JP3865558B2 - Process for producing optically active perfluoroalkyl carbinol derivative - Google Patents

Description

【００１２】
［式中、Ｒは、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ¹は水素を表し、Ｒ²およびＲ³は、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、無置換もしくは置換ヘテロ環、アルコキシカルボニル基、または、ヒドロキシアルキル基を表し、Ｒ²とＲ³は同時に同じ置換基になることはなく、＊は不斉炭素を表す］で示される光学活性イミンと、一般式［４］
【００１３】
【化７】

【００１４】
［式中、Ｒ⁴は、水素、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ_fは、パーフルオロアルキル基を表す］で示されるパーフルオロアルキルアルデヒドのヘミアセタールまたは水和物を縮合させ、酸性条件下、加水分解することによって、一般式［５］
【００１５】
【化８】

【００１６】
［式中、Ｒは、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ¹は水素を表し、Ｒ_fは、パーフルオロアルキル基を表し、＊は不斉炭素を表す］で示される光学活性パーフルオロアルキルカルビノール誘導体を製造する方法である。
【００１７】
【発明の実施の形態】
以下、本発明の光学活性パーフルオロアルキルカルビノール誘導体の製造方法について詳細に説明する。
【００１８】
本発明の製造方法は、原料である一般式［３］で示される光学活性イミンを製造する過程と、該光学活性イミンと一般式［４］で示されるパーフルオロアルキルアルデヒドのヘミアセタールまたは水和物を縮合させ、酸性条件下、加水分解する過程よりなる。
【００１９】
本発明の前過程においては、一般式［３］で示される光学活性イミンは、以下の方法により、工業的に簡便で且つ効率良く製造することができる。
【００２０】
すなわち、一般式［１］で示されるケトンと一般式［２］で示される光学活性一級アミンを酸性条件下、脱水縮合することによって製造することができる。
【００２１】
一般式［１］で示されるケトンとしては、具体的には、アセトン、メチルエチルケトン、メチルｎ−プロピルケトン、メチルｉ−プロピルケトン、ピナコリン、メチルｃ−ヘキシルケトン、アセトフェノン、２’−メチルアセトフェノン、４’−メチルアセトフェノン、２’−メトキシアセトフェノン、４’−メトキシアセトフェノン、２’−クロロアセトフェノン、４’−クロロアセトフェノン、２’−エトキシカルボニルアセトフェノン、４’−エトキシカルボニルアセトフェノン、２’−ニトロアセトフェノン、４’−ニトロアセトフェノン、２’，４’，６’−トリメチルアセトフェノン、２−チエニルメチルケトン等が挙げられる。
【００２２】
一般式［２］で示される光学活性一級アミンとしては、具体的には、１−フェニルエチルアミン、１−１’−ナフチルエチルアミン、１−２’−ナフチルエチルアミン、１−ｃ−ヘキシルエチルアミン、フェニルグリシンメチルエステル、バリンメチルエステル、フェニルグリシノール等が挙げられる。その中でも、１−フェニルエチルアミン、１−１’−ナフチルエチルアミン、１−２’−ナフチルエチルアミンおよびフェニルグリシノールが好ましく、特に、１−フェニルエチルアミンおよび１−２’−ナフチルエチルアミンがより好ましい。また、該光学活性一級アミンにはＲ体またはＳ体が存在するため、それから誘導される一般式［３］で示される光学活性イミンにもＲ体またはＳ体が存在するが、これらの鏡像体は目的とする生成物の絶対配置に応じて適宜決めればよい。
【００２３】
一般式［２］で示される光学活性一級アミンの使用量は、通常は一般式［１］で示されるケトンに対して、等モル反応であるため、１モル当量以上使用すればよく、１〜１０モル当量が好ましく、特に、１〜５モル当量がより好ましい。
【００２４】
本反応は、一般式［１］で示されるケトンと一般式［２］で示される光学活性一級アミンの脱水縮合であるため、酸性条件下、副生する水を除きながら反応を行う。好ましくは、水と混和せず、水よりも比重が小さく、水と共沸する溶媒を用いて、環流条件下、ディーン・スターク管で副生する水を除く。
【００２５】
使用される溶媒としては、水と共沸する溶媒であればよく、ベンゼン、トルエン、エチルベンゼンおよびキシレン等の芳香族炭化水素が好ましく、特に、トルエンがより好ましい。これらの溶媒は、単独または組み合わせて用いることができる。
【００２６】
溶媒の使用量としては、理論的に副生する水の量を共沸除去できるだけの溶媒量を必要とするが、ディーン・スターク管を用いることによって、使用量を極端に減らすことができる。
【００２７】
本脱水縮合において、使用される酸としては、ｐ−トルエンスルホン酸、１０−カンファースルホン酸等の有機酸、塩酸、硫酸、リン酸等の無機酸等が挙げられる。その中でも、ｐ−トルエンスルホン酸および硫酸が好ましく、特に、ｐ−トルエンスルホン酸がより好ましい。
【００２８】
酸の使用量としては、一般式［１］で示されるケトンに対して、触媒量使用すればよく、０．００１〜１モル当量が好ましく、特に、０．００５〜０．５モル当量がより好ましい。
【００２９】
本脱水縮合の温度条件は、使用する溶媒と水の共沸温度から溶媒の沸点までの範囲で行なえばよく、特に、使用する溶媒の沸点付近がより好ましい。
【００３０】
前過程の後処理においては、反応終了後、通常の後処理操作を行うことによって、粗生成物を得ることができる。粗生成物は、必要に応じて、活性炭、蒸留、再結晶、カラムクロマトグラフィー等の精製操作を行い、目的の一般式［３］で示される光学活性イミンを高い純度で得ることができる。また、単離精製せず、後過程に用いることができる。具体的には、反応終了液を、または、反応終了液を炭酸水素ナトリウムまたは水酸化ナトリウム等のアルカリ水溶液で洗浄し、無水硫酸マグネシウムまたは無水硫酸ナトリウム等で乾燥し、濾過して得られる光学活性イミンのトルエン溶液等を後過程に用いることができる。
【００３１】
本発明の後過程においては、一般式［５］で示される光学活性パーフルオロアルキルカルビノール誘導体は、以下の方法により、工業的に簡便で且つ効率良く製造することができる。
【００３２】
すなわち、前過程において得られた、一般式［３］で示される光学活性イミンと一般式［４］で示されるパーフルオロアルキルアルデヒドのヘミアセタールまたは水和物を縮合させ、酸性条件下、加水分解することによって製造することができる。
【００３３】
一般式［４］で示されるパーフルオロアルキルアルデヒドのヘミアセタールまたは水和物としては、具体的には、フルオラール・メチルヘミアセタール、フルオラール・エチルヘミアセタール、フルオラール・ｎ−プロピルヘミアセタール、フルオラール・ｉ−プロピルヘミアセタール、フルオラール・水和物、ペンタフルオロプロピオンアルデヒド・エチルヘミアセタール、ペンタフルオロプロピオンアルデヒド・水和物、ｎ−ヘプタブチルアルデヒド・エチルヘミアセタール、ｎ−ヘプタブチルアルデヒド・水和物等が挙げられる。
【００３４】
一般式［４］で示されるパーフルオロアルキルアルデヒドのヘミアセタールまたは水和物の使用量は、通常は一般式［３］で示される光学活性イミンに対して、当モル反応であるため、１モル当量以上使用すればよく、１〜１０モル当量が好ましく、特に、１〜５モル当量がより好ましい。
【００３５】
本縮合は、無溶媒で行うこともできるが、通常は溶媒が使用される。使用される溶媒としては、具体的には、ｎ−ペンタン、ｎ−ヘキサン、ｃ−ヘキサン、ｎ−ヘプタン等の脂肪族炭化水素、ベンゼン、トルエン、エチルベンゼン、キシレン等の芳香族炭化水素、塩化メチレン、クロロホルム、１，２−ジクロロエタン等のハロゲン化炭化水素、ジエチルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、テトラヒドロフラン、１，４−ジオキサン等のエーテル、酢酸エチル、酢酸ｎ−ブチル等のエステル、アセトニトリル、プロピオニトリル等のニトリル等が挙げられる。その中でも、ｎ−ヘキサン、ベンゼン、トルエン、塩化メチレン、１，２−ジクロロエタン、テトラヒドロフランおよびアセトニトリルが好ましく、特に、ｎ−ヘキサンおよびトルエンがより好ましい。これらの溶媒は、単独または組み合わせて用いることができる。
【００３６】
溶媒の使用量としては、特に制限はない。
【００３７】
本縮合の温度条件は、反応温度−４０〜２５０℃で行えばよく、−２０〜１００℃が好ましく、特に、−１０℃〜８０℃がより好ましい。
【００３８】
本発明の後過程においては、縮合後に、酸性条件下、加水分解を行うが、これは、縮合で生成する一般式［６］
【００３９】
【化９】

【００４０】
［式中、Ｒは、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ¹は水素を表し、Ｒ²およびＲ³は、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、無置換もしくは置換ヘテロ環、アルコキシカルボニル基、または、ヒドロキシアルキル基を表し、Ｒ²とＲ³は同時に同じ置換基になることはなく、Ｒ_fは、パーフルオロアルキル基を表し、＊は不斉炭素を表す］で示されるオキセタン、一般式［７］
【００４１】
【化１０】

【００４２】
［式中、Ｒは、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ¹は水素を表し、Ｒ²およびＲ³は、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、無置換もしくは置換ヘテロ環、アルコキシカルボニル基、または、ヒドロキシアルキル基を表し、Ｒ²とＲ³は同時に同じ置換基になることはなく、Ｒ⁴は、水素、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ_fは、パーフルオロアルキル基を表し、＊は不斉炭素を表す］で示されるＮ、Ｏ−アセタール、または、一般式［８］
【００４３】
【化１１】

【００４４】
［式中、Ｒは、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、または、無置換もしくは置換ヘテロ環を表し、Ｒ¹は水素を表し、Ｒ²およびＲ³は、Ｃ_1-6鎖状アルキル基、Ｃ_3-8環状アルキル基、無置換もしくは置換アリール基、無置換もしくは置換ヘテロ環、アルコキシカルボニル基、または、ヒドロキシアルキル基を表し、Ｒ²とＲ³は同時に同じ置換基になることはなく、Ｒ_fは、パーフルオロアルキル基を表し、＊は不斉炭素を表す］で示されるイミンを一般式［５］で示される光学活性パーフルオロアルキルカルビノール誘導体へ変換するためである。
【００４５】
本加水分解において、使用される酸としては、ｐ−トルエンスルホン酸、１０−カンファースルホン酸等の有機酸、塩酸、硫酸、リン酸等の無機酸等が挙げられる。その中でも、塩酸および硫酸が好ましく、特に、塩酸がより好ましい。
【００４６】
酸の濃度としては、０．１〜１２Ｎを使用すればよく、０．２〜６Ｎが好ましく、特に、０．５〜２Ｎがより好ましい。
【００４７】
酸の使用量としては、一般式［３］で示される光学活性イミンに対して、０．１〜２０モル当量使用すればよく、０．２〜１０モル当量が好ましく、特に、０．５〜８モル当量がより好ましい。
【００４８】
本加水分解の温度条件は、室温付近で行なえばよく、加熱条件下においては、効率よく行うことができ、冷却条件下においても、充分な反応速度で行うことができる。
【００４９】
後過程の後処理においては、反応終了後、通常の後処理操作を行うことによって、粗生成物を得ることができる。粗生成物は、必要に応じて、活性炭、蒸留、再結晶、カラムクロマトグラフィー等の精製操作を行い、目的の一般式［５］で示される光学活性パーフルオロアルキルカルビノール誘導体を高い純度で得ることができる。
【００５０】
また、加水分解によって副生する一般式［２］で示される光学活性一級アミンを回収し、再利用することができる。例えば、後処理で得られる酸性水層から中和・抽出等の操作によって、粗の光学活性一級アミンを回収することができる。粗回収物は、必要に応じて、活性炭、蒸留、再結晶、カラムクロマトグラフィー等の精製操作を行い、光学活性一級アミンを高い純度で回収することができる。回収した光学活性一級アミンの光学純度は低下しておらず、前過程の一般式［３］で示される光学活性イミンの合成に繰り返し再利用することができる。
【００５１】
【実施例】
以下、実施例により本発明の実施の形態を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
【００５２】
「１」光学活性イミンの製造
［実施例１］
ケトンとしてアセトフェノン（１ａ、５０ｍｍｏｌ）、光学活性一級アミンとして（Ｒ）−１−フェニルエチルアミン（（Ｒ）−２ａ、１００ｍｍｏｌ）を含むトルエン（１５０ｍｌ）溶液に、ｐ−トルエンスルホン酸一水和物（０．５ｍｍｏｌ）を加えて、２４時間、加熱還流し、副生する水をディーン・スターク管で除いた。反応終了液を飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥、濾過、濃縮、真空乾燥し、粗体を得た。粗体を減圧蒸留（１４３℃／６ｍｍＨｇ）し、光学活性イミンとして（Ｒ）−Ｎ−（１−フェニルエチリデン）−１−フェニルエチルアミン（（Ｒ）−３ａａ、３９ｍｍｏｌ、７８％）を得た。
【００５３】
［実施例２］
ケトンとしてアセトフェノン（１ａ、５０ｍｍｏｌ）、光学活性一級アミンとして（Ｒ）−１−２’−ナフチルエチルアミン（（Ｒ）−２ｂ、１００ｍｍｏｌ）を含むトルエン（１５０ｍｌ）溶液に、ｐ−トルエンスルホン酸一水和物（０．５ｍｍｏｌ）を加えて、２４時間、加熱還流し、副生する水をディーン・スターク管で除いた。反応終了液を飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥、濾過、濃縮、真空乾燥し、粗体を得た。粗体を減圧蒸留し、光学活性イミンとして（Ｒ）−Ｎ−（１−フェニルエチリデン）−１−２’−ナフチルエチルアミン（（Ｒ）−３ａｂ、４０．５ｍｍｏｌ、８１％）を得た。
【００５４】
［実施例３〜７］
実施例１と同様の実験操作を行い、これらの結果を表１のラン２および４〜７としてまとめた。表中、ラン１および３はそれぞれ実施例１、実施例２に対応する。
【００５５】
【化１２】

【００５６】
【表１】

【００５７】
「２」光学活性パーフルオロアルキルカルビノール誘導体の製造
［実施例８］
（Ｒ）−Ｎ−（１−フェニルエチリデン）−１−フェニルエチルアミン（（Ｒ）−３ａａ，０．５ｍｍｏｌ）およびフルオラール・エチルヘミアセタール（４ａ，０．５ｍｍｏｌ）を含むｎ−ヘキサン（２ｍｌ）溶液を７時間、１８−１９℃で撹拌後、１．５Ｎ−ＨＣｌ２mlを加え、室温で１時間撹拌した。反応終了液を酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、濾過、濃縮、真空乾燥し、粗体を得た。
【００５８】
粗体をカラムクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：５）で精製し、（Ｓ）−４，４，４−トリフルオロ−３−ヒドロキシ−１−フェニル−１−ブタノン（（Ｓ）−５ａａ、０．３１ｍｍｏｌ、６２％）を得た。光学純度はキラルＨＰＬＣ（ダイセルＯＤ、ｎ−ヘキサン／ｉ−プロパノール＝９５／５、２５４ｎｍ）分析で、６０％ｅｅと決定した。
【００５９】
［実施例９］
（Ｒ）−Ｎ−（１−フェニルエチリデン）−１−２’−ナフチルエチルアミン（（Ｒ）−３ａｂ，０．５ｍｍｏｌ）およびフルオラール・エチルヘミアセタール（４ａ，０．５ｍｍｏｌ）を含むｎ−ヘキサン（２ｍｌ）溶液を１６８時間、−２−０℃で撹拌後、１．５Ｎ−ＨＣｌ２mlを加え、室温で１時間撹拌した。反応終了液を酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、濾過、濃縮、真空乾燥し、粗体を得た。
【００６０】
粗体をカラムクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：５）で精製し、（Ｓ）−４，４，４−トリフルオロ−３−ヒドロキシ−１−フェニル−１−ブタノン （（Ｓ）−５ａａ、０．２８５ｍｍｏｌ、５７％）を得た。光学純度は実施例８に記載した分析で、８１％ｅｅと決定した。
【００６１】
［実施例１０〜２６］
実施例８と同様の実験操作を行い、これらの結果を表２のラン８、１０〜１８および２０〜２６としてまとめた。表中、ラン９および１９は、それぞれ実施例８、実施例９に対応する。
【００６２】
【化１３】

【００６３】
【表２】

【００６４】
［実施例２７］
（Ｒ）−１−フェニルエチルアミン（（Ｒ）−２ａ）の回収、再利用
実施例８の後処理で得られた塩酸水層を１Ｎ−水酸化ナトリウム水溶液でアルカリ性にし、酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、濾過、濃縮、真空乾燥し、粗体を回収した。粗体を減圧蒸留し、（Ｒ）−１−フェニルエチルアミン（（Ｒ）−２ａ、０．４ｍｍｏｌ、８０％）を回収した。回収した光学活性一級アミンの光学純度は９８．５％ｅｅ（Ｒ）で低下しておらず、実施例１、ひき続いて実施例８と同様の実験操作を行い、同等の結果が得られることを確認した。
【００６５】
【発明の効果】
医薬、農薬および強誘電性液晶を初めとする機能性材料の重要中間体である光学活性３−パーフルオロアルキル−３−ヒドロキシプロピオン酸誘導体の前駆体である光学活性パーフルオロアルキルカルビノール誘導体を工業的に簡便で且つ効率良く製造できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an optically active perfluoroalkylcarbide which is a precursor of an optically active 3-perfluoroalkyl-3-hydroxypropionic acid derivative which is an important intermediate of functional materials such as pharmaceuticals, agricultural chemicals and ferroelectric liquid crystals. The present invention relates to a method for producing a diol derivative.
[0002]
[Prior art]
Research has been actively conducted to introduce a perfluoroalkyl group at a specific site of a compound and to develop unique physiological activity and physical properties in functional materials such as pharmaceuticals, agricultural chemicals and ferroelectric liquid crystals. Perfluoroalkyl aldehyde can be used for the construction of perfluoroalkyl carbinol derivatives as a synthon (synthetic element) having a perfluoroalkyl group. In particular, optical active perfluoroalkyl carbinol derivatives are increasingly selected as target compounds for the purpose of higher functionality, and asymmetric reactions using perfluoroalkyl aldehydes are simple and efficient with optical active perfluoroalkyl carbinol derivatives. It can be a simple synthesis method.
[0003]
For example, an optically active trifluoromethyl carbinol is obtained by hydrolyzing a Friedel-Crafts-type product obtained by reacting an α-methoxystyrene derivative with fluoral in the presence of an optically active binaphthol-titanium complex under acidic conditions. A derivative is obtained.
[0004]
However, perfluoroalkyl aldehyde has a low boiling point and a very high reactivity, so it easily self-polymerizes and is a compound that is very difficult to handle.
[0005]
Therefore, it is usually stabilized in the form of hemiacetal or hydrate, and the gas generated by dripping into concentrated sulfuric acid or phosphorous pentoxide when heated is used for the reaction, but a part of the generated perfluoroalkyl aldehyde is polymerized. Or an excess amount of hemiacetal or hydrate is required because it remains in the acid. Moreover, since the post-treatment of the acid used excessively becomes a problem, it is difficult to say that the reaction using perfluoroalkyl aldehyde is practical from the industrial viewpoint.
[0006]
From such a viewpoint, a method for synthesizing a perfluoroalkyl carbinol derivative in which a nucleophilic species is directly reacted with a hemiacetal or hydrate of perfluoroalkyl aldehyde which is stable and easy to handle has been reported. For example, Tetrahedron Lett., 33, 1351 (1992) includes a synthesis example of fluoroethyl hemiacetal and trimethylsilyl nitrile in dioxane in the presence of zinc iodide, and Chem. Commun., 1996, 1929. In the presence of indium in water, a synthesis example of fluoral ethyl hemiacetal and allyl bromide has been reported. The inventors of the present invention have made it easy for the condensation of fluoral ethyl hemiacetal or hydrate and enamine or imine to proceed without a catalyst (Chem. Commun., 1998, 2051, Synlett, 1999, 1477), 4 , 4,4-trifluoro-3-hydroxy-1-aryl-1-butanone derivatives can be easily synthesized.
[0007]
[Problems to be solved by the invention]
The above known reaction is very practical as a method for synthesizing a racemic perfluoroalkyl carbinol derivative, but there is no description regarding the asymmetric reaction.
[0008]
An object of the present invention is to develop an asymmetric synthesis method of an optically active perfluoroalkyl carbinol derivative using a hemiacetal or hydrate of perfluoroalkyl aldehyde which is stable and easy to handle.
[0009]
[Means for solving the problems]
As a result of diligent studies to solve the above problems, the present inventors condensated an optically active primary amine and an optically active imine derived from a ketone and a hemiacetal or hydrate of perfluoroalkyl aldehyde to produce an acid. It was revealed that optically active perfluoroalkyl carbinol derivatives can be obtained with high optical purity by hydrolysis under the conditions.
[0010]
That is, the present invention provides a general formula [3] derived from an optically active primary amine and a ketone.
[0011]
[Chemical 6]

[0012]
[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R ² and R ³ represent a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocycle, an alkoxycarbonyl group, or a hydroxyalkyl group; ² and R ³ are not the same substituent at the same time, * represents an asymmetric carbon, and an optically active imine represented by the general formula [4]
[0013]
[Chemical 7]

[0014]
Wherein, R ⁴ represents hydrogen, C _1-6 linear alkyl group, C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or, an unsubstituted or substituted heterocycle, is R _f, par A perfluoroalkylaldehyde hemiacetal or hydrate represented by the general formula [5] is condensed with an acidic condition and hydrolyzed under acidic conditions.
[0015]
[Chemical 8]

[0016]
[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R _f represents a perfluoroalkyl group, and * represents an asymmetric carbon.] is a method for producing an optically active perfluoroalkyl carbinol derivative represented by.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
Hereafter, the manufacturing method of the optically active perfluoroalkyl carbinol derivative of this invention is demonstrated in detail.
[0018]
The production method of the present invention includes a process for producing an optically active imine represented by the general formula [3] as a raw material, and a hemiacetal or hydrate of the perfluoroalkylaldehyde represented by the optically active imine and the general formula [4]. It consists of the process of condensing the product and hydrolyzing it under acidic conditions.
[0019]
In the pre-process of the present invention, the optically active imine represented by the general formula [3] can be produced industrially simply and efficiently by the following method.
[0020]
That is, it can be produced by dehydrating condensation of a ketone represented by the general formula [1] and an optically active primary amine represented by the general formula [2] under acidic conditions.
[0021]
Specific examples of the ketone represented by the general formula [1] include acetone, methyl ethyl ketone, methyl n-propyl ketone, methyl i-propyl ketone, pinacholine, methyl c-hexyl ketone, acetophenone, 2′-methylacetophenone, 4 '-Methylacetophenone, 2'-methoxyacetophenone, 4'-methoxyacetophenone, 2'-chloroacetophenone, 4'-chloroacetophenone, 2'-ethoxycarbonylacetophenone, 4'-ethoxycarbonylacetophenone, 2'-nitroacetophenone, 4' Examples include '-nitroacetophenone, 2', 4 ', 6'-trimethylacetophenone, 2-thienylmethylketone and the like.
[0022]
Specific examples of the optically active primary amine represented by the general formula [2] include 1-phenylethylamine, 1-1′-naphthylethylamine, 1-2′-naphthylethylamine, 1-c-hexylethylamine, and phenylglycine. Examples include methyl ester, valine methyl ester, and phenylglycinol. Among them, 1-phenylethylamine, 1-1′-naphthylethylamine, 1-2′-naphthylethylamine and phenylglycinol are preferable, and 1-phenylethylamine and 1-2′-naphthylethylamine are particularly preferable. In addition, since the optically active primary amine has an R-form or S-form, the optically active imine represented by the general formula [3] also has an R-form or S-form. May be appropriately determined according to the absolute configuration of the target product.
[0023]
The amount of the optically active primary amine represented by the general formula [2] is usually an equimolar reaction with respect to the ketone represented by the general formula [1]. 10 molar equivalents are preferred, with 1 to 5 molar equivalents being particularly preferred.
[0024]
Since this reaction is a dehydration condensation of the ketone represented by the general formula [1] and the optically active primary amine represented by the general formula [2], the reaction is carried out under acidic conditions while removing by-product water. Preferably, a water that is immiscible with water and has a specific gravity smaller than water and azeotropically with water is used to remove water by-produced in the Dean-Stark tube under reflux conditions.
[0025]
The solvent used may be any solvent that azeotropes with water, and is preferably an aromatic hydrocarbon such as benzene, toluene, ethylbenzene, and xylene, and more preferably toluene. These solvents can be used alone or in combination.
[0026]
As the amount of the solvent used, a solvent amount that can theoretically remove the amount of water by-produced azeotropically is required, but the amount used can be extremely reduced by using a Dean-Stark tube.
[0027]
Examples of the acid used in the dehydration condensation include organic acids such as p-toluenesulfonic acid and 10-camphorsulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Among these, p-toluenesulfonic acid and sulfuric acid are preferable, and p-toluenesulfonic acid is particularly preferable.
[0028]
The amount of acid used may be a catalytic amount with respect to the ketone represented by the general formula [1], preferably 0.001 to 1 molar equivalent, more preferably 0.005 to 0.5 molar equivalent. preferable.
[0029]
The temperature condition of the dehydration condensation may be performed in the range from the azeotropic temperature of the solvent to be used and water to the boiling point of the solvent, and particularly around the boiling point of the solvent to be used.
[0030]
In the post-treatment in the pre-process, a crude product can be obtained by performing a normal post-treatment operation after completion of the reaction. The crude product can be subjected to purification operations such as activated carbon, distillation, recrystallization, column chromatography, etc., if necessary, to obtain the target optically active imine represented by the general formula [3] with high purity. Further, it can be used in the subsequent process without isolation and purification. Specifically, the optical activity obtained by washing the reaction completion liquid or the reaction completion liquid with an aqueous alkali solution such as sodium bicarbonate or sodium hydroxide, drying over anhydrous magnesium sulfate or anhydrous sodium sulfate, and filtering. A toluene solution of imine or the like can be used in the subsequent process.
[0031]
In the subsequent process of the present invention, the optically active perfluoroalkyl carbinol derivative represented by the general formula [5] can be produced industrially simply and efficiently by the following method.
[0032]
That is, the optically active imine represented by the general formula [3] obtained by the previous process and the hemiacetal or hydrate of perfluoroalkyl aldehyde represented by the general formula [4] are condensed and hydrolyzed under acidic conditions. Can be manufactured.
[0033]
Specific examples of hemiacetals or hydrates of perfluoroalkyl aldehydes represented by the general formula [4] include fluoral methyl hemiacetal, fluoral ethyl hemiacetal, fluoral n-propyl hemiacetal, fluoral i -Propyl hemiacetal, fluoral hydrate, pentafluoropropionaldehyde / ethyl hemiacetal, pentafluoropropionaldehyde / hydrate, n-heptabutyraldehyde / ethyl hemiacetal, n-heptabutyraldehyde / hydrate, etc. Can be mentioned.
[0034]
The amount of the perfluoroalkylaldehyde hemiacetal or hydrate represented by the general formula [4] is usually 1 mole because the reaction is equivalent to the optically active imine represented by the general formula [3]. What is necessary is just to use 1 equivalent or more, and 1-10 molar equivalent is preferable, and 1-5 molar equivalent is more preferable especially.
[0035]
This condensation can be carried out without a solvent, but usually a solvent is used. Specific examples of the solvent used include aliphatic hydrocarbons such as n-pentane, n-hexane, c-hexane, and n-heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, and xylene, and methylene chloride. Halogenated hydrocarbons such as chloroform and 1,2-dichloroethane, diethyl ether, methyl-tert-butyl ether, ethers such as tetrahydrofuran and 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, acetonitrile, propio Examples include nitriles such as nitriles. Among these, n-hexane, benzene, toluene, methylene chloride, 1,2-dichloroethane, tetrahydrofuran and acetonitrile are preferable, and n-hexane and toluene are particularly preferable. These solvents can be used alone or in combination.
[0036]
There is no restriction | limiting in particular as the usage-amount of a solvent.
[0037]
The temperature condition of this condensation may be performed at a reaction temperature of −40 to 250 ° C., preferably −20 to 100 ° C., and more preferably −10 ° C. to 80 ° C.
[0038]
In the subsequent process of the present invention, hydrolysis is performed under acidic conditions after the condensation, which is represented by the general formula [6] generated by the condensation.
[0039]
[Chemical 9]

[0040]
[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R ² and R ³ represent a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocycle, an alkoxycarbonyl group, or a hydroxyalkyl group; ² and R ³ are not the same substituent at the same time, R _f represents a perfluoroalkyl group, and * represents an asymmetric carbon.] Oxetane represented by the general formula [7]
[0041]
Embedded image

[0042]
[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R ² and R ³ represent a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocycle, an alkoxycarbonyl group, or a hydroxyalkyl group; ² and R ³ are not simultaneously the same substituent, and R ⁴ is hydrogen, a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or Represents a substituted heterocycle, R _f represents a perfluoroalkyl group, and * represents an asymmetric carbon], or an N, O-acetal represented by the general formula [8]
[0043]
Embedded image

[0044]
[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R ² and R ³ represent a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocycle, an alkoxycarbonyl group, or a hydroxyalkyl group; ² and R ³ are not the same substituent at the same time, R _f represents a perfluoroalkyl group, and * represents an asymmetric carbon.] An imine represented by the general formula [5] This is for conversion to a fluoroalkyl carbinol derivative.
[0045]
Examples of the acid used in the hydrolysis include organic acids such as p-toluenesulfonic acid and 10-camphorsulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Among these, hydrochloric acid and sulfuric acid are preferable, and hydrochloric acid is more preferable.
[0046]
The acid concentration may be 0.1 to 12N, preferably 0.2 to 6N, and more preferably 0.5 to 2N.
[0047]
The amount of the acid used may be 0.1 to 20 molar equivalents with respect to the optically active imine represented by the general formula [3], preferably 0.2 to 10 molar equivalents, particularly 0.5 to 8 molar equivalents are more preferred.
[0048]
The temperature condition of the hydrolysis may be performed near room temperature, can be efficiently performed under heating conditions, and can be performed at a sufficient reaction rate even under cooling conditions.
[0049]
In the post-treatment in the post-process, a crude product can be obtained by performing a normal post-treatment operation after the reaction is completed. The crude product is subjected to purification operations such as activated carbon, distillation, recrystallization, column chromatography, etc. as necessary to obtain the target optically active perfluoroalkylcarbinol derivative represented by the general formula [5] with high purity. be able to.
[0050]
In addition, the optically active primary amine represented by the general formula [2] by-produced by hydrolysis can be recovered and reused. For example, a crude optically active primary amine can be recovered from an acidic aqueous layer obtained by post-treatment by an operation such as neutralization and extraction. If necessary, the crudely recovered product can be subjected to purification operations such as activated carbon, distillation, recrystallization, column chromatography, etc., and the optically active primary amine can be recovered with high purity. The optical purity of the recovered optically active primary amine is not lowered, and can be repeatedly reused for the synthesis of the optically active imine represented by the general formula [3] in the preceding process.
[0051]
【Example】
Hereinafter, the embodiments of the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
[0052]
[1] Production of optically active imine [Example 1]
To a toluene (150 ml) solution containing acetophenone (1a, 50 mmol) as a ketone and (R) -1-phenylethylamine ((R) -2a, 100 mmol) as an optically active primary amine, p-toluenesulfonic acid monohydrate ( 0.5 mmol) was added, and the mixture was heated to reflux for 24 hours. The reaction-terminated liquid was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum-dried to obtain a crude product. The crude product was distilled under reduced pressure (143 ° C./6 mmHg) to obtain (R) -N- (1-phenylethylidene) -1-phenylethylamine ((R) -3aa, 39 mmol, 78%) as an optically active imine.
[0053]
[Example 2]
To a toluene (150 ml) solution containing acetophenone (1a, 50 mmol) as a ketone and (R) -1-2′-naphthylethylamine ((R) -2b, 100 mmol) as an optically active primary amine, p-toluenesulfonic acid monohydrate A Japanese product (0.5 mmol) was added, and the mixture was heated to reflux for 24 hours, and water produced as a by-product was removed with a Dean-Stark tube. The reaction-terminated liquid was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum-dried to obtain a crude product. The crude product was distilled under reduced pressure to obtain (R) -N- (1-phenylethylidene) -1-2'-naphthylethylamine ((R) -3ab, 40.5 mmol, 81%) as an optically active imine.
[0054]
[Examples 3 to 7]
The same experimental operation as in Example 1 was performed, and these results were summarized as runs 2 and 4-7 in Table 1. In the table, runs 1 and 3 correspond to Example 1 and Example 2, respectively.
[0055]
Embedded image

[0056]
[Table 1]

[0057]
[2] Production of optically active perfluoroalkyl carbinol derivative [Example 8]
N-hexane (2 ml) solution containing (R) -N- (1-phenylethylidene) -1-phenylethylamine ((R) -3aa, 0.5 mmol) and fluoroethyl hemiacetal (4a, 0.5 mmol) After stirring at 18-19 ° C. for 7 hours, 2 ml of 1.5N HCl was added and stirred at room temperature for 1 hour. The reaction-terminated liquid was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and vacuum dried to obtain a crude product.
[0058]
The crude product was purified by column chromatography (ethyl acetate: n-hexane = 1: 5), and (S) -4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butanone ((S) -5aa, 0.31 mmol, 62%). The optical purity was determined to be 60% ee by chiral HPLC (Daicel OD, n-hexane / i-propanol = 95/5, 254 nm) analysis.
[0059]
[Example 9]
N-hexane ((R) -N- (1-phenylethylidene) -1-2'-naphthylethylamine ((R) -3ab, 0.5 mmol) and fluoroethyl hemiacetal (4a, 0.5 mmol) ( 2 ml) The solution was stirred for 168 hours at −2 ° C., 2 ml of 1.5N HCl was added, and the mixture was stirred at room temperature for 1 hour. The reaction-terminated liquid was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and vacuum dried to obtain a crude product.
[0060]
The crude product was purified by column chromatography (ethyl acetate: n-hexane = 1: 5), and (S) -4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butanone ((S) -5aa, 0.285 mmol, 57%). The optical purity was determined to be 81% ee by the analysis described in Example 8.
[0061]
[Examples 10 to 26]
The same experimental operation as in Example 8 was performed, and these results were summarized as runs 8, 10-18, and 20-26 in Table 2. In the table, runs 9 and 19 correspond to Example 8 and Example 9, respectively.
[0062]
Embedded image

[0063]
[Table 2]

[0064]
[Example 27]
Recovery and reuse of (R) -1-phenylethylamine ((R) -2a) The hydrochloric acid aqueous layer obtained in the post-treatment of Example 8 was made alkaline with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried to recover a crude product. The crude product was distilled under reduced pressure to recover (R) -1-phenylethylamine ((R) -2a, 0.4 mmol, 80%). The optical purity of the recovered optically active primary amine is not lowered at 98.5% ee (R), and the same experimental results are obtained by performing the same experimental operation as in Example 1 and subsequently in Example 8. It was confirmed.
[0065]
【The invention's effect】
Industrial production of optically active perfluoroalkyl carbinol derivatives, precursors of optically active 3-perfluoroalkyl-3-hydroxypropionic acid derivatives, which are important intermediates for functional materials such as pharmaceuticals, agricultural chemicals and ferroelectric liquid crystals Is simple and efficient.

Claims (4)

General formula [3]

[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R ² and R ³ represent a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocycle, an alkoxycarbonyl group, or a hydroxyalkyl group; ² and R ³ are not the same substituent at the same time, * represents an asymmetric carbon, and an optically active imine represented by the general formula [4]

Wherein, R ⁴ represents hydrogen, C _1-6 linear alkyl group, C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or, an unsubstituted or substituted heterocycle, is R _f, par A perfluoroalkylaldehyde hemiacetal or hydrate represented by the general formula [5] is condensed with an acidic condition and hydrolyzed under acidic conditions.

[Wherein, R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, R ¹ represents hydrogen , R _f represents a perfluoroalkyl group, and * represents an asymmetric carbon]. A method for producing an optically active perfluoroalkylcarbinol derivative represented by: The optically active imine represented by the general formula [3] according to claim 1 is represented by the general formula [1].

[Wherein R represents a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heterocycle, and R ¹ represents hydrogen ] The ketone shown and the general formula [2]

[R ² and R ³ represent a C _1-6 chain alkyl group, a C _3-8 cyclic alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heterocycle, an alkoxycarbonyl group, or a hydroxyalkyl group. And R ² and R ³ are not the same substituent at the same time, and * represents an asymmetric carbon.] Is an optically active imine obtained by dehydration condensation of an optically active primary amine represented by Item 2. The manufacturing method according to Item 1. 3. The production method according to claim 2, wherein the optically active imine represented by the general formula [3] is not isolated and purified.   The production method according to claim 2, wherein the optically active primary amine represented by the general formula [2] is recovered and reused.