound represented by the optically active general formula (3) or the general formula (4) is obtained. Can be produced.
[0012]
Further, the resulting compound represented by the general formula (3) or (4) is hydrolyzed or hydrogenolyzed to obtain a compound represented by the general formula (5) or (6).
[0013]
Embedded image

[0014]
(Here, R ¹ , R ² , m, and n are the same as described above.) The saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the formula ( ¹ ) can be produced. Here, when all of the compounds represented by the general formulas (1), (2), (3) and (4) are optically active compounds, the obtained general formulas (5) and (5) The compound represented by the formula (6) is also an optically active substance.
[0015]
BEST MODE FOR CARRYING OUT THE INVENTION
Specific examples of the saturated or unsaturated nitrogen-containing heterocyclic compound represented by the general formula (1) used as a raw material in the present invention include 3-amino-1-benzylpyrrolidine, 3-amino-1-toluenesulfonylpyrrolidine, Pyrrolidine derivatives such as 3-amino-1-benzyloxycarbonylpyrrolidine; 3-aminomethyl-1-benzylpyrrol; 3-aminomethyl-1-toluenesulfonylpyrrole; 3-aminomethyl-1-benzyloxycarbonylpyrrole; Pyrrole derivatives, piperidine derivatives such as 3-amino-1-benzylpiperidine, 3-amino-1-ethoxycarbonylpiperidine, 3-amino-1-benzyloxycarbonylpiperidine, 4-amino-1-benzyl-1,4-dihydropyridine , 4-amino-1-phenyl-1,4-dihydro 1,4-dihydropyridine derivatives such as lysine, 4-amino-1-benzyloxycarbonyl-1,4-dihydropyridine, 3-amino-1-benzylpyridine, 3-amino-1-toluenesulfonylpyridine, 3-amino-1 Pyridine derivatives such as -benzyloxycarbonylpyridine, hexamethyleneimines such as 3-amino-1-benzylhexamethyleneimine, 3-amino-1-toluenesulfonylhexamethyleneimine, 3-amino-1-benzyloxycarbonylhexamethyleneimine It is a derivative.
[0016]
Specific examples of the saturated or unsaturated nitrogen-containing heterocyclic compound represented by the general formula (2) include 3-ethylamino-1-benzylpyrrolidine, 3-ethylamino-1-toluenesulfonylpyrrolidine, 3-ethyl Pyrrolidine derivatives such as amino-1-benzyloxycarbonylpyrrolidine, pyrrole derivatives such as 1-benzyl-3-propylaminomethylpyrrol, 3-ethylaminomethyl-1-toluenesulfonylpyrrole, 3-ethylamino-1-benzyl Piperidine derivatives such as piperidine, 3-propylamino-1-toluenesulfonylpiperidine, 3-ethylamino-1-benzyloxycarbonyl-3-ethylaminopiperidine, 1-benzyl-4-ethylamino-1,4-dihydropyridine, -Ethylamino-1-toluenesulfonyl- 1,4-dihydropyridine derivatives such as 1,4-dihydropyridine, 1-benzyloxycarbonyl-4-butylamino-1,4-dihydropyridine, 1-benzyl-3-ethylaminopyridine, 4-butylamino-1-toluenesulfonylpyridine And pyridine derivatives such as 1-benzyloxycarbonyl-4-methylaminopyridine and hexamethyleneimine derivatives such as 1-benzyl-3-butylaminohexamethyleneimine and 3-butylamino-1-toluenesulfonylhexamethyleneimine.
[0017]
As the other raw material, formaldehyde, an aqueous solution easily available as formalin can be used. Any concentration of aqueous solution can be used. Usually, methanol is often contained as a stabilizer, but this can also be used. Paraformaldehyde (paraform), which is a polymer of formaldehyde, can also be used. There is no problem in practicing the present invention using any formaldehyde. The amount used is 0.8 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, more preferably 1.1 to 1.4 equivalents, relative to the hydrogen atom of the amino group to be subjected to methylation. Within this range, the reaction yield is high and the waste is small. Any reaction solvent may be used as long as it is inert to the reaction, preferably alcohols such as methanol and ethanol and water, and a mixture thereof may be used, but water is particularly preferred. The reaction can be carried out at any concentration as long as it can be operated. However, considering productivity, the nitrogen-containing heterocyclic compound to be charged is 10 to 40% by weight, preferably 15 to 25% by weight. In the reaction method, a nitrogen-containing heterocyclic compound and formaldehyde or paraformaldehyde are mixed in a solvent, and the reaction is performed in the presence of hydrogen or a hydrogen generation source. Here, when hydrogen is allowed to coexist, either a normal pressure system or a pressurized system can be selected, but a pressurized system is preferable. In that case, the hydrogen pressure is preferably from 0.2 to 1.0 MPa. When the method is carried out in an autoclave, the hydrogen pressure decreases as the hydrogen is consumed. Therefore, the hydrogen may be additionally pressurized each time. When a hydrogen generation source is used, formic acid can be preferably used. When the reaction is carried out in water or an aqueous solution, formic acid commercially available as an aqueous solution can also be used. The used amount of formic acid is 0.9 to 3.0 equivalents, preferably 0.95 to 1.5 equivalents, more preferably 1.0 to 1.2 equivalents, based on the hydrogen atom of the amino group to be subjected to methylation. However, since it is also used for neutralizing a nitrogen-containing heterocycle, it is necessary to further add a neutralized component. Therefore, the amount of formic acid used is 0.9 to 3.0 equivalents, preferably 0.95 to 1.5 equivalents, more preferably 1 to 1.5 equivalents to the total of the hydrogen atom of the amino group and the nitrogen atom contained in the heterocyclic ring. 0.0 to 1.2 equivalents. Within this range, the reaction yield is high and the amount of waste is small. When formic acid is used, carbon dioxide gas is generated as the reaction proceeds. Therefore, a device capable of maintaining a ventilation state without sealing the reaction vessel is preferable. When a closed apparatus using hydrogen is used, the reaction temperature is preferably from 30 to 150 ° C, particularly preferably from 50 to 100 ° C. When formic acid is used, the temperature is preferably from room temperature to the boiling point of the solvent, and particularly preferably from 50 to 80 ° C. The reaction time varies depending on the compound and is usually 5 to 20 hours, but it is preferable to determine the end point while checking the progress of the reaction by analysis. An ordinary method can be employed for isolating the reaction product of the nitrogen-containing heterocyclic compound. For example, a method of extracting the reaction solution after making it basic, can be employed. For the purification, a distillation method, a recrystallization method or a column purification method can be adopted.
[0018]
Thus, a compound represented by the general formula (3) or (4) is obtained.
[0019]
Embedded image

[0020]
(Here, R ¹ , R ² , l, m, and n are the same as described above.) Hydrogenolysis or hydrolysis of a saturated or unsaturated nitrogen-containing heterocyclic derivative. When R ² is an aralkyl group or a benzyloxycarbonyl group, hydrogenolysis can be preferably applied. When R ² is an alkoxycarbonyl group or a sulfonyl group, hydrolysis can be preferably applied.
[0021]
As the hydrocracking catalyst, a catalyst in which palladium or platinum is supported on activated carbon, alumina or the like is preferable. These catalysts can be used either in a dry state or in a water-containing state.
[0022]
The amount of the catalyst used is preferably 1 to 50% by weight, particularly preferably 5 to 20% by weight, based on the substrate. Within this range, the reaction speed is high and the operability is good.
[0023]
As the reaction solvent, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, hydrocarbons such as toluene, and water can be preferably used, and methanol and ethanol are particularly preferable.
[0024]
The hydrogen pressure is preferably from normal pressure to 5 MPa, particularly preferably from normal pressure to 2 MPa.
[0025]
The reaction temperature is preferably from room temperature to 120 ° C, particularly preferably from 50 to 90 ° C. Within this range, the reaction rate is high and side reactions are suppressed.
[0026]
As a reaction method, a method in which the reaction mixture is charged into an autoclave and stirred at a predetermined temperature is preferably employed. When R ² is a benzyloxycarbonyl group, a method in which hydrogen is passed at normal pressure while flowing is preferable.
[0027]
Thus, a saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the general formula (5) or (6) is obtained.
[0028]
Conventional methods can be employed for isolation. Specifically, a distillation method, a recrystallization method, a column separation method and the like can be employed.
[0029]
The hydrolysis is achieved by heating with an aqueous solution of an inorganic acid such as hydrochloric acid, bromic acid, or sulfuric acid, or an aqueous alkali solution such as an aqueous solution of sodium hydroxide. The concentration of the aqueous solution varies depending on the type of the inorganic acid or alkali, but usually a saturated aqueous solution from 5 wt% is used. The reaction temperature varies depending on the concentration and type of the inorganic acid or alkali, but is from room temperature to reflux temperature, preferably from 50 to reflux temperature. The reaction time varies depending on the reaction conditions, but is usually 1 to 70 hours. Thus, a saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the general formula (5) or (6) is obtained.
[0030]
Conventional methods can be used for isolation. For example, a method in which an aqueous solution of an inorganic acid obtained after the reaction is made basic by adding an alkali such as sodium hydroxide, potassium hydroxide or sodium carbonate and then extracted with an organic solvent can be employed. Alternatively, an aqueous solution of an inorganic acid obtained after the reaction is passed through a cation exchange resin, and sodium ions and potassium ions are adsorbed to the ion exchange resin, and the eluted saturated formula represented by the general formula (5) or (6) is obtained. Alternatively, a method of concentrating the unsaturated nitrogen-containing heterocyclic derivative can be employed.
[0031]
【Example】
Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
[0032]
Example 1
In a 1-liter (hereinafter abbreviated as L) 4-necked flask equipped with a stirrer, Dim funnel, dropping funnel and thermometer, 215 g of water and 61.7 g (0.35 g) of (S) -3-amino-1-benzylpyrrolidine were added. Mol, self-made, optical purity 99.4% ee), industrial use 90% formic acid 35.8 g (0.70 mol), powdered paraformaldehyde (purity 95%, industrial use) 24.3 g (0.77 mol) And stirred at room temperature. After the temperature was raised to 70 ° C. with stirring, 37.6 g (0.73 mol) of industrial 90% formic acid was added dropwise in about 1 hour, and the mixture was further stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature with stirring, neutralized by dropwise addition of 72.9 g (0.88 mol) of a 48% aqueous sodium hydroxide solution, and then stirred for 1 hour after adding 100 g of toluene. After standing, the toluene layer was separated, 100 g of toluene was added again to the aqueous layer, and the toluene layer was separated in the same manner. The two toluene layers were combined, concentrated by an evaporator, and vacuum-distilled to obtain 67.9 g (0.33 mol) of (S) -1-benzyl-3-dimethylaminopyrrolidine as a fraction at 122 to 124 ° C./133 Pa. Was. The yield was 95%, the optical purity was 99.4% ee, and the chemical purity was 99.5%.
[0033]
Example 2
In a 1 L four-necked flask equipped with a stirrer, Dim funnel, dropping funnel and thermometer, 215 g of water, 61.7 g (0.35 mol, self-made) of 3-amino-1-benzylpyrrolidine, 35.8 g of industrial 90% formic acid (0.70 mol) and 24.3 g (0.77 mol) of powdered paraformaldehyde (purity: 95%, industrial grade) were stirred and stirred at room temperature. After the temperature was raised to 70 ° C. with stirring, 37.6 g (0.73 mol) of industrial 90% formic acid was added dropwise in about 1 hour, and the mixture was further stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature with stirring, neutralized by dropwise addition of 72.9 g (0.88 mol) of a 48% aqueous sodium hydroxide solution, and then stirred for 1 hour after adding 100 g of toluene. After standing, the toluene layer was separated, 100 g of toluene was added again to the aqueous layer, and the toluene layer was separated in the same manner. Both toluene layers were combined and concentrated by an evaporator to obtain 83 g of a concentrate containing 70.0 g of 1-benzyl-3-dimethylaminopyrrolidine.
[0034]
82 g of the concentrated solution, 500 ml of methanol, and 14 g of 5% Pd / C (water content: 50%, manufactured by ENQ Cat Inc.) were charged into a 1 L autoclave, and the mixture was adjusted to a hydrogen pressure of 4 MPa and reacted at 80 ° C. for 8 hours. After completion of the reaction, Pd / C was filtered, and the filtrate was concentrated by an evaporator to obtain 52 g of a concentrate containing 39.2 g of 3-dimethylaminopyrrolidine. The yield was almost quantitative.
[0035]
Example 3
In a 100 ml four-necked flask equipped with a stirrer, Dim funnel, dropping funnel and thermometer, 10 g of water and 2.3 g of 1-benzyloxycarbonyl-3-aminopiperidine (synthesized in-house from 3-aminopiperidine from Aldrich) (0.3 g). 01 mol), 1.0 g (0.02 mol) of industrial 90% formic acid, and 2.0 g (0.02 mol) of a 30% aqueous solution of formalin (Wako Pure Chemical Industries) were stirred at room temperature. After the temperature was raised to 60 ° C. while stirring, 1.5 g (0.03 mol) of industrial 90% formic acid was added dropwise over about 20 minutes, and the mixture was further stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature with stirring, and neutralized by dropwise addition of 3.3 g (0.04 mol) of a 48% aqueous sodium hydroxide solution, followed by extraction with 20 g of toluene and extraction with 1-benzyloxycarbonyl-3-. Dimethylaminopiperidine was obtained. The conversion was almost 100%, and no by-product was detected by GC analysis.
[0036]
Example 4
In a 100 ml four-necked flask equipped with a stirrer, Dim funnel, dropping funnel and thermometer, 10 g of water and 2.3 g of 1-benzyl-3-butylaminopyrrolidine (synthesized in-house from 1-benzyl-3-oxopyrrolidine) (0 g). 0.011 mol), 0.5 g (0.01 mol) of 90% formic acid for industrial use, and 1.0 g (0.01 mol) of a 30% aqueous solution of formalin (Wako Pure Chemical Industries, Ltd.). 2.8 g of a concentrated solution of benzyl-3-butylmethylaminopyrrolidine was obtained. The pure content was 2.4 g, which was almost quantitative. No by-product peak other than toluene was detected by GC analysis.
[0037]
Example 5
A 100 ml autoclave was charged with 2.8 g of the 1-benzyl-3-butylmethylaminopyrrolidine concentrate obtained in Example 4, 30 ml of methanol and 0.3 g of 5% Pd / C (containing 50% water), and adjusted to a hydrogen pressure of 2 MPa. And stirred at 80 ° C. for 5 hours. After cooling, the solution was taken out of the autoclave, Pd / C was removed by filtration, and the filtrate was concentrated to obtain 2.1 g of a 3-butylmethylaminopyrrolidine concentrate. The pure content was 1.6 g, and the debenzylation reaction proceeded almost quantitatively.
[0038]
Example 6
In a 100 ml four-necked flask equipped with a stirrer, Dim funnel, dropping funnel and thermometer, 10 g of water and 1.6 g of 3-amino-1-ethoxycarbonylpyrrolidine (synthesized in-house from 3-aminopyrrolidine and ethyl chlorocarbonate) were added. .01 mol), 1.0 g (0.02 mol) of industrial 90% formic acid, and 2.0 g (0.02 mol) of a 30% formalin aqueous solution (Wako Pure Chemical Industries, Ltd.). 2.5 g of a concentrated solution of ethoxycarbonyl-3-dimethylaminopyrrolidine was obtained. The pure content was 1.9 g, which was almost quantitative. No by-product peak other than toluene was detected by GC analysis. The obtained concentrate was added to 20 g of a 30% aqueous solution of bromic acid, and the mixture was refluxed for 5 hours. After cooling, the pH of the reaction solution was adjusted to 13 or more with a 20% aqueous sodium hydroxide solution, and the mixture was extracted with 50 ml of chloroform to obtain a 3-dimethylaminopyrrolidine solution. The pure content was 1.0 g, and the yield was 88%.
[0039]
【The invention's effect】
According to the present invention, an inexpensive reagent and a nitrogen-containing heterocyclic derivative substituted with a methylamino group can be easily produced under mild conditions. Furthermore, when an optically active substance is used as a raw material, an optically active nitrogen-containing heterocyclic derivative substituted with a methylamino group can be produced without lowering the optical purity.

Claims (6)

General formula (1) or general formula (2)

(Here, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms, an allyl group, an aralkyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, or a sulfonyl group. l represents 0 to 2, m represents 1 or 2, and n represents an integer of 4 to 6) and a saturated or unsaturated nitrogen-containing heterocyclic compound represented by the following formula: General formula (3) or general formula (4) characterized by reacting in the presence of

(Wherein, R ¹ , R ² , l, m, and n are the same as described above.) A method for producing a saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the formula: The method for producing a nitrogen-containing heterocyclic derivative according to claim 1, wherein the hydrogen generating source is formic acid. The compound represented by the general formula (1) or (2) is an optically active substance, and the compound represented by the general formula (3) or (4) is also an optically active substance. A method for producing the saturated or unsaturated nitrogen-containing heterocyclic derivative according to claim 1. General formula (1) or general formula (2)

(Here, R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 4 carbon atoms, an allyl group, an aralkyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, or a sulfonyl group. l represents 0 to 2, m represents 1 or 2, and n represents an integer of 4 to 6) and a saturated or unsaturated nitrogen-containing heterocyclic compound represented by the following formula: Formula (3) or Formula (4) produced by reacting in the presence of

(Wherein R ¹ , R ² , l, m, and n are the same as those described above), wherein a saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the general formula is hydrolyzed or hydrogenolyzed. (5) or general formula (6)

(Wherein R ¹ , R ² , m, and n are the same as described above.) A method for producing a saturated or unsaturated nitrogen-containing heterocyclic derivative represented by the formula: The compounds represented by the general formulas (1), (2), (3), (4), (5) and (6) are all optically active compounds. The method for producing a saturated or unsaturated nitrogen-containing heterocyclic derivative according to claim 4, characterized in that: The method for producing a nitrogen-containing heterocyclic derivative according to any one of claims 1 to 5, wherein the compound represented by the general formula (1) is 3-amino-1-benzylpyrrolidine.