JP3606620B2 - Semi-continuous process for the production of optically active alcohols. - Google Patents

Description

一般式（１）
〔但し、式（１）中、Ａ≠Ｂであり、Ａはフェニル基または下記一般式（２）
〔化６〕

一般式（２）
（式（２）においてＤ_１、Ｄ_２、Ｄ_３、Ｄ_４およびＤ_５はハロゲン原子または炭素数１〜３のアルキル基または炭素数１〜３のアルコキシ基）で表される置換基であり、Ｂは炭素数１〜３のアルキル基またはＣＦ_３またはＣＮ〕で表されるラセミ体アルコールであれば、以下に述べる本発明の方法により効率良く光学分割を行うことができる。
【０００９】
具体的には２−ブタノール、２−ペンタノール、２−ヘキサノール、２−ヘプタノール、２−オクタノール、２−ノナノール、２−デカノール、１−フェニルエタノール、１−フェニル−１−プロパノール、エチル−３−ヒドロキシ−ブタネート、エチル−３−ヒドロキシ−プロピオネート、メチル−３−ヒドロキシ−ペンタネート、１−フェニル−１，３−プロパンジオール、２−フェニル−１−シクロヘキサノール、１−ペンチン−３−オール、１−（２−ブロモフェニル）エタノール、１−パラクロロフェニルエタノール、１−（４−クロロフェニル）エタノール、１−クロロ−２−オクタノール、１，１−ジフルオロ−２−オクタノール、１−（２，４−ジクロロフェニル）エタノール等のラセミ体アルコールがある。このうち、好ましくは２−オクタノール、１−フェニルエタノール、１−フェニル−１，３−プロパンジオール、２−フェニル−１−シクロヘキサノールであり、最も好ましくは１−フェニルエタノール、２−オクタノール、１−（２−ブロモフェニル）エタノールである。
【００１０】
本発明に用いる１，３−プロパンジオールは、その２位炭素に同一あるいは異なる２種類のアルキル基が置換もしくは非置換したものであり、ここにアルキル基とはメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基およびｓｅｃ−ブチル基からなる群より選ばれるものであって、具体例として１，３−プロパンジオール、２，２−ジメチル−１，３−プロパンジオール（ネオペンチルグリコール）、２，２−ジエチル−１，３−プロパンジオール、２，２−ジｎ−プロピル−１，３−プロパンジオール、２，２−ジｎ−ブチル−１，３−プロパンジオール、２−メチル−２−エチル−１，３−プロパンジオール、２−メチル−２−ｎ−プロピル−１，３−プロパンジオール、２−メチル−２−ｎ−ブチル−１，３−プロパンジオール、２−エチル−２−ｎ−プロピル−１，３−プロパンジオール、２−エチル−２−ｎ−ブチル−１，３−プロパンジオール、２−ｎ−プロピル−２−ｎ−ブチル−１，３−プロパンジオール等をあげることができる。このうちアルキル基が非置換の１，３−プロパンジオール、さらには２，２−ジメチル−１，３−プロパンジオール、２，２−ジエチル−１，３−プロパンジオールがより好ましく、また１，３−プロパンジオールが最も好ましい。
【００１１】
本発明で用いるエステルとは前記１，３−プロパンジオールと炭素数が１６以上の脂肪酸とのエステルをいい、１，３−プロパンジオールのパルミチン酸エステル、２−ヘキシルデカン酸エステル、パルミトオレイン酸エステル、ステアリン酸エステル、イソステアリン酸（２−ヘプチルウンデカン酸、エメリー社製イソステアリン酸等）エステル、オレイン酸エステル、リノール酸エステル、リノレン酸エステル、アラキジン酸エステル、ベヘン酸エステル、エルシン酸エステル、リグノセリン酸エステル、セロチン酸エステル、モンタン酸エステル、メリシン酸エステル等を具体的に例示できる。これらのエステルは任意の割合の混合物としても使用でき、またその構成脂肪酸も植物油脂（大豆油、菜種油、オリーブ油、コーン油、サフラワー油、ひまわり油、綿実油、パーム油等）、動物油脂（牛脂、豚脂等）、魚油（イワシ油、サンマ油、タラ肝油等）を加水分解して得られる混合脂肪酸、それらの水素添加物を用いてもよい。このうち好ましいエステルは１，３−プロパンジオールのパルミチン酸エステル、ステアリン酸エステル、オレイン酸エステル、ベヘン酸エステル（いずれも直鎖状脂肪酸のエステル）であり、最も好ましくはステアリン酸エステル、ベヘン酸エステルである。また、モノエステルでもジエステルでも使用できるが、エステル交換反応の効率性の点からジエステルが望ましい。前記エステルは、望ましくは炭素数が１８以上３０程度までの直鎖状飽和脂肪酸で構成されるものであって、高融点（好ましくは６０℃以上、より好ましくは７０℃以上）であることを特徴とする。これにより、本発明のエステル交換反応物から目的の光学活性アルコールを効率良く分離できる利点がある。
【００１２】
なおラセミ体アルコールと反応させるエステルは１，３−プロパンジオールの脂肪酸エステルである必要があり、１価アルコールの脂肪酸エステルでは蒸留処理の際に不純物が混入し、高純度の光学活性アルコールが得られない。またトリグリセリドを用いるとエステル交換反応は進行するものの、リパーゼが１、３特異性である場合、生成した１，２型ジグリセリドが１，３型ジグリセリドに転移し、２段目反応で減圧操作を行っても光学活性アルコールが再び遊離することはない。さらには、４価以上の多価アルコールのエステルでは反応速度が極端に低下してしまう。
【００１３】
本発明のエステル交換反応では、耐熱性リパーゼを用いることを特徴とする。これによりエステル交換反応を高温に維持して速やかに進行させることができ、さらにまた高温かつ減圧下でエステル交換反応を行うことができ、該反応を進めながら反応生成物として発生してくる光学活性アルコールを同時に回収することが可能となる。
【００１４】
耐熱性リパーゼとしては、特公昭５８−３６９５３号公報に記載のアルカリゲネス（Ａｌｃａｌｉｇｅｎｅｓ ）属由来のリパーゼ、特開昭５９−１５６２８２号公報に記載のリゾプス キネンシス（Ｒｈｉｚｏｐｕｓ ｃｈｉｎｅｎｓｉｓ）等を例示できる。本発明ではとりわけ、特公昭５８−３６９５３号公報に記載されたアルカリゲネス エスピー（Ａｌｃａｌｉｇｅｎｅｓ ｓｐ．ＰＬ−２６６）（微工研菌寄第３１８７号）が生産するリパーゼＰＬ−２６６、特公昭６０−１５３１２号公報に記載のアルカリゲネス
エスピー（Ａｌｃａｌｉｇｅｎｅｓ ｓｐ． ＰＬ−６７９）（微工研菌寄第３７８３号）が生産するリパーゼＰＬ−６７９が好ましく、さらには名糖産業（株）製のリパーゼＰＬおよびリパーゼＱＬ、とりわけリパーゼＱＬが望ましい。かかる耐熱性リパーゼは、活性炭、セライト、吸着性樹脂、イオン交換樹脂、セラミックス等の公知の担体に固定化してもよいが、後述するように粉末状態のままで原料に共存させることが望ましい。
【００１５】
エステル交換反応は、前記したラセミ体アルコールとエステルとをラセミ体アルコールを基準にして１：５以下、好ましくは１：２〜１のモル比率で原料として混合し、該原料の溶媒を使用することなく、なおかつ実質的に水分を含まない（すなわち原料中の平衡水分含量である約０．１重量％以下、望ましくは０．０５重量％以下の）反応系に、好ましくは前記リパーゼの粉末を分散させて、攪拌しながら反応を行う。このときリパーゼ粉末の粒子の９０％以上が１〜１００μｍ、好ましくは２０〜５０μｍの大きさになるようにコントロールしてエステル交換反応を行うことが望ましい。この粒子サイズをそろえる手段としては、必要に応じて加温し溶解した原料にリパーゼ粉末を分散させた後、超音波処理、分散液の精密膜または限外濾過膜による濾過処理、遠心沈降処理等を施せばよいが、好ましくは反応温度以下、２０〜１５０ｋＨｚ 、１００〜２５０Ｗの条件下で１〜３０分間超音波を照射処理することが簡便である。
【００１６】
反応温度は８１℃以上、より好ましくは９１〜１３０℃、最も好ましくは１０１〜１２０℃に設定し、エステル交換（本発明ではアルコリシス）反応を第１工程では常圧状態また第２工程では減圧状態で、緩やかに攪拌もしくは振とうしながら、反応率を例えばガスクロマトグラフィーでチェックして、所定の時間、望ましくは数時間から１００時間、エステル交換反応を行わせる。反応温度が８１℃を下回ると該反応の進行が遅く、逆に１３０℃を超えるとリパーゼの失活を招く。第１工程では、この反応によってラセミ体アルコールの鏡像異性体（Ｒ体またはＳ体）のいずれか一方が前記１，３−プロパンジオールの脂肪酸エステルとエステル交換（アルコリシス）され、Ｒ体またはＳ体のいずれか一方の光学活性アルコールの脂肪酸エステルと未反応の光学活性アルコールとを生じる。かかる成分を含むエステル交換反応物は、これから耐熱性リパーゼを望ましくは濾別除去せずに、減圧状態（５〜１ｍｍＨｇ）で前記未反応の光学活性アルコールを単蒸留し、Ｒ体またはＳ体のいずれか一方に富む光学活性アルコールを得るとともに残分を分離する。
【００１７】
前記第１工程で得られる減圧蒸留処理した残分中には、エステル交換したＲ体またはＳ体のいずれか一方の光学活性アルコール（減圧蒸留されなかった鏡像異性体の他方）の脂肪酸エステル、原料として用いた前記１，３−プロパンジオールの脂肪酸エステルが部分的ないし完全に加アルコール分解された成分等が共存することになるから、第１工程にひき続き第２工程では前記残分をそのまま減圧状態（５〜１ｍｍＨｇ）に維持して、第１工程と同様の条件下（耐熱性リパーゼの共存下、無溶媒かつ実質的無水の条件で８１℃以上）でエステル交換（アルコリシス）反応させ、該反応により生成してくるＲ体またはＳ体のいずれか一方の光学活性アルコールを、該反応を行いながら減圧蒸留して分離する。ここで耐熱性リパーゼは第１工程に用いたものをそのまま反応物に共存させて第２工程のエステル交換反応を行わせることが簡便であるが、第２工程の開始時に新たに添加してもよい。
かくしてラセミ体アルコールから高純度のＲ体およＳ体の各光学活性アルコールを容易に高収率で分割することができる。
【００１８】
本発明では、前述の第１工程および第２工程を経てＲ体およびＳ体の両光学活性アルコールを分離した後の残分に、少なくともラセミ体アルコールを添加し、前記第１工程および第２工程の操作を繰り返して該ラセミ体アルコールの光学分割を行うことを特徴とする。すなわち第２工程の操作を終了して得られる残分は、第１工程において原料として用いた１，３−プロパンジオール類の脂肪酸エステルと耐熱性リパーゼとの混合物に戻るため、これに第１工程で使用したものと同種もしくは異種のラセミ体アルコールを添加し、さらに必要に応じて耐熱性リパーゼを加え、前記第１工程ついで第２工程の各操作を繰り返すものである。この方法によれば、ラセミ体アルコールからＲ体およびＳ体の各光学活性アルコールをそれぞれ高純度化して得ることができ、その収率も高く、しかも光学分割方法として操作は簡便であり、半連続化でき、光学活性アルコールの大量生産を可能ならしめるものである。
【００１９】
【実施例】
以下の実施例および比較例において得られた化合物の物質純度はガスクロマトグラフィー（（株）島津製作所製、ＧＣ−１４Ａ）を用いて、また光学純度は比旋光度を旋光度計（日本分光（株）製、ＤＩＰ−３７０）を用いてそれぞれ測定し、その測定値を標準試料の値と比較することにより算出した。
【００２０】
実施例１
アルカリゲネス エスピー（Ａｌｃａｌｉｇｅｎｅｓ ｓｐ．）由来のリパーゼＱＬ （名糖産業（株）製）３ｇ、（Ｒ，Ｓ）−１−フェニルエタノール５０ｇおよび１，３−プロパンジオールのオレイン酸ジエステル（１，３−プロパンジオールとオレイン酸とを、パラトルエンスルホン酸を触媒とし、１５０〜２００℃で５時間エステル化反応させて得たもの。純度：９９％）２７０ｇを５００ｍｌセパラブルフラスコに入れ、室温で超音波発生装置（（株）島津製作所製、ＳＵＳ−１０３）を用いて４５ｋＨｚ で１分間超音波を照射した。その後、９０℃にて攪拌速度３５０ｒｐｍ で攪拌し、常圧状態で２３時間エステル交換反応を行った。反応系の水分量（カールフィッシャー法）：０．０５重量％、リパーゼ粒子のサイズ（コールターエレクトロニクス社製の粒度分布測定装置：マルチサイザーによる測定）：９５％以上が２０〜５０μｍであった。反応終了後、反応物をガスクロマトグラフィーで測定したところ、（Ｒ，Ｓ）−１−フェニルエタノールの４９モル％がオレイン酸エステルに変換されていた。そのまま反応系内を９０℃、１ｍｍＨｇに減圧して２０分間蒸留し、未反応の（Ｓ）−（−）−１−フェニルエタノール（収率：９８％、物質純度：１００％、光学純度：９９％ｅｅ以上）を得た。さらにそのまま減圧状態を維持しながら前記リパーゼの共存下でエステル交換反応を９０℃にて２２時間つづけて（Ｒ）−（＋）−１−フェニルエタノール（収率：９３％、物質純度：１００％、光学純度：９９％ｅｅ以上）を減圧蒸留して分離した。この一連の反応終了後、新たに（Ｒ，Ｓ）−１−フェニルエタノール５０ｇを加えて前記と同様の操作を合計３回繰り返した。この繰り返し操作１回目〜３回目の各光学活性アルコールの収率は、（Ｓ）−（−）体が９８％、９９％および９７％、（Ｒ）−（＋）体が９２％、９０％および９３％であり、両光学活性アルコールの物質純度はすべて１００％であり、光学純度はすべて９９％ｅｅ以上であった。
【００２１】
実施例２
アルカリゲネス エスピー（Ａｌｃａｌｉｇｅｎｅｓ ｓｐ．）由来のリパーゼＰＬ（名糖産業（株）製）５ｇ、（Ｒ，Ｓ）−１−（ｐ−クロロフェニル）エタノール５０ｇおよび２，２−ジメチル−１，３−プロパンジオールのパルミチン酸ジエステル（２，２−ジメチル−１，３−プロパンジオールとパルミチン酸とを実施例１記載の方法でエステル化反応させて得たもの。純度：９９％）２７０ｇを５００ｍｌセパラブルフラスコに入れ、８５℃で超音波発生装置（実施例１と同じ）を用いて４５ｋＨｚ で１分間超音波を照射した。その後、８５℃にて攪拌速度３５０ｒｐｍ で攪拌し、常圧状態で２２時間エステル交換反応を行った。実施例１に記載の方法で測定した反応系の水分量：０．０３重量％リパーゼ粒子のサイズ：９０％以上が２０〜５０μｍであった。反応終了後、反応物をガスクロマトグラフィーで測定したところ、（Ｒ，Ｓ）−１−（ｐ−クロロフェニル）エタノールの４８モル％がパルミチン酸エステルに変換されていた。そのまま反応系内を９０℃、１ｍｍＨｇに減圧して３０分間蒸留し、未反応の（Ｓ）−（−）−１−（ｐ−クロロフェニル）エタノール（収率：９１％、物質純度：１００％、光学純度：９９％ｅｅ以上）を得た。さらにそのまま減圧状態を維持しながら８５℃で前記リパーゼの共存下でエステル交換反応を７２時間つづけて（Ｒ）−（＋）−１−（ｐ−クロロフェニル）エタノール（収率：８２％、物質純度：１００％、光学純度：９９％ｅｅ以上） を減圧蒸留して分離した。この一連の反応終了後、新たに（Ｒ，Ｓ）−１−（ｐ−クロロフェニル）エタノール５０ｇのみを加えて前記と同様の操作を合計２回繰り返した。この繰り返し操作１回目および２回目の各光学活性アルコールの収率は、（Ｓ）−（−）体が９２％および９０％、（Ｒ）−（＋）体が８３％および８１％であり、両光学活性アルコールの物質純度はすべて１００％であり、光学純度はすべて９９％ｅｅ以上であった。
【００２２】
実施例３
実施例１に記載のリパーゼＱＬ３ｇを、（Ｒ，Ｓ）−２−オクタノール５０ｇに入れ、室温で超音波発生装置（実施例１と同じ）を用いて４５ｋＨｚ で１分間超音波を照射した。その後、実施例１と同様の方法でエステル合成した１，３−プロパンジオールのステアリン酸ジエステル（純度：９９％）２７０ｇを加えて５００ｍｌセパラブルフラスコで１０５℃にて攪拌速度３５０ｒｐｍ で攪拌し、常圧状態で１２時間エステル交換反応を行った。実施例１に記載の方法で測定した反応系の水分量：０．０４重量％、リパーゼ粒子のサイズ：９５％以上が２０〜４０μｍであった。反応終了後、反応物をガスクロマトグラフィーで測定したところ、（Ｒ，Ｓ）−２−オクタノールの５２モル％がステアリン酸エステルに変換されていた。そのまま反応系内を１０５℃、３ｍｍＨｇに減圧して１０分間蒸留し、未反応の（Ｓ）−（＋）−２−オクタノール（収率：８９％、物質純度：１００％、光学純度：９９％ｅｅ以上）を得た。さらにそのまま減圧状態を維持しながら１１０℃で前記リパーゼの共存下にエステル交換反応を２５時間つづけて（Ｒ）−（−）−２−オクタノール（収率：９８％、物質純度：１００％、光学純度：９８％ｅｅ）を減圧蒸留して得た。この一連の反応終了後、新たに（Ｒ，Ｓ）−２−オクタノール５０ｇおよびリパーゼＱＬ（前出）１ｇを加えて前記と同様の操作を合計５回繰り返した。この繰り返し操作１回目〜５回目の各光学活性アルコールの収率は、（Ｓ）−（＋）体が９３％、９３％、９４％、９１％および９０％、（Ｒ）−（−）体が９９％、９８％、９８％、９７％および９８％であり、両光学活性アルコールの物質純度はすべて１００％であり、光学純度は（Ｓ）−（＋）体がすべて９９％ｅｅ以上、また（Ｒ）−（−）体が９９％ｅｅ以上、９９％ｅｅ以上、９８％ｅｅ、９９％ｅｅ以上および９９％ｅｅであった。
【００２３】
実施例４
実施例３において、１，３−プロパンジオールに代えて２，２−ジエチル−１，３−プロパンジオール、２−メチル−２−ｎ−プロピル−１，３−プロパンジオールおよび２−エチル−２−ｎ−ブチル−１，３−プロパンジオールを用い、それぞれ（Ｒ，Ｓ）−２−オクタノールを同様に処理したところ、分離した（Ｓ）−（＋）−２−オクタノールおよび（Ｒ）−（−）−２−オクタノールの収率：８８〜９６％、物質純度：いずれも１００％、光学純度：９６〜９９％ｅｅ以上であった。
【００２４】
比較例１
実施例１において、１，３−プロパンジオールのオレイン酸ジエステルに代えてｎ−プロパノールのオレイン酸モノエステル２７０ｇを用いて同様に処理し、エステル交換反応物を同条件で減圧蒸留したところ、留出物にはｎ−プロパノールが混在し、（Ｓ）−（−）−１−フェニルエタノールの収率：９９％、物質純度：７８％、光学純度：６９％ｅｅであった。さらに減圧蒸留後の残分を同条件下で処理したが留出物は得られなかった。繰り返し操作は、不可能であった。
【００２５】
【発明の効果】
本発明によれば、ラセミ体アルコールと１，３−プロパンジオール類の脂肪酸エステルとを、耐熱性リパーゼの共存下に高温でエステル交換（アルコリシス）反応を行わせるため、該反応が短時間に速やかに進行し、鏡像異性体の一方を簡単に高純度かつ高収率で得ることができる。さらに前記鏡像異性体の一方を分離した残分をそのまま減圧状態で同様にエステル交換（アルコリシス）反応させるため、鏡像異性体の他方が再び遊離し、該反応を行いながら同時に前記鏡像異性体の他方をも高純度かつ高収率で得ることができ、その製造工程は簡略化される。また本発明の方法は、一連の操作を終了した後に原料のラセミ体アルコールを新たに添加すれば、同様に繰り返し操作が可能であり、高純度の鏡像異性体を半連続的に高収率で大量生産する方法として好適である。[0001]
[Industrial application fields]
The present invention relates to a semi-continuous process for producing optically active alcohols that are important as raw materials for pharmaceuticals, agricultural chemicals, etc., or as intermediates for fine chemicals such as liquid crystals.
[0002]
[Prior art]
Optically active alcohols are important substances as raw materials for pharmaceuticals, agricultural chemicals, etc. or intermediates, and synthetic intermediates in the field of fine chemicals such as ferroelectric liquid crystals. However, the purity of the substance itself is necessary to develop sufficient physiological activity and properties. In addition, a considerably high accuracy is required for both optical purity and optical purity. On the other hand, in a reaction using an enzyme such as lipase, lipoprotein lipase, or esterase, it is possible to identify an enantiomer that is difficult to obtain by a chemical reaction involving a normal high temperature. For this reason, the enzyme reaction is useful as a means for increasing optical purity, that is, optical resolution. In recent years, methods for producing optically active alcohols using this enzymatic reaction have been intensively studied.
[0003]
However, the enzyme reaction currently being carried out must be carried out for a very long time of several days to several tens of days (for example, Japanese Patent Laid-Open Nos. 62-166898, 63-273499 and 2). -86797 publications). Moreover, the temperature range in which the enzyme reaction can be performed is at most about 20 to 70 ° C., preferably 30 to 50 ° C. when lipase is used. For example, is the ester transesterified with racemic alcohol in a liquid state in that temperature range? It must be dissolved in a solvent and reacted (Japanese Patent Laid-Open Nos. 62-166898, 63-284184, 2-282340, and 4-349894).
[0004]
Therefore, the ester to be transesterified and the racemic alcohol often have physical properties such as boiling point and melting point that are almost similar, and are usually reactants containing various components such as unreacted substances and by-products. As a purification means for efficiently separating and recovering the target substance from among them and increasing the substance purity and optical purity, it is difficult to use the difference in physical properties, and other complicated and expensive processes must be performed. Such transesterification products are usually purified by a batch process. In other words, after the transesterification reaction is completed, in order to recover the target optically active alcohol from the reaction product, further treatment such as hydrolysis reaction is required, and azeotropic distillation, molecular distillation or preparative liquid chromatography is used. In fact, it is the fact that the substance purity is increased.
[0005]
[Problems to be solved by the invention]
As described above, the current optically active alcohol production method has a drawback that the enzyme reaction must be performed for a very long time. Furthermore, since the enzyme reaction temperature is substantially limited to 30 to 50 ° C. and a suitable raw material is selected, it is difficult to use differences in physical properties such as melting point and boiling point in the separation and purification process of the target product after the reaction. However, there is a problem that a complicated method and means of the batch method must be selected, and an excessive cost is required to efficiently recover the target optically active alcohol from the reaction product. Accordingly, the present invention provides a method for producing an optically active alcohol utilizing transesterification, whereby an enzymatic reaction can be carried out in a short time, the target product can be easily separated and purified, and the optically active alcohol production process is simplified. It was also aimed to develop such a method that could be semi-continuous.
[0006]
[Means for Solving the Problems]
The present inventors have intensively studied to solve the above problems and obtain an optically active alcohol by an industrially simple and advantageous method. As a result, the optically active alcohol can be efficiently converted from the racemic alcohol by allowing the racemic alcohol and the specific ester to be continuously transesterified at a high temperature in the presence of a heat-resistant lipase. It was found that it can be divided, and the present invention has been completed.
[0007]
That is, the gist of the present invention is to obtain R-form and S-form optically active alcohols through the following first step and then second step, add at least racemic alcohol to the remainder of the second step, A semi-continuous process for producing an optically active alcohol characterized by repeating the second step.
(First step) Using a racemic alcohol and a fatty acid ester having a carbon number of 16 or more of 1,3-propanediol having an alkyl group substituted or unsubstituted at the 2-position carbon in the presence of a heat-resistant lipase The transesterification reaction is carried out under normal pressure at 81 ° C. or higher under conditions that are substantially free of water, and after the reaction, optical activity rich in either unreacted R-form or S-form A step of separating alcohol from the residue by distillation under reduced pressure.
(Second Step) Maintaining the remainder of the first step as it is under reduced pressure, coexisting a heat-resistant lipase as in the first step, using no solvent and substantially free of moisture. The step of separating the residue from the residue by performing distillation under reduced pressure on the optically active alcohol rich in either the R-form or the S-form while performing the transesterification reaction at 81 ° C. or higher.
[0008]
In the present invention, the racemic alcohol for optical resolution is not particularly limited, but 2-alkanol is easily resolved, and preferably the following general formula (1)
[Chemical formula 5]

General formula (1)
[In the formula (1), A ≠ B, and A is a phenyl group or the following general formula (2)
[Chemical formula 6]

General formula (2)
(In formula (2), D ₁ , D ₂ , D ₃ , D ₄ and D ₅ are halogen atoms, alkyl groups having 1 to 3 carbon atoms or alkoxy groups having 1 to 3 carbon atoms). , B is a racemic alcohol represented by an alkyl group having 1 to 3 carbon atoms, CF ₃ or CN], the optical resolution can be efficiently performed by the method of the present invention described below.
[0009]
Specifically, 2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 1-phenylethanol, 1-phenyl-1-propanol, ethyl-3- Hydroxy-butanate, ethyl-3-hydroxy-propionate, methyl-3-hydroxy-pentanate, 1-phenyl-1,3-propanediol, 2-phenyl-1-cyclohexanol, 1-pentin-3-ol, 1- (2-bromophenyl) ethanol, 1-parachlorophenylethanol, 1- (4-chlorophenyl) ethanol, 1-chloro-2-octanol, 1,1-difluoro-2-octanol, 1- (2,4-dichlorophenyl) There are racemic alcohols such as ethanol. Of these, 2-octanol, 1-phenylethanol, 1-phenyl-1,3-propanediol, and 2-phenyl-1-cyclohexanol are preferable, and 1-phenylethanol, 2-octanol, (2-bromophenyl) ethanol.
[0010]
The 1,3-propanediol used in the present invention is one in which two identical or different alkyl groups are substituted or unsubstituted at the 2-position carbon, where the alkyl group is a methyl group, an ethyl group, or n-propyl. Group selected from the group consisting of a group, isopropyl group, n-butyl group and sec-butyl group, and specific examples thereof include 1,3-propanediol, 2,2-dimethyl-1,3-propanediol (neopentyl) Glycol), 2,2-diethyl-1,3-propanediol, 2,2-di-n-propyl-1,3-propanediol, 2,2-di-n-butyl-1,3-propanediol, 2- Methyl-2-ethyl-1,3-propanediol, 2-methyl-2-n-propyl-1,3-propanediol, 2-methyl-2-n-butyl-1,3-pro Diol, 2-ethyl-2-n-propyl-1,3-propanediol, 2-ethyl-2-n-butyl-1,3-propanediol, 2-n-propyl-2-n-butyl-1, 3-propanediol etc. can be mention | raise | lifted. Of these, 1,3-propanediol having an unsubstituted alkyl group, 2,2-dimethyl-1,3-propanediol, and 2,2-diethyl-1,3-propanediol are more preferable, and 1,3 -Propanediol is most preferred.
[0011]
The ester used in the present invention refers to an ester of the above 1,3-propanediol and a fatty acid having 16 or more carbon atoms. 1,3-propanediol palmitate, 2-hexyldecanoate, palmitooleate , Stearic acid ester, isostearic acid (2-heptylundecanoic acid, Emery's isostearic acid etc.) ester, oleic acid ester, linoleic acid ester, linolenic acid ester, arachidic acid ester, behenic acid ester, erucic acid ester, lignoceric acid ester Specific examples include serotic acid esters, montanic acid esters, melicic acid esters, and the like. These esters can also be used as a mixture in any proportion, and their constituent fatty acids are vegetable oils (soybean oil, rapeseed oil, olive oil, corn oil, safflower oil, sunflower oil, cottonseed oil, palm oil, etc.), animal oils (beef fat) Mixed fats obtained by hydrolyzing fish oil (sardine oil, saury oil, cod liver oil, etc.), and hydrogenated products thereof. Among these, preferred esters are 1,3-propanediol palmitic acid ester, stearic acid ester, oleic acid ester, and behenic acid ester (all of which are linear fatty acid esters), most preferably stearic acid ester and behenic acid ester. It is. Moreover, although it is possible to use either a monoester or a diester, a diester is desirable from the viewpoint of the efficiency of the transesterification reaction. The ester is desirably composed of a linear saturated fatty acid having 18 to 30 carbon atoms, and has a high melting point (preferably 60 ° C. or higher, more preferably 70 ° C. or higher). And Thereby, there exists an advantage which can isolate | separate the target optically active alcohol efficiently from the transesterification product of this invention.
[0012]
The ester to be reacted with the racemic alcohol must be a fatty acid ester of 1,3-propanediol. In the fatty acid ester of a monohydric alcohol, impurities are mixed during the distillation treatment, and a high-purity optically active alcohol is obtained. Absent. When triglyceride is used, the transesterification proceeds, but when the lipase is 1,3 specific, the produced 1,2-type diglyceride is transferred to 1,3-type diglyceride, and decompression operation is performed in the second-stage reaction. However, the optically active alcohol is not liberated again. Furthermore, the reaction rate of the ester of a tetrahydric or higher polyhydric alcohol is extremely reduced.
[0013]
The transesterification reaction of the present invention is characterized by using a heat-resistant lipase. As a result, the transesterification reaction can be carried out quickly while maintaining a high temperature, and further, the transesterification reaction can be carried out at a high temperature and under reduced pressure, and the optical activity generated as a reaction product while the reaction proceeds. Alcohol can be recovered simultaneously.
[0014]
Examples of the heat-resistant lipase include lipases derived from the genus Alcaligenes described in JP-B-58-36953, Rhizopus chinensis described in JP-A-59-156282, and the like. In the present invention, lipase PL-266 produced by Alcaligenes sp. PL-266 (Mikken Kenki No. 3187) described in Japanese Patent Publication No. 58-36953 is disclosed, and Japanese Patent Publication No. 60-15312. The lipase PL-679 produced by Alcaligenes sp. PL-679 described in the publication is preferably lipase PL and lipase QL produced by Meikatsu Sangyo Co., Ltd. In particular, lipase QL is desirable. Such heat-resistant lipase may be immobilized on a known carrier such as activated carbon, celite, adsorptive resin, ion exchange resin, ceramics, etc., but it is desirable to coexist with the raw material in a powder state as described later.
[0015]
In the transesterification reaction, the racemic alcohol and the ester are mixed as raw materials in a molar ratio of 1: 5 or less, preferably 1: 2-1 based on the racemic alcohol, and a solvent of the raw materials is used. Preferably, the lipase powder is dispersed in a reaction system that is free of water and substantially free of water (ie, the equilibrium water content in the raw material is about 0.1 wt% or less, desirably 0.05 wt% or less). The reaction is carried out with stirring. At this time, it is desirable to carry out the transesterification by controlling 90% or more of the particles of the lipase powder to have a size of 1 to 100 μm, preferably 20 to 50 μm. As a means of aligning the particle size, after dispersing the lipase powder in the raw material heated and dissolved as necessary, ultrasonic treatment, filtration treatment with a precision membrane of the dispersion or ultrafiltration membrane, centrifugal sedimentation treatment, etc. However, it is convenient to irradiate with ultrasonic waves for 1 to 30 minutes, preferably at a reaction temperature or lower, 20 to 150 kHz, and 100 to 250 W.
[0016]
The reaction temperature is set to 81 ° C. or more, more preferably 91 to 130 ° C., most preferably 101 to 120 ° C., and the transesterification (in the present invention, alcoholysis) reaction is performed under normal pressure in the first step or under reduced pressure in the second step. The reaction rate is checked by, for example, gas chromatography while gently stirring or shaking, and the transesterification reaction is performed for a predetermined time, preferably several hours to 100 hours. When the reaction temperature is lower than 81 ° C., the reaction proceeds slowly. Conversely, when the reaction temperature exceeds 130 ° C., lipase is deactivated. In the first step, either one of the enantiomers (R-form or S-form) of racemic alcohol is transesterified with the fatty acid ester of 1,3-propanediol (alcolysis) by this reaction, and R-form or S-form The fatty acid ester of any one of these optically active alcohols and an unreacted optically active alcohol are produced. The transesterification reaction product containing such components is not subjected to filtration and removal of the heat-resistant lipase from this, and the unreacted optically active alcohol is simply distilled under reduced pressure (5 to 1 mmHg) to obtain R-form or S-form. An optically active alcohol rich in either one is obtained and the residue is separated.
[0017]
In the residue obtained by the vacuum distillation treatment obtained in the first step, the fatty acid ester of the optically active alcohol (the other of the enantiomers not distilled under reduced pressure) of either the transesterified R or S form, the raw material Since the 1,3-propanediol fatty acid ester used as a component is partially or completely alcoholically coexisted, the residue is decompressed as it is in the second step following the first step. Maintained in a state (5 to 1 mmHg), and subjected to a transesterification (alcolysis) reaction under the same conditions as in the first step (in the presence of a heat-resistant lipase, at 81 ° C. or higher under a solvent-free and substantially anhydrous condition), Either the R-form or S-form optically active alcohol produced by the reaction is separated by distillation under reduced pressure while carrying out the reaction. Here, the heat-resistant lipase is convenient to allow the transesterification of the second step to be carried out by allowing the reactant used in the first step to coexist as it is, but even if it is newly added at the start of the second step Good.
Thus, the optically active alcohols of high purity R-form and S-form can be easily separated from the racemic alcohol with high yield.
[0018]
In the present invention, at least racemic alcohol is added to the residue after separation of both R-form and S-form optically active alcohols through the first step and the second step, and the first step and the second step. The racemic alcohol is optically resolved by repeating the above operation. That is, the residue obtained by finishing the operation in the second step returns to the mixture of the fatty acid ester of 1,3-propanediols and the heat-resistant lipase used as a raw material in the first step, and therefore the first step A racemic alcohol of the same kind or different kind from that used in Step 1 is added, a heat-resistant lipase is added if necessary, and each operation of the second step is repeated after the first step. According to this method, R-form and S-form optically active alcohols can be obtained from racemic alcohols with high purity, the yield is high, and the operation is simple as an optical resolution method. This enables mass production of optically active alcohols.
[0019]
【Example】
The substance purity of the compounds obtained in the following examples and comparative examples was determined by gas chromatography (manufactured by Shimadzu Corporation, GC-14A), and the optical purity was determined by measuring the specific rotation with a polarimeter (JASCO ( It was measured by using DIP-370), and the measured value was calculated by comparing with the value of the standard sample.
[0020]
Example 1
3 g of lipase QL derived from Alcaligenes sp. (Manufactured by Meika Sangyo Co., Ltd.), 50 g of (R, S) -1-phenylethanol and 1,3-propanediol oleic acid diester (1,3-propane Diol and oleic acid obtained by esterification reaction at 150 to 200 ° C. for 5 hours using p-toluenesulfonic acid as a catalyst. Purity: 99%) 270 g was put into a 500 ml separable flask and generated ultrasonically at room temperature Using an apparatus (manufactured by Shimadzu Corporation, SUS-103), ultrasonic waves were irradiated at 45 kHz for 1 minute. Thereafter, the mixture was stirred at 90 ° C. at a stirring speed of 350 rpm, and a transesterification reaction was performed for 23 hours at a normal pressure. Water content in the reaction system (Karl Fischer method): 0.05% by weight, size of lipase particles (particle size distribution measuring device manufactured by Coulter Electronics Co., Ltd .: measurement with Multisizer): 95% or more was 20 to 50 μm. After completion of the reaction, the reaction product was measured by gas chromatography. As a result, 49 mol% of (R, S) -1-phenylethanol was converted to an oleate. The reaction system was reduced in pressure to 90 ° C. and 1 mmHg and distilled for 20 minutes, and unreacted (S)-(−)-1-phenylethanol (yield: 98%, substance purity: 100%, optical purity: 99 % Ee or higher). Furthermore, the transesterification reaction was continued at 90 ° C. for 22 hours in the presence of the lipase while maintaining the reduced pressure state as it was, and (R)-(+)-1-phenylethanol (yield: 93%, substance purity: 100%). , Optical purity: 99% ee or higher) was separated by distillation under reduced pressure. After completion of this series of reactions, 50 g of (R, S) -1-phenylethanol was newly added, and the same operation as described above was repeated a total of 3 times. The yield of each optically active alcohol in the first to third repetitions of this repeating operation was 98%, 99% and 97% for the (S)-(−) isomer, 92% for the (R)-(+) isomer, 90% The material purity of both optically active alcohols was 100% and the optical purity was 99% ee or higher.
[0021]
Example 2
5 g of lipase PL (manufactured by Meisei Sangyo Co., Ltd.) derived from Alcaligenes sp., 50 g of (R, S) -1- (p-chlorophenyl) ethanol and 2,2-dimethyl-1,3-propanediol 270 g of palmitic acid diester (obtained by esterification of 2,2-dimethyl-1,3-propanediol and palmitic acid by the method described in Example 1. Purity: 99%) in a 500 ml separable flask Then, at 85 ° C., ultrasonic waves were radiated at 45 kHz for 1 minute using an ultrasonic generator (same as in Example 1). Thereafter, the mixture was stirred at 85 ° C. and a stirring speed of 350 rpm, and a transesterification reaction was performed for 22 hours under normal pressure. The water content of the reaction system measured by the method described in Example 1: 0.03% by weight The size of lipase particles: 90% or more was 20 to 50 μm. When the reaction product was measured by gas chromatography after the completion of the reaction, 48 mol% of (R, S) -1- (p-chlorophenyl) ethanol was converted to a palmitate ester. The reaction system was reduced in pressure to 90 ° C. and 1 mmHg and distilled for 30 minutes, and unreacted (S)-(−)-1- (p-chlorophenyl) ethanol (yield: 91%, substance purity: 100%, Optical purity: 99% ee or higher) was obtained. Furthermore, the transesterification reaction was continued for 72 hours in the presence of the lipase at 85 ° C. while maintaining the reduced pressure state, and (R)-(+)-1- (p-chlorophenyl) ethanol (yield: 82%, substance purity). : 100%, optical purity: 99% ee or higher) were separated by distillation under reduced pressure. After completion of this series of reactions, only 50 g of (R, S) -1- (p-chlorophenyl) ethanol was newly added, and the same operation as described above was repeated twice. The yield of each optically active alcohol in the first and second iterations was 92% and 90% for the (S)-(−) isomer, 83% and 81% for the (R)-(+) isomer, The substance purity of both optically active alcohols was 100%, and the optical purity was 99% ee or higher.
[0022]
Example 3
3 g of lipase QL described in Example 1 was put into 50 g of (R, S) -2-octanol, and irradiated with ultrasonic waves at 45 kHz for 1 minute at room temperature using an ultrasonic generator (same as in Example 1). Thereafter, 270 g of 1,3-propanediol stearic acid diester (purity: 99%) synthesized by ester synthesis in the same manner as in Example 1 was added and stirred in a 500 ml separable flask at 105 ° C. at a stirring speed of 350 rpm. Transesterification was performed for 12 hours under pressure. The water content of the reaction system measured by the method described in Example 1 was 0.04% by weight, and the size of lipase particles: 95% or more was 20 to 40 μm. After completion of the reaction, the reaction product was measured by gas chromatography. As a result, 52 mol% of (R, S) -2-octanol was converted to stearic acid ester. The reaction system was reduced in pressure to 105 ° C. and 3 mmHg as it was, and distilled for 10 minutes. Unreacted (S)-(+)-2-octanol (yield: 89%, substance purity: 100%, optical purity: 99% ee or higher). Furthermore, the transesterification reaction was continued for 25 hours in the presence of the lipase at 110 ° C. while maintaining the reduced pressure state as it was, and (R)-(−)-2-octanol (yield: 98%, substance purity: 100%, optical) Purity: 98% ee) was obtained by distillation under reduced pressure. After completion of this series of reactions, 50 g of (R, S) -2-octanol and 1 g of lipase QL (supra) were added, and the same operation as described above was repeated a total of 5 times. The yield of each optically active alcohol in the first to fifth repetitions of this repeating operation is as follows: (S)-(+) isomers are 93%, 93%, 94%, 91% and 90%, (R)-(−) isomers. Is 99%, 98%, 98%, 97% and 98%, and the substance purity of both optically active alcohols is 100%, and the optical purity is 99% ee or higher for all (S)-(+) isomers, The (R)-(−) isomers were 99% ee or more, 99% ee or more, 98% ee, 99% ee or more, and 99% ee.
[0023]
Example 4
In Example 3, instead of 1,3-propanediol, 2,2-diethyl-1,3-propanediol, 2-methyl-2-n-propyl-1,3-propanediol and 2-ethyl-2- When (R, S) -2-octanol was similarly treated with n-butyl-1,3-propanediol, the separated (S)-(+)-2-octanol and (R)-(- ) -2-octanol yield: 88-96%, substance purity: 100%, optical purity: 96-99% ee or more.
[0024]
Comparative Example 1
In Example 1, 270 g of oleic acid monoester of n-propanol was used instead of oleic acid diester of 1,3-propanediol, and the transesterification product was distilled under reduced pressure under the same conditions. N-propanol was mixed in the product, and the yield of (S)-(−)-1-phenylethanol was 99%, the substance purity was 78%, and the optical purity was 69% ee. Further, the residue after distillation under reduced pressure was treated under the same conditions, but no distillate was obtained. Repeated operation was impossible.
[0025]
【The invention's effect】
According to the present invention, a racemic alcohol and a fatty acid ester of 1,3-propanediol are subjected to a transesterification (alcolysis) reaction at a high temperature in the presence of a heat-resistant lipase. And one of the enantiomers can be easily obtained in high purity and high yield. Furthermore, since the residue obtained by separating one of the enantiomers is subjected to a transesterification (alcolysis) reaction in the same manner under reduced pressure, the other of the enantiomers is liberated again, and at the same time while performing the reaction, Can be obtained with high purity and high yield, and the manufacturing process is simplified. In addition, the method of the present invention can be repeated in the same manner if a raw racemic alcohol is newly added after a series of operations is completed, and a high-purity enantiomer is semi-continuously obtained in a high yield. It is suitable as a method for mass production.

Claims (7)

The R-form and S-form optically active alcohols are obtained through the following first step and then the second step, and at least 2-alkanol or a racemic form of the compound represented by the following general formula (1) in the remainder of the second step A semi-continuous method for producing an optically active alcohol, comprising adding alcohol and repeating the first step and then the second step.
(First Step) A racemic alcohol of a compound represented by 2-alkanol or the following general formula (1) and 1,3-propanediol having an alkyl group substituted or unsubstituted at the 2-position carbon having 16 or more carbon atoms Fatty acid ester is transesterified in the presence of a heat-resistant lipase derived from the genus Alcaligenes without using a solvent and substantially free of moisture at 81 ° C. or higher under normal pressure. Performing the reaction, and separating the residue from the residue by distillation under reduced pressure of the optically active alcohol rich in either unreacted R-form or S-form.
(2nd process) The remainder of 1st process is maintained in a reduced pressure state as it is, and the heat-resistant lipase derived from the genus Alcaligenes is made to coexist like the 1st process, without using a solvent, and substantially. A step of separating an optically active alcohol rich in either the R-form or S-form liberated by the reaction by distillation under reduced pressure and performing a transesterification reaction at 81 ° C. or higher under a condition that does not contain moisture, and separating it from the residue. .

General formula (1)
[In formula (1), A ≠ B, A is a phenyl group or the following general formula (2) (in formula (2), D ₁ , D ₂ , D ₃ , D ₄ and D ₅ are halogen atoms or carbon atoms 1 to 3 alkyl groups or alkoxy groups having 1 to 3 carbon atoms), and B is an alkyl group having 1 to 3 carbon atoms.

General formula (2) 2. The optically active alcohol according to claim 1, wherein 2-alkanol or a racemic alcohol of a compound represented by the following general formula (1) and a heat-resistant lipase derived from the genus Alcaligenes are added to the residue of the second step. Semi-continuous manufacturing method.

General formula (1)
[In formula (1), A ≠ B, A is a phenyl group or the following general formula (2) (in formula (2), D ₁ , D ₂ , D ₃ , D ₄ and D ₅ are halogen atoms or carbon atoms 1 to 3 alkyl groups or C1 to C3 alkoxy groups), and B is an alkyl group having 1 to 3 carbon atoms.

General formula (2) The semi-continuous process for producing an optically active alcohol according to claim 1 or 2, wherein the 2-position carbon of 1,3-propanediol is unsubstituted with an alkyl group . The semi-continuous process for producing an optically active alcohol according to any one of claims 1 to 3, wherein the fatty acid is a linear saturated fatty acid having 18 or more carbon atoms . The semi-continuous method for producing an optically active alcohol according to any one of claims 1 to 4, wherein the heat-resistant lipase derived from the genus Alcaligenes is a lipase derived from Alcaligenes sp. The semi-continuous production of the optically active alcohol according to any one of claims 1 to 5, wherein the heat-resistant lipase derived from the genus Alcaligenes is in a powder form and 90% or more of the particles have a particle diameter of 1 to 100 µm. Law. Transesterification temperature is 101-120 degreeC , The semi-continuous manufacturing method of the optically active alcohol of any one of Claims 1-6.