JP4273528B2 - Method for optical resolution of 1-phenylethylamines - Google Patents
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- JP4273528B2 JP4273528B2 JP8404196A JP8404196A JP4273528B2 JP 4273528 B2 JP4273528 B2 JP 4273528B2 JP 8404196 A JP8404196 A JP 8404196A JP 8404196 A JP8404196 A JP 8404196A JP 4273528 B2 JP4273528 B2 JP 4273528B2
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Description
【０００１】
【発明の属する技術分野】
本発明は、１−フェニルエチルアミン類の光学分割方法に関する。
【０００２】
【従来の技術】
１−フェニルエチルアミン類の光学活性体は医薬、農薬などの中間体として有用な化合物である。
かかる１−フェニルエチルアミン類の光学活性体を得る方法としては、そのラセミ体を光学活性マンデル酸を用いて溶媒中で光学分割する方法などが一般的であり、中でも１−フェニルエチルアミン類のラセミ体と光学活性マンデル酸とを溶媒に溶解したのち、１−フェニルエチルアミン類の光学活性体と光学活性マンデル酸とのジアステレオマー塩を得、次いで該ジアステレオマー塩をアルカリ処理する方法などが広く知られている。
【０００３】
従来よりジアステレオマー塩を得る際の溶媒として水（特開昭５６−２６８４８号公報）、アンモニア水（特開平６−１７５７号公報）、メタノール（Bull.Chem.Soc.Jpn.,66,3414(1993)）を用いる方法などが提案されているが、水を用いる方法は得られたジアステレオマー塩の濾過性が悪くそれを濾過することが困難であり、アンモニア水を用いる方法はアンモニア水を取り扱うための特別の設備を必要とし、メタノールを用いる方法は目的とする光学活性１−フェニルエチルアミン類の収量が少ないため、これらの方法はいずれも工業的に十分に満足し得る方法であるとは言えなかった。
【０００４】
【発明が解決しようとする課題】
そこで本発明者は、特別の設備を用いることなく、容易にかつ高い収量で１−フェニルエチルアミン類を光学分割する方法を開発するべく鋭意検討した結果、本発明に至った。
【０００５】
【課題を解決するための手段】
すなわち本発明は、一般式（１）
で示される１−フェニルエチルアミン類を光学活性マンデル酸を用いて一般式（２）
Ｒ3 −Ｏ−Ｒ4 （２）
（式中、Ｒ3 は炭素数１〜６のアルキル基を、Ｒ4 は炭素数４〜６のアルキル基をそれぞれ示す。）
で示されるジアルキルエーテル中で光学分割することを特徴とする１−フェニルエチルアミン類の光学分割方法を提供するものである。
【０００６】
【発明の実施の形態】
本発明に適用される１−フェニルエチルアミン類において、置換基Ｒ1 、Ｒ2 におけるハロゲン原子としてはフッ素原子、塩素原子、臭素原子などが、アルコキシ基としてはメトキシ基、エトキシ基などが、ハロアルキル基としてはトリフルオロメチル基、ジフルオロメチル基、トリクロロメチル基などがそれぞれ例示される。
【０００７】
かかる１−フェニルエチルアミン類としては、例えば１−フェニルエチルアミン、１−（２−フルオロフェニル）エチルアミン、１−（３−フルオロフェニル）エチルアミン、１−（２−クロロフェニル）エチルアミン、１−（３−クロロフェニル）エチルアミン、１−（２−ブロモフェニル）エチルアミン、１−（３−ブロモフェニル）エチルアミンなどの１−（モノハロ置換フェニル）エチルアミン類、１−（２−メトキシフェニル）エチルアミン、１−（３−メトキシフェニル）エチルアミンなどの１−（モノアルコキシ置換フェニル）エチルアミン類、１−（３，４−ジメトキシフェニル）エチルアミンなどの１−（ジアルコキシ置換フェニル）エチルアミン類、１−（２−トリフルオロメチルフェニル）エチルアミン、１−（３−トリフルオロメチルフェニル）エチルアミン、１−（３−ジフルオロメチルフェニル）エチルアミンなどの１−（ハロアルキル置換フェニル）エチルアミン類、１−（２−ニトロフェニル）エチルアミン、１−（３−ニトロフェニル）エチルアミンなどの１−（ニトロフェニル）エチルアミン類などが挙げられる。これらの１−フェニルエチルアミン類はいずれもアセトフェノン類を原料とするロイカルト（Ｌｅｕｋｅｒｔ）反応によって容易に製造することができる〔Organic Reaction Vol.5,pp.301-330(1949) 〕。
【０００８】
かかる一般式（１）で示される１−フェニルエチルアミン類には＊で示される不斉炭素原子を中心とする２種類の光学活性体が存在するが、本発明の方法に用いられる１−フェニルエチルアミン類はそれらの混合物であってもよいし、ラセミ体であってもよい。
【０００９】
光学活性マンデル酸はＤ−マンデル酸、Ｌ−マンデル酸のいずれであってもよく、その使用量は、１−フェニルエチルアミン類に対して通常は０．１〜１．２モル倍、好ましくは０．３〜１モル倍の範囲である。
【００１０】
一般式（２）で示されるジアルキルエーテルにおける置換基Ｒ3 としてはメチル基、エチル基、ｎ−プロピル基などの炭素数１〜６のアルキル基が、置換基Ｒ4 としてはｎ−ブチル基、ｔ−ブチル基、ｎ−ヘキシル基などの炭素数４〜６のアルキル基がそれぞれ挙げられる。
かかるジアルキルエーテルとしては、例えばメチル−ｔ−ブチルエーテル、エチル−ｔ−ブチルエーテル、メチル−ｎ−ブチルエーテル、エチル−ｎ−ブチルエーテルなどが挙げられ、中でもメチル−ｔ−ブチルエーテル（以下、ＭＴＢＥと称する。）が好ましく用いられる。これらのジアルキルエーテルはそれぞれ単独または２種以上を混合して用いられ、さらには他の有機溶媒や水を含有していてもよい。かかるジアルキルエーテルの使用量は１−フェニルエチルアミン類に対して通常２〜１００重量倍の範囲である。
【００１１】
光学分割に際しては、例えば１−フェニルエチルアミン類および光学活性マンデル酸をジアルキルエーテルに溶解させたのち、１−フェニルエチルアミン類の光学活性体と光学活性マンデル酸とのジアステレオマー塩を得、次いで該ジアステレオマー塩をアルカリ処理すればよい。
【００１２】
１−フェニルエチルアミン類および光学活性マンデル酸をジアルキルエーテルに溶解させるに際しては、例えばジアルキルエーテルに１−フェニルエチルアミン類と光学活性マンデル酸とを加えて両者を溶解してもよいし、１−フェニルエチルアミン類のジアルキルエーテル溶液と光学活性マンデル酸のジアルキルエーテル溶液とを混合してもよく、さらには予め両者を反応させて得た１−フェニルエチルアミン類と光学活性マンデル酸との塩をジアルキルエーテルに溶解してもよい。溶解温度は通常１５℃以上、ジアルキルエーテルの沸点以下の範囲である。
【００１３】
溶解後、通常の方法、例えば冷却、濃縮する方法などによって、１−フェニルエチルアミン類の一方の光学活性体が優先的に光学活性マンデル酸とのジアステレオマー塩を形成し、該ジアステレオマー塩が析出するが、場合によってはそのまま静置または攪拌することによってかかるジアステレオマー塩を析出させてもよい。
【００１４】
ジアステレオマー塩の析出後、これを取り出し、母液と分離するが、かかるジアステレオマー塩は濾過性に優れており、通常の濾過操作などによって容易に両者を分離することができる。
【００１５】
かくして得られる１−フェニルエチルアミン類の光学活性体と光学活性マンデル酸とのジアステレオマー塩は、アルカリ処理されることによって容易に１−フェニルエチルアミン類の光学活性体へ導かれる。
【００１６】
アルカリ処理に際して通常は水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウムなどの塩基が用いられ、その使用量は通常ジアステレオマー塩に対して１〜５モル倍の範囲である。かかる塩基は通常、水溶液として用いられ、その濃度は通常１〜５０重量％、好ましくは５〜２０重量％の範囲である。
【００１７】
アルカリ処理に際しては、例えば塩基の水溶液およびジアステレオマー塩を混合すればよく、処理温度は通常−１０〜５０℃の範囲である。
【００１８】
かかるアルカリ処理によって１−フェニルエチルアミン類の光学活性体が生成するが、これは、場合によってはアルカリ処理後の反応混合物において層分離したものを分液する方法などによって取り出してもよいし、該反応混合物から、例えば水に不溶の有機溶媒を用いて抽出処理し、得られた有機層を溶媒留去する方法などによって容易に取り出してもよい。後者の場合、水に不溶の有機溶媒としては、例えば前記したと同様のジアルキルエーテルやジエチルエーテル、ジオキサンなどのエーテル系溶媒、酢酸エチルなどのエステル系溶媒、トルエン、キシレン、クロロベンゼンなどの芳香族系溶媒などが用いられ、その使用量は先のアルカリ処理に用いたジアステレオマー塩に対して通常０．１〜５重量倍の範囲である。
【００１９】
なお、１−フェニルエチルアミン類の光学活性体を取り出した後の反応混合物は光学活性マンデル酸を含有するものであり、かかる光学活性マンデル酸は該反応混合物から容易に回収し、本発明の方法に再使用することができる。かかる光学活性マンデル酸の回収方法としては、例えば水層に塩酸、硫酸、リン酸などの鉱酸を加えてそのｐＨを０．５〜２の範囲としたのち、前記したと同様の水に不溶の有機溶媒を用いて抽出し、得られた有機層を溶媒留去する方法などが挙げられるが、かかる有機溶媒としてジアルキルエーテルを用いた場合には、得られた有機層から溶媒を留去することなく本発明の方法に再使用し得るため、好ましい。
【００２０】
かくして１−フェニルエチルアミン類の光学活性体が得られるが、これとの対掌体である他方の光学活性体は、先の濾過操作によってジアステレオマー塩を分離した後の母液に含まれており、かかる母液から通常の方法、例えば母液を水酸化ナトリウム水溶液などのアルカリ性水溶液などを用いて洗浄したのち溶媒を留去する方法などによって容易に得ることができる。
【００２１】
【発明の効果】
本発明の方法によれば、特別の設備を用いることなく、容易にかつ高収量で１−フェニルエチルアミン類を光学分割することができる。
【００２２】
【実施例】
以下、実施例によって本発明をより詳細に説明するが、本発明はこれら実施例により限定されるものではない。
なお、得られた１−フェニルエチルアミン類の光学純度は、光学活性カラムを用いる高速液体クロマトグラフ分析法によって求めた。
【００２３】
実施例１
（ＲＳ）−１−フェニルエチルアミン５６ｇをＭＴＢＥ６０ｇに溶解し、攪拌下、４５℃に加熱し、次いで同温度で攪拌下、これにＬ−マンデル酸３１．７ｇをＭＴＢＥ１８０ｇに溶解して得た溶液を３０分かけて加え、さらに同温度で３０分間攪拌した。その後、６時間かけて２０℃まで冷却して、（Ｓ）−１−フェニルエチルアミンとＬ−マンデル酸とのジアステレオマー塩を析出させ、次いで濾過操作によって、ジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、ＭＴＢＥ１００ｇを用いて２回洗浄したのち乾燥させて、ジアステレオマー塩５６．８ｇを得た。次いで、５％水酸化ナトリウム水溶液１８５ｇを加えて２５℃で３０分間攪拌後、ＭＴＢＥ４５ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｓ）−１−フェニルエチルアミン２５．２ｇ（８７％ｅｅ）を得た。
【００２４】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液とを合わせ、５％水酸化ナトリウム水溶液１８ｇを加えたのち、ＭＴＢＥ３０ｇを用いる抽出処理を２回行い、有機層を合わせたのち溶媒を留去して、（Ｒ）−１−フェニルエチルアミン３０．８ｇ（７０．４％ｅｅ）を得た。
【００２５】
実施例２
（ＲＳ）−１−（２−フルオロフェニル）エチルアミン５ｇをＭＴＢＥ１０ｇに溶解し、これを攪拌下、４５℃に加熱したのち、同温度下で攪拌しながらこれにＬ−マンデル酸２．４６ｇをＭＴＢＥ３０ｇに溶解して得た溶液を３０分かけて滴下して加え、さらに３０分間攪拌したのち、３時間かけて２０℃まで冷却して、（Ｓ）−１−（２−フルオロフェニル）エチルアミンとＬ−マンデル酸とのジアステレオマー塩を析出させ、次いで濾過操作によって、ジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、ＭＴＢＥ１０ｇを用いて２回洗浄したのち乾燥して、ジアステレオマー塩４．６ｇを得た。次いで、５％水酸化ナトリウム水溶液１６ｇを加えて２５℃で３０分間攪拌後、ＭＴＢＥ１０ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｓ）−１−（２−フルオロフェニル）エチルアミン２．２ｇ（８７．２％ｅｅ）を得た。
【００２６】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液とを合わせ、５％水酸化ナトリウム水溶液１３ｇを用いて洗浄したのち溶媒を留去して、（Ｒ）−１−（２−フルオロフェニル）エチルアミン２．８ｇ（７１．６％ｅｅ）を得た。
【００２７】
実施例３
（ＲＳ）−１−（３−メトキシフェニル）エチルアミン５ｇをＭＴＢＥ２０ｇに溶解し、これを攪拌下、５０℃に加熱したのち、同温度下で攪拌しながらこれにＬ−マンデル酸２ｇをＭＴＢＥ２０ｇに溶解して得た溶液を３０分かけて滴下して加え、さらに３０分間攪拌したのち、３時間かけて２０℃まで冷却して、（Ｓ）−１−（３−メトキシフェニル）エチルアミンとＬ−マンデル酸とのジアステレオマー塩を析出させ、次いで濾過操作によって、ジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、ＭＴＢＥ１０ｇを用いて２回洗浄したのち乾燥して、ジアステレオマー塩４．１ｇを得た。次いで、５％水酸化ナトリウム水溶液１６ｇを加えて２５℃で３０分間攪拌後、ＭＴＢＥ１０ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｓ）−１−（３−メトキシフェニル）エチルアミン２ｇ（５５．４％ｅｅ）を得た。
【００２８】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液と合わせ、５％水酸化ナトリウム水溶液１３ｇを用いて洗浄したのち溶媒を留去して、（Ｒ）−１−（３−メトキシフェニル）エチルアミン３ｇ（４３．８％ｅｅ）を得た。
【００２９】
比較例１
（ＲＳ）−１−（３−メトキシフェニル）エチルアミン５ｇ、Ｌ−マンデル酸２ｇおよびメタノール１３ｇを混合して得た溶液を６０℃に加熱し、同温度下、３０分間攪拌した。３時間かけて２０℃まで冷却しながら、３０℃になった時点で種晶として（Ｓ）−１−（３−メトキシフェニル）エチルアミン（光学純度（Ｓ）体９９．９％、（Ｒ）体０．１％）とＬ−マンデル酸とのジアステレオマー塩０．０１ｇを加えた。２０℃に冷却後、濾過操作によって（Ｓ）−１−（３−メトキシフェニル）エチルアミンとＬ−マンデル酸とのジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、メタノール３ｇを用いて１回洗浄したのち乾燥して、ジアステレオマー塩１．２ｇを得た。次いで、５％水酸化ナトリウム水溶液１０ｇを加えて２５℃で３０分間攪拌後、トルエン１０ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｓ）−１−（３−メトキシフェニル）エチルアミン０．６ｇ（８８．２％ｅｅ）を得た。
【００３０】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液とを合わせ、トルエン１０ｇを加えたのち、５％水酸化ナトリウム水溶液１３ｇを用いて洗浄し、溶媒を留去して、（Ｒ）−１−（３−メトキシフェニル）エチルアミン４．４ｇ（１２．２％ｅｅ）を得た。
【００３１】
実施例４
（ＲＳ）−１−（２−ニトロフェニル）エチルアミン３．１ｇをＭＴＢＥ１５ｇに溶解し、これを攪拌下、４５℃に加熱したのち、同温度下で攪拌しながらこれにＬ−マンデル酸１．３ｇをＭＴＢＥ１５ｇに溶解して得た溶液を３０分かけて滴下して加え、さらに３０分間攪拌したのち、３時間かけて２０℃まで冷却して、（Ｓ）−１−（２−ニトロフェニル）エチルアミンとＬ−マンデル酸とのジアステレオマー塩を析出させ、次いで濾過操作によって、ジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、ＭＴＢＥ５ｇを用いて２回洗浄したのち乾燥して、ジアステレオマー塩２．４ｇを得た。次いで、５％水酸化ナトリウム水溶液１０ｇを加えて２５℃で３０分間攪拌後、ＭＴＢＥ１０ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｓ）−１−（２−ニトロフェニル）エチルアミン１．３ｇ（９０．４％ｅｅ）を得た。
【００３２】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液とを合わせ、５％水酸化ナトリウム水溶液１０ｇを用い洗浄したのち溶媒を留去して、（Ｒ）−１−（２−ニトロフェニル）エチルアミン１．８ｇ（６１．６％ｅｅ）を得た。
【００３３】
実施例５
（ＲＳ）−１−（３−トリフルオロメチルフェニル）エチルアミン４ｇをＭＴＢＥ２０ｇに溶解し、これを攪拌下、４５℃に加熱したのち、同温度下で攪拌しながらこれにＬ−マンデル酸１．６ｇをＭＴＢＥ１５ｇに溶解して得た溶液を３０分かけて滴下して加え、さらに３０分間攪拌したのち、３時間かけて２０℃まで冷却して、（Ｓ）−１−（３−トリフルオロメチルフェニル）エチルアミンとＬ−マンデル酸とのジアステレオマー塩を析出させ、次いで濾過操作によって、ジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、ＭＴＢＥ５ｇを用いて２回洗浄したのち乾燥して、ジアステレオマー塩３．３ｇを得た。次いで、５％水酸化ナトリウム水溶液１０ｇを加えて２５℃で３０分間攪拌後、ＭＴＢＥ１０ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｓ）−１−（３−トリフルオロメチルフェニル）エチルアミン１．８ｇ（６０％ｅｅ）を得た。
【００３４】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液とを合わせ、５％水酸化ナトリウム水溶液１０ｇを用いて洗浄し、溶媒を留去して、（Ｒ）−１−（３−トリフルオロメチルフェニル）エチルアミン２．２ｇ（５０％ｅｅ）を得た。
【００３５】
実施例６
（ＲＳ）−１−（３，４−ジメトキシフェニル）エチルアミン２０ｇをＭＴＢＥ３０ｇに溶解し、これを攪拌下、４５℃に加熱したのち、同温度下で攪拌しながらこれにＬ−マンデル酸７．６ｇをＭＴＢＥ８０ｇに溶解して得た溶液を３０分かけて滴下して加え、さらに３０分間攪拌したのち、３時間かけて２０℃まで冷却して、（Ｒ）−１−（３，４−ジメトキシフェニル）エチルアミンとＬ−マンデル酸とのジアステレオマー塩を析出させ、次いで濾過操作によって、ジアステレオマー塩を得、同時に母液を得た。
このジアステレオマー塩を、ＭＴＢＥ３０ｇを用いて２回洗浄したのち乾燥して、ジアステレオマー塩１６．６ｇを得た。次いで、１５％水酸化ナトリウム水溶液１８ｇを加えて２５℃で３０分間攪拌後、ＭＴＢＥ２０ｇを用いる抽出を２回行い、有機層を合わせたのち溶媒を留去して、（Ｒ）−１−（３，４−ジメトキシフェニル）エチルアミン８．８ｇ（５０．８％ｅｅ）を得た。
【００３６】
上記で得た母液とジアステレオマー塩を洗浄したのちの洗液とを合わせ、５％水酸化ナトリウム水溶液５０ｇを用いて洗浄し、溶媒を留去して、（Ｓ）−１−（３，４−ジメトキシフェニル）エチルアミン１１．２ｇ（６２．４％ｅｅ）を得た。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an optical resolution method for 1-phenylethylamines.
[0002]
[Prior art]
Optically active substances of 1-phenylethylamines are useful compounds as intermediates for pharmaceuticals, agricultural chemicals and the like.
As a method for obtaining such an optically active form of 1-phenylethylamines, a method in which the racemate is optically resolved in a solvent using optically active mandelic acid is generally used. And an optically active mandelic acid are dissolved in a solvent, a diastereomeric salt of an optically active form of 1-phenylethylamines and an optically active mandelic acid is obtained, and then the diastereomeric salt is treated with an alkali. Are known.
[0003]
Conventionally, water (Japanese Patent Laid-Open No. 56-26848), aqueous ammonia (Japanese Patent Laid-Open No. 6-1757), methanol (Bull. Chem. Soc. Jpn. , 66, 3414) are used as solvents for obtaining diastereomeric salts. (1993)) has been proposed, but the method using water is difficult to filter the obtained diastereomeric salt because the filterability of the obtained diastereomeric salt is poor. Special methods are required for handling the methanol, and the method using methanol has a low yield of the target optically active 1-phenylethylamines. Therefore, all of these methods are industrially satisfactory methods. I could not say.
[0004]
[Problems to be solved by the invention]
Therefore, the present inventors have intensively studied to develop a method for optically resolving 1-phenylethylamines easily and with high yield without using special equipment, and as a result, have reached the present invention.
[0005]
[Means for Solving the Problems]
That is, the present invention provides the general formula (1)
1-phenylethylamines represented by general formula (2) using optically active mandelic acid
R 3 —O—R 4 (2)
(In the formula, R 3 represents an alkyl group having 1 to 6 carbon atoms, and R 4 represents an alkyl group having 4 to 6 carbon atoms.)
An optical resolution method for 1-phenylethylamines, which is characterized in that it is optically resolved in a dialkyl ether represented by formula (1).
[0006]
DETAILED DESCRIPTION OF THE INVENTION
In the 1-phenylethylamines applied to the present invention, the halogen atoms in the substituents R 1 and R 2 are fluorine atoms, chlorine atoms, bromine atoms, etc., the alkoxy groups are methoxy groups, ethoxy groups, etc. are haloalkyl groups. Examples thereof include a trifluoromethyl group, a difluoromethyl group, and a trichloromethyl group.
[0007]
Examples of such 1-phenylethylamines include 1-phenylethylamine, 1- (2-fluorophenyl) ethylamine, 1- (3-fluorophenyl) ethylamine, 1- (2-chlorophenyl) ethylamine, 1- (3-chlorophenyl). ) 1- (monohalo-substituted phenyl) ethylamines such as ethylamine, 1- (2-bromophenyl) ethylamine, 1- (3-bromophenyl) ethylamine, 1- (2-methoxyphenyl) ethylamine, 1- (3-methoxy 1- (monoalkoxy-substituted phenyl) ethylamines such as phenyl) ethylamine, 1- (dialkoxy-substituted phenyl) ethylamines such as 1- (3,4-dimethoxyphenyl) ethylamine, 1- (2-trifluoromethylphenyl) Ethylamine, 1- (3- 1- (haloalkyl-substituted phenyl) ethylamines such as 1- (3-difluoromethylphenyl) ethylamine, 1- (2-nitrophenyl) ethylamine, 1- (3-nitrophenyl) ethylamine, etc. Examples thereof include 1- (nitrophenyl) ethylamines. Any of these 1-phenylethylamines can be easily produced by a Leukert reaction using acetophenones as raw materials [Organic Reaction Vol. 5, pp. 301-330 (1949)].
[0008]
In the 1-phenylethylamines represented by the general formula (1), there are two types of optically active substances centered on the asymmetric carbon atom represented by *, but 1-phenylethylamine used in the method of the present invention is present. The class may be a mixture thereof or a racemate.
[0009]
The optically active mandelic acid may be either D-mandelic acid or L-mandelic acid, and the amount used is usually 0.1 to 1.2 moles, preferably 0, relative to 1-phenylethylamines. The range is 3 to 1 mole times.
[0010]
In the dialkyl ether represented by the general formula (2), the substituent R 3 is an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group or an n-propyl group, and the substituent R 4 is an n-butyl group, Examples thereof include alkyl groups having 4 to 6 carbon atoms such as t-butyl group and n-hexyl group.
Examples of such dialkyl ethers include methyl-t-butyl ether, ethyl-t-butyl ether, methyl-n-butyl ether, ethyl-n-butyl ether, and the like, and among them, methyl-t-butyl ether (hereinafter referred to as MTBE). Preferably used. These dialkyl ethers are used alone or in combination of two or more, and may further contain other organic solvents and water. The amount of such dialkyl ether used is usually in the range of 2 to 100 times the weight of 1-phenylethylamines.
[0011]
In the optical resolution, for example, 1-phenylethylamines and optically active mandelic acid are dissolved in dialkyl ether, and then a diastereomeric salt of 1-phenylethylamines optically active substance and optically active mandelic acid is obtained. The diastereomeric salt may be alkali-treated.
[0012]
When 1-phenylethylamines and optically active mandelic acid are dissolved in dialkyl ether, for example, 1-phenylethylamines and optically active mandelic acid may be added to dialkyl ether to dissolve both, or 1-phenylethylamine may be dissolved. A dialkyl ether solution of an optically active mandelic acid and a dialkyl ether solution of an optically active mandelic acid may be mixed, and a salt of 1-phenylethylamines and an optically active mandelic acid obtained by reacting both in advance is dissolved in the dialkyl ether. May be. The dissolution temperature is usually in the range of 15 ° C. or more and the boiling point of the dialkyl ether.
[0013]
After dissolution, one optically active form of 1-phenylethylamines preferentially forms a diastereomeric salt with optically active mandelic acid by a usual method such as cooling or concentrating, and the diastereomeric salt. In some cases, the diastereomeric salt may be precipitated by standing or stirring as it is.
[0014]
After precipitation of the diastereomeric salt, this is taken out and separated from the mother liquor, but such diastereomeric salt is excellent in filterability and can be easily separated by ordinary filtration operations.
[0015]
The diastereomeric salt of the optically active form of 1-phenylethylamines and optically active mandelic acid thus obtained is easily led to the optically active form of 1-phenylethylamines by alkali treatment.
[0016]
In the alkali treatment, a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium hydrogen carbonate is usually used, and the amount used is usually in the range of 1 to 5 times the diastereomeric salt. Such a base is usually used as an aqueous solution, and its concentration is usually in the range of 1 to 50% by weight, preferably 5 to 20% by weight.
[0017]
In the alkali treatment, for example, an aqueous base solution and a diastereomeric salt may be mixed, and the treatment temperature is usually in the range of −10 to 50 ° C.
[0018]
Such an alkali treatment produces an optically active form of 1-phenylethylamines, which may be taken out by a method of separating the layers separated in the reaction mixture after the alkali treatment, or the reaction. The mixture may be easily extracted from the mixture by, for example, a method of performing extraction using an organic solvent insoluble in water and distilling off the resulting organic layer. In the latter case, the organic solvent insoluble in water includes, for example, the same dialkyl ether, diethyl ether, dioxane and other ether solvents as described above, ethyl acetate and other ester solvents, toluene, xylene and chlorobenzene and other aromatic solvents. A solvent or the like is used, and the amount used is usually in the range of 0.1 to 5 times by weight with respect to the diastereomeric salt used in the previous alkali treatment.
[0019]
The reaction mixture after taking out the optically active form of 1-phenylethylamines contains optically active mandelic acid, and such optically active mandelic acid is easily recovered from the reaction mixture and used in the method of the present invention. Can be reused. Such optically active mandelic acid is recovered by, for example, adding a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid to the aqueous layer to adjust the pH to a range of 0.5 to 2, and then insoluble in water as described above. For example, when the dialkyl ether is used as the organic solvent, the solvent is distilled off from the obtained organic layer. This is preferable because it can be reused in the method of the present invention without any problem.
[0020]
Thus, an optically active form of 1-phenylethylamines can be obtained. The other optically active form, which is an enantiomer of the 1-phenylethylamines, is contained in the mother liquor after the diastereomeric salt is separated by the previous filtration operation. The mother liquor can be easily obtained by a usual method, for example, a method in which the mother liquor is washed with an alkaline aqueous solution such as an aqueous sodium hydroxide solution and then the solvent is distilled off.
[0021]
【The invention's effect】
According to the method of the present invention, 1-phenylethylamines can be optically resolved easily and with high yield without using special equipment.
[0022]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these Examples.
The optical purity of the obtained 1-phenylethylamines was determined by a high performance liquid chromatograph analysis method using an optically active column.
[0023]
Example 1
A solution obtained by dissolving 56 g of (RS) -1-phenylethylamine in 60 g of MTBE, heating to 45 ° C. with stirring, and then dissolving 31.7 g of L-mandelic acid in 180 g of MTBE while stirring at the same temperature. The mixture was added over 30 minutes and further stirred at the same temperature for 30 minutes. Thereafter, the mixture is cooled to 20 ° C. over 6 hours to precipitate a diastereomeric salt of (S) -1-phenylethylamine and L-mandelic acid, and then a diastereomeric salt is obtained by a filtration operation. Got.
This diastereomeric salt was washed twice with 100 g of MTBE and then dried to obtain 56.8 g of a diastereomeric salt. Next, after adding 185 g of 5% aqueous sodium hydroxide solution and stirring at 25 ° C. for 30 minutes, extraction with 45 g of MTBE was performed twice, and after combining the organic layers, the solvent was distilled off to obtain (S) -1-phenylethylamine. 25.2 g (87% ee) were obtained.
[0024]
The mother liquor obtained above and the washing solution after washing the diastereomeric salt are combined, 18 g of 5% aqueous sodium hydroxide solution is added, extraction processing using 30 g of MTBE is performed twice, the organic layers are combined, and then the solvent is added. Was distilled off to obtain 30.8 g (70.4% ee) of (R) -1-phenylethylamine.
[0025]
Example 2
5 g of (RS) -1- (2-fluorophenyl) ethylamine was dissolved in 10 g of MTBE, and this was heated to 45 ° C. with stirring. Then, 2.46 g of L-mandelic acid was added to 30 g of MTBE while stirring at the same temperature. The solution obtained by dissolving in was added dropwise over 30 minutes, stirred for another 30 minutes, cooled to 20 ° C. over 3 hours, and (S) -1- (2-fluorophenyl) ethylamine and L -A diastereomeric salt with mandelic acid was precipitated and then filtered to obtain a diastereomeric salt and simultaneously a mother liquor.
This diastereomeric salt was washed twice with 10 g of MTBE and then dried to obtain 4.6 g of a diastereomeric salt. Next, 16 g of 5% aqueous sodium hydroxide solution was added and stirred at 25 ° C. for 30 minutes, followed by extraction with 10 g of MTBE twice. After combining the organic layers, the solvent was distilled off to obtain (S) -1- (2 -Fluorophenyl) ethylamine 2.2 g (87.2% ee) was obtained.
[0026]
The mother liquor obtained above and the washing solution after washing the diastereomeric salt were combined, washed with 13 g of 5% aqueous sodium hydroxide, and then the solvent was distilled off to obtain (R) -1- (2- 2.8 g (71.6% ee) of fluorophenyl) ethylamine were obtained.
[0027]
Example 3
5 g of (RS) -1- (3-methoxyphenyl) ethylamine was dissolved in 20 g of MTBE, heated to 50 ° C. with stirring, and 2 g of L-mandelic acid was dissolved in 20 g of MTBE while stirring at the same temperature. The resulting solution was added dropwise over 30 minutes, stirred for another 30 minutes, cooled to 20 ° C. over 3 hours, and (S) -1- (3-methoxyphenyl) ethylamine and L-Mandel. A diastereomeric salt with an acid was precipitated, and then a diastereomeric salt was obtained by filtration, and simultaneously a mother liquor was obtained.
This diastereomeric salt was washed twice with 10 g of MTBE and then dried to obtain 4.1 g of a diastereomeric salt. Next, 16 g of 5% aqueous sodium hydroxide solution was added, and the mixture was stirred at 25 ° C. for 30 minutes. Then, extraction with 10 g of MTBE was performed twice, the organic layers were combined, the solvent was distilled off, and (S) -1- (3 2 g (55.4% ee) of -methoxyphenyl) ethylamine were obtained.
[0028]
The mother liquor obtained above and the diastereomeric salt were washed and combined with the washing solution. After washing with 13 g of 5% aqueous sodium hydroxide, the solvent was distilled off to give (R) -1- (3-methoxy 3 g (43.8% ee) of phenyl) ethylamine were obtained.
[0029]
Comparative Example 1
A solution obtained by mixing 5 g of (RS) -1- (3-methoxyphenyl) ethylamine, 2 g of L-mandelic acid and 13 g of methanol was heated to 60 ° C. and stirred at the same temperature for 30 minutes. (S) -1- (3-methoxyphenyl) ethylamine (99.9% optical purity (S) isomer, (R) isomer as seed crystals at 30 ° C. while cooling to 20 ° C. over 3 hours 0.1%) and 0.01 g of a diastereomeric salt of L-mandelic acid. After cooling to 20 ° C., a diastereomeric salt of (S) -1- (3-methoxyphenyl) ethylamine and L-mandelic acid was obtained by filtration, and simultaneously a mother liquor was obtained.
This diastereomeric salt was washed once with 3 g of methanol and then dried to obtain 1.2 g of a diastereomeric salt. Next, 10 g of a 5% aqueous sodium hydroxide solution was added and stirred at 25 ° C. for 30 minutes, followed by extraction with 10 g of toluene twice. After combining the organic layers, the solvent was distilled off to obtain (S) -1- ( 0.6 g (88.2% ee) of 3-methoxyphenyl) ethylamine was obtained.
[0030]
The mother liquor obtained above and the washing solution after washing the diastereomeric salt were combined, and after adding 10 g of toluene, the mixture was washed with 13 g of 5% aqueous sodium hydroxide solution, the solvent was distilled off, and (R ) -1- (3-methoxyphenyl) ethylamine 4.4g (12.2% ee) was obtained.
[0031]
Example 4
(RS) -1- (2-Nitrophenyl) ethylamine (3.1 g) was dissolved in MTBE (15 g), heated to 45 ° C. with stirring, and stirred at the same temperature with 1.3 g of L-mandelic acid. Was added dropwise over 15 minutes, and the mixture was further stirred for 30 minutes, cooled to 20 ° C. over 3 hours, and (S) -1- (2-nitrophenyl) ethylamine. And diastereomeric salt of L-mandelic acid were precipitated, followed by filtration to obtain a diastereomeric salt, and simultaneously a mother liquor.
This diastereomeric salt was washed twice with 5 g of MTBE and then dried to obtain 2.4 g of a diastereomeric salt. Next, 10 g of 5% aqueous sodium hydroxide solution was added and the mixture was stirred at 25 ° C. for 30 minutes. Then, extraction with 10 g of MTBE was performed twice, the organic layers were combined, the solvent was distilled off, and (S) -1- (2 -Nitrophenyl) ethylamine 1.3 g (90.4% ee) was obtained.
[0032]
The mother liquor obtained above and the washing solution after washing the diastereomeric salt were combined, washed with 10 g of 5% aqueous sodium hydroxide solution, the solvent was distilled off, and (R) -1- (2-nitro 1.8 g (61.6% ee) of phenyl) ethylamine were obtained.
[0033]
Example 5
(RS) -1- (3-trifluoromethylphenyl) ethylamine (4 g) was dissolved in MTBE (20 g), heated to 45 ° C. with stirring, and then stirred at the same temperature with 1.6 g of L-mandelic acid. Was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes, cooled to 20 ° C. over 3 hours, and (S) -1- (3-trifluoromethylphenyl). ) A diastereomeric salt of ethylamine and L-mandelic acid was precipitated, followed by filtration to obtain a diastereomeric salt, and simultaneously a mother liquor.
This diastereomeric salt was washed twice with 5 g of MTBE and then dried to obtain 3.3 g of a diastereomeric salt. Next, 10 g of 5% aqueous sodium hydroxide solution was added and the mixture was stirred at 25 ° C. for 30 minutes. Then, extraction with 10 g of MTBE was performed twice, the organic layers were combined, the solvent was distilled off, and (S) -1- (3 1.8 g (60% ee) of -trifluoromethylphenyl) ethylamine were obtained.
[0034]
The mother liquor obtained above and the washing solution after washing the diastereomeric salt were combined, washed with 10 g of 5% aqueous sodium hydroxide solution, the solvent was distilled off, and (R) -1- (3- Obtained 2.2 g (50% ee) of trifluoromethylphenyl) ethylamine.
[0035]
Example 6
20 g of (RS) -1- (3,4-dimethoxyphenyl) ethylamine was dissolved in 30 g of MTBE, heated to 45 ° C. with stirring, and then stirred with 7.6 g of L-mandelic acid at the same temperature. Was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes, cooled to 20 ° C. over 3 hours, and (R) -1- (3,4-dimethoxyphenyl). ) A diastereomeric salt of ethylamine and L-mandelic acid was precipitated, followed by filtration to obtain a diastereomeric salt, and simultaneously a mother liquor.
This diastereomeric salt was washed twice with 30 g of MTBE and then dried to obtain 16.6 g of a diastereomeric salt. Next, 18 g of a 15% aqueous sodium hydroxide solution was added, and the mixture was stirred at 25 ° C. for 30 minutes, followed by extraction with 20 g of MTBE twice. , 4-Dimethoxyphenyl) ethylamine 8.8 g (50.8% ee) was obtained.
[0036]
The mother liquor obtained above and the washing solution after washing the diastereomeric salt were combined, washed with 50 g of 5% aqueous sodium hydroxide, the solvent was distilled off, and (S) -1- (3, 11.2 g (62.4% ee) of 4-dimethoxyphenyl) ethylamine was obtained.
Claims (4)
で示される１−フェニルエチルアミン類を光学活性マンデル酸を用いてメチル−ｔ−ブチルエーテル中で光学分割することを特徴とする１−フェニルエチルアミン類の光学分割方法。General formula (1)
A method for optical resolution of 1-phenylethylamines, which comprises optically resolving 1-phenylethylamines represented by formula (1) in methyl-t-butyl ether using optically active mandelic acid.
で示される１−フェニルエチルアミン類および光学活性マンデル酸をメチル−ｔ−ブチルエーテルに溶解したのち、１−フェニルエチルアミン類の光学活性体と光学活性マンデル酸とのジアステレオマー塩を得、次いで該ジアステレオマー塩をアルカリ処理することを特徴とする１−フェニルエチルアミン類の光学分割方法。General formula (1)
1-phenylethylamines and optically active mandelic acid represented by formula (1) are dissolved in methyl-t-butyl ether to obtain a diastereomeric salt of the optically active form of 1-phenylethylamines and optically active mandelic acid. A method for optical resolution of 1-phenylethylamines, which comprises treating a stereomeric salt with an alkali.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8404196A JP4273528B2 (en) | 1996-04-05 | 1996-04-05 | Method for optical resolution of 1-phenylethylamines |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8404196A JP4273528B2 (en) | 1996-04-05 | 1996-04-05 | Method for optical resolution of 1-phenylethylamines |
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| Publication Number | Publication Date |
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| JPH09278718A JPH09278718A (en) | 1997-10-28 |
| JP4273528B2 true JP4273528B2 (en) | 2009-06-03 |
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| US6342636B1 (en) * | 1997-11-06 | 2002-01-29 | Yamakawa Chemical Industry Co., Ltd. | Process for preparing optically active amines and optically active carboxylic acids, and intermediates for preparation |
| US6797842B2 (en) | 2000-05-11 | 2004-09-28 | Central Glass Company, Limited | Process for producing optically active 1-(fluoro- or trifluoromethyl-substituted phenyl) ethylamine and process for purifying same |
| DE10336185A1 (en) * | 2003-08-07 | 2005-02-24 | Bayer Chemicals Ag | Enantiomerically enriched 1-phenylethylamines |
| JP5510040B2 (en) * | 2010-04-28 | 2014-06-04 | セントラル硝子株式会社 | Optical resolution to obtain optically active (R) -1- (4-fluorophenyl) ethylamine |
| CN114804989B (en) * | 2022-05-06 | 2023-12-26 | 华中科技大学 | Purification method and racemization recycling of rivastigmine key chiral intermediate |
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