JP4085601B2 - Process for producing optically active pyridyl alcohols - Google Patents

Description

【０００６】
（式中、Ｒ^１ は置換基を有していてもよい低級アルキル基またはハロゲン原子を表し、ｎは３〜５の整数を表す。）
で示される(±)−trans −２−（２−ピリジル）シクロアルカン−１−オール類と、一般式[II]
【化１１】

【０００７】
（式中、１位のカルボキシル基またはその誘導基とこれに隣接する２位のメチル基の立体配置はcis であり、Ｘは水酸基、アルコキシ基またはハロゲン原子を表し、Ｒ^２ およびＲ^３ は、同一または異なって、置換基を有していてもよいアルキル基を表す。Ｒ^２ およびＲ^３ は、互いに結合して、炭素−炭素二重結合を有していてもよい単環または縮合環を形成する炭化水素基であってもよい。）で示される絶対配置既知の光学活性カルボン酸またはその誘導体とをエステル化反応により縮合し、一般式[III]
【化１２】

【０００８】
（式中、Ｒ^１ 、Ｒ^２ 、Ｒ^３ およびｎは上記式のものと同じ意味を表す。）で示される縮合体のジアステレオマー対を得た後、これを水不溶性の有機溶媒に溶解し、得られた有機溶液を酸性水溶液で洗浄することによって一方のジアステレオマーを有機層に他方のジアステレオマーを水層にそれぞれ分配し、得られた各ジアステレオマーのエステル結合を還元するかまたは加水分解して、対応する光学活性trans −２−（２−ピリジル）シクロアルカン−１−オールを得ることを特徴とする方法である。
【０００９】
本発明は、また、一般式[VII]
【化１３】

【００１０】
（式中、Ｒ^１ は置換基を有していてもよい低級アルキル基またはハロゲン原子を表す。Ｒ^２ およびＲ^３ は、同一または異なって、置換基を有していてもよいアルキル基を表す。Ｒ^２ およびＲ^３ は、互いに結合して、炭素−炭素二重結合を有していてもよい単環または縮合環を形成する炭化水素基であってもよい。ｎは３〜５の整数を表す。）
で示される新規ピリジルアルコール類のエステルを提供する。
【００１１】
上記ピリジルアルコール類のエステル[VII] は、一般式[Ｉ]
【化１４】

【００１２】
（式中、Ｒ^１ は置換基を有していてもよい低級アルキル基またはハロゲン原子を表し、ｎは３〜５の整数を表す。）
で示される２−（２−ピリジル）シクロアルカン−１−オール類と、
一般式[VI]
【化１５】

【００１３】
（式中、Ｘは水酸基、アルコキシ基またはハロゲン原子を表し、Ｒ^２ およびＲ^３ は、同一または異なって、置換基を有していてもよいアルキル基を表す。Ｒ^２ およびＲ^３ は、互いに結合して、炭素−炭素二重結合を有していてもよい単環または縮合環を形成する炭化水素基であってもよい。）
で示されるカルボン酸またはその誘導体とをエステル化反応により縮合することにより得ることができる。
【００１４】
【発明の実施の形態】
本発明方法により分割されるべきラセミ体は、一般式[Ｉ]で示される(±)−trans −２−（２−ピリジル）シクロアルカン−１−オール類である。ここで、ｎは３〜５の整数を表すが、特に４が好ましい。Ｒ^１ は、置換基を有していてもよい低級アルキル基、またはハロゲン原子を表すが、低級アルキル基としてはメチル基、エチル基などの炭素数１〜３のアルキル基が好ましく、ハロゲン原子としては塩素、臭素が好ましい。Ｒ^１ は好ましくは水素原子、メチル基または塩素原子である。ピリジン環上のＲ^１ の位置は好ましくは４位である。
【００１５】
一方、ジアステレオマー体を形成するために用いる光学活性体は、上記一般式[II]で示される絶対配置既知の光学活性カルボン酸またはその誘導体であり、好ましくは一般式[IV]
【化１６】

【００１６】
（式中、１３位のメチル基と１７位のカルボキシル基またはその誘導基の立体配置はcis であり、１３位および１７位以外の環形成炭素原子は置換基を有していてもよく隣接炭素間に二重結合を有していてもよい。Ｘは水酸基、アルコキシ基またはハロゲン原子を表す。）
で示されるステロイド骨格を有する絶対配置既知の光学活性カルボン酸またはその誘導体であり、さらに好ましくは一般式[Ｖ]
【化１７】

【００１７】
（式中、Ｘは水酸基、アルコキシ基またはハロゲン原子を表す。）
で示される３β−アセトキシ−Δ５−エチオコレン酸(3β-acetoxy-Δ5-etiocholenic acid)またはその誘導体である。
【００１８】
一般式[Ｉ]で示される(±)−trans −２−（２−ピリジル）シクロアルカン−１−オール類と一般式[II]で示される光学活性カルボン酸またはその誘導体とを縮合させる方法は特に限定されず、例えば前者の化合物[Ｉ]とカルボン酸の酸塩化物とを、塩基性条件下でまたはカルボジイミド類等の脱水縮合剤の存在下で、エステル化反応させることにより縮合する方法等がある。
【００１９】
縮合によって得られた縮合体[III] のジアステレオマーを溶解する有機溶媒としては、水と混合しないものであれば特に限定されず、ヘキサンやヘプタン等の脂肪族炭化水素類、ジエチルエーテル、ジブチルエーテル、ジイソプロピルエーテル、tert−ブチルメチルエーテル、ジブチルエーテル等のエーテル類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、クロロホルム、塩化メチレン、１，２−ジクロロエタン等のハロゲン化炭化水素類、ｎ−ブチルアルコール、ｎ−ヘキサノール、シクロヘキサノール等のアルコール類、またはこれらの混合溶媒が挙げられるが、エーテル類が好ましく、特に好ましくはジエチルエーテルである。
【００２０】
有機溶液の洗浄に用いられる酸性水溶液としては、塩酸、硫酸、硝酸等の鉱酸の水溶液が好ましく、特に好ましくは塩酸水溶液である。
【００２１】
有機層と水層に各々分配された各ジアステレオマーを光学活性trans −２−（２−ピリジル）シクロアルカン−１−オールへと変換する方法としては、水素化アルミニウムリチウムや水素化ジイソブチルアルミニウム、水素化ホウ素リチウムなどの還元剤を用いてエステル結合を還元する方法や、酸あるいは塩基の存在下でエステル結合を加水分解する方法が挙げられる。前者の方法が好ましく、特に還元剤としては水素化アルミニウムリチウムや水素化ジイソブチルアルミニウムを用いる方法が好ましい。
【００２２】
また、カルボン酸またはその誘導体[VI]、およびピリジルアルコール類のエステル[VII] における、Ｒ^１ 、Ｒ^２ 、Ｒ^３ 、Ｘおよびｎは上述したものと同じであってよい。２−（２−ピリジル）シクロアルカン−１−オール類[Ｉ]とカルボン酸またはその誘導体[VI]のエステル化反応は、上述したように、例えば前者の化合物[Ｉ]とカルボン酸の酸塩化物とを、塩基性条件下でまたはカルボジイミド類等の脱水縮合剤の存在下で、エステル化反応させることにより縮合する方法等であってよい。
【００２３】
ピリジルアルコール類のエステル[VII] は新規化合物である。このうち、ピリジルアルコール類部分の水酸基とピリジル基がtrans に位置し、カルボン酸（またはその誘導体）部分の１位のカルボキシル基またはその誘導基とこれに隣接する２位のメチル基の立体配置がcis である化合物は、上述したように、(±)−trans −２−（２−ピリジル）シクロアルカン−１−オール類の光学分割工程中に得られる縮合体のジアステレオマーであって有用であり、特に(±)−trans −２−（２−ピリジル）シクロアルカン−１−オール類[Ｉ]と、ステロイド骨格を有する化合物［IV］のエステルが好ましく、(±)−trans −２−（２−ピリジル）シクロアルカン−１−オール類[Ｉ]と、３β−アセトキシ−Δ５−エチオコレン酸またはその誘導体［Ｖ］のエステルが最も好ましい。
【００２４】
【実施例】
以下の実施例により本発明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。
【００２５】
実施例１
３β−アセトキシ−Δ５−エチオコレン酸クロライド（２．１９ｇ，５．７７ｍｍｏｌ）を塩化メチレン（１０ｍＬ）に溶解し、これにトリエチルアミン（０．６４ｍＬ，４．６２ｍｍｏｌ）と、(±)−trans −２−（２−ピリジル）シクロヘキサン−１−オール（６８２ｍｇ，３．８５ｍｍｏｌ）の塩化メチレン溶液（２ｍＬ）を氷冷下で加え、さらに塩化メチレン（８ｍＬ）を追加した後、全体を室温で６８時間撹拌した。反応液を水洗した後、塩化メチレンを留去し、得られた残渣をカラムクロマトグラフィー（溶離剤：ヘキサン／酢酸エチル＝５／１）により精製することにより、化学式[VIII]で示される縮合体（trans −２−［（２−ピリジル）シクロヘキシル］−Δ５−３β−アセトキシエチオコレン酸エステル）をジアステレオマー混合物として１．８４ｇ（９０％）得た。
【００２６】
【化１８】

【００２７】
このジアステレオマー混合物を単離、精製して、下記の特性を有する（１Ｓ，２Ｒ）体と（１Ｒ，２Ｓ）体を得た。
【００２８】
（１Ｓ，２Ｒ）体
白色結晶；
ｍ．ｐ．：１２６．０−１２９．０℃（ジエチルエーテル−ヘキサン）；
[α]_Ｄ ^２８：＋２２．３（ｃ０．６３，ＣＨＣｌ_３ ）；
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３ ）δ：８．５２（ｄ，Ｊ＝４．５Ｈｚ，１Ｈ），７．５７（ｔｄ，Ｊ＝７．７ and １．８Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．０９（ｄｄｄ，Ｊ＝７．７，４．５ and ０．８Ｈｚ，１Ｈ），５．３３（ｄ，Ｊ＝４．２Ｈｚ，１Ｈ），５．２４（ｔｄ，Ｊ＝１０．８ and ４．３Ｈｚ，１Ｈ），４．５８（ｍ，１Ｈ），２．９１（ｔｄ，Ｊ＝１１．５ and ３．５Ｈｚ，１Ｈ），２．３１−０．８４（ｍ，２８Ｈ），２．０３（ｓ，３Ｈ），０．９５（ｓ，３Ｈ），０．１１（ｓ，３Ｈ）；
ＩＲ（ＫＢｒ）：１７３２ｃｍ^−１；
ＭＳ ＥＩ（＋）ｍ／ｚ：５２０［（Ｍ＋Ｈ）^＋，３］，５１９（Ｍ^＋，３），４６０（２２），４５９（５９），３００（９），１７６（５６），１７５（３２），１６１（１９），１６０（１００），１５９（２０），９３（１８），８１（２６）；
ＨＲＭＳ：Ｃ_３３Ｈ_４５ＮＯ_４（Ｍ^＋）としての計算値：５１９．３３４８、実測値：５１９．３３６７；
元素分析：Ｃ_３３Ｈ_４５ＮＯ_４としての計算値：Ｃ，７６．２６；Ｈ，８．７３；Ｎ，２．７０、実測値：Ｃ，７６．０６；Ｈ，８．７２；Ｎ，２．６２；
【００２９】
（１Ｒ，２Ｓ）体
白色結晶；
ｍ．ｐ．：１４９．５−１５０．０℃（ジエチルエーテル−ヘキサン）；
[α]_Ｄ ^２８：−７０．７（ｃ０．５９，ＣＨＣｌ_３ ）；
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３ ）δ：８．５１（ｄ，Ｊ＝４．４Ｈｚ，１Ｈ），７．５６（ｔｄ，Ｊ＝７．７ and １．８Ｈｚ，１Ｈ），７．１３（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．０９（ｄｄｄ，Ｊ＝７．７，４．４ and ０．９Ｈｚ，１Ｈ），５．３４（ｄ，Ｊ＝４．４Ｈｚ，１Ｈ），５．１３（ｔｄ，Ｊ＝１１．０ and ４．２Ｈｚ，１Ｈ），４．５９（ｍ，１Ｈ），２．８８（ｔｄ，Ｊ＝１１．０ and ３．６Ｈｚ，１Ｈ），２．３２−０．８８（ｍ，２８Ｈ），２．０３（ｓ，３Ｈ），０．９９（ｓ，３Ｈ），０．４６（ｓ，３Ｈ）；
ＩＲ（ＫＢｒ）：１７３２ｃｍ^−１；
ＭＳ ＥＩ（＋）ｍ／ｚ：５２０［（Ｍ＋Ｈ）^＋，１］，５１９（Ｍ^＋，１），４６０（３５），４５９（１００），３００（６），１７６（４０），１６１（１６），１６０（９７），１５９（１５），９３（１１），８１（８）；
ＨＲＭＳ：Ｃ_３３Ｈ_４５ＮＯ_４（Ｍ^＋）としての計算値：５１９．３３４８、実測値：５１９．３３５８；
元素分析：Ｃ_３３Ｈ_４５ＮＯ_４としての計算値：Ｃ，７６．２６；Ｈ，８．７３；Ｎ，２．７０ 、実測値：Ｃ，７５．９６；Ｈ，８．６２；Ｎ，２．７０；
【００３０】
このジアステレオマー混合物（３００ｍｇ）をジエチルエーテル（５０ｍＬ）に溶解し、得られた有機溶液を３％塩酸水溶液（２０ｍＬ）で洗浄した。有機層と水層を分離し、有機層は炭酸ナトリウムで乾燥し、ジエチルエーテルを留去した後に残渣を再度ジエチルエーテル（３７ｍＬ）に溶解し、得られた有機溶液を７％塩酸（１５ｍＬ）で洗浄した。その後、有機層を上記と同様に処理することによって一方のジアステレオマーを５７ｍｇ（４４％，８１％ｄｅ）得た。水層は炭酸水素ナトリウムでｐＨ８に調整した後、吸引ろ過により他方のジアステレオマーを７５ｍｇ（２3％，９３％ｄｅ）回収した。
【００３１】
有機層より得られた一方のジアステレオマー（８１％ｄｅ，５７ｍｇ，０．１１ｍｍｏｌ）のＴＨＦ溶液（１ｍＬ）を水素化アルミニウムリチウム（４２ｍｇ，１．１０ｍｍｏｌ）のＴＨＦ懸濁液（１ｍＬ）に氷冷下でゆっくり滴下し、さらにＴＨＦ（３ｍＬ）を追加した後、全体を室温で２時間撹拌した。反応液を氷冷した後、飽和硫酸ナトリウム水溶液を滴下してしばらく撹拌した後、反応液を炭酸カリウムで乾燥した。乾燥剤を除去し、塩化メチレンで洗浄した後、洗浄溶液を濃縮し、残渣を再度塩化メチレンに溶解し、得られた有機溶液を５％塩酸水溶液で洗浄した。塩酸水溶液層を炭酸カリウムでアルカリ性（ｐＨ１２）とし、塩化メチレンで抽出し、有機層を炭酸ナトリウムで乾燥し、乾燥剤を除去し、塩化メチレンを留去した。得られた残渣をカラムクロマトグラフィー（溶離剤剤：ヘキサン／酢酸エチル＝１／１）により精製し、(＋)−trans −２−（２−ピリジル）シクロヘキサン−１−オールを１３ｍｇ（６８％，７７％ｅｅ）得た。
【００３２】
水層より得られた他方のジアステレオマー（９３％ｄｅ，６０ｍｇ，０．１２ｍｍｏｌ）も上記と同様の操作で処理することによって(−)−trans −２−（２−ピリジル）シクロヘキサン−１−オールを１８ｍｇ（９０％，９３％ｅｅ）得た。
【００３３】
(＋)−trans −２−（２−ピリジル）シクロヘキサン−１−オール
白色結晶；
ｍ．ｐ．：６２．５−６５．０℃；
[α]_Ｄ ^２８：＋２０．４（ｃ０．４９，ＣＨＣｌ_３ ）；
光学純度：７７％ｅｅ［ＨＰＬＣ分析（ダイセル社製、「Chiralcel OD」；ヘキサン／イソプロパノール＝９５／５；流量：１．０ｍＬ／分；２５℃；保持時間：９．９分）により測定した。］
【００３４】
(−)−trans −２−（２−ピリジル）シクロヘキサン−１−オール
白色結晶；
ｍ．ｐ．：８１．０−８２．５℃；
[α]_Ｄ ^２７：−２３．５（ｃ０．５３，ＣＨＣｌ_３ ）；
光学純度：９３％ｅｅ［ＨＰＬＣ分析（ダイセル社製、「Chiralcel OD」；ヘキサン／イソプロパノール＝９５／５；流量：１．０ｍＬ／分；２５℃；保持時間：１４．２分）により測定した。］
【００３５】
実施例２
３β−アセトキシ−Δ５−エチオコレン酸クロライド（１．１６ｇ，３．０５ｍｍｏｌ）を塩化メチレン（８ｍＬ）に溶解し、これにトリエチルアミン（０．３４ｍＬ，２．４４ｍｍｏｌ）と、(±)−trans −２−（４−メチル−２−ピリジル）シクロヘキサン−１−オール（３８９ｍｇ，２．０３ｍｍｏｌ）の塩化メチレン溶液（２ｍＬ）を氷冷下で加え、さらに塩化メチレン（６ｍＬ）を追加した後、全体を室温で１９時間撹拌した。反応液を水洗した後、塩化メチレンを留去し、得られた残渣をカラムクロマトグラフィー（溶離剤：ヘキサン／酢酸エチル＝５／１）により精製し、化学式[IX]で示される縮合体（trans −２−［（４−メチル−２−ピリジルシ）クロヘキシル］−Δ５−３β−アセトキシエチオコレン酸エステル）をジアステレオマー混合物として９３４ｍｇ（８６％）を得た。
【００３６】
【化１９】

【００３７】
このジアステレオマー混合物を単離、精製して、下記の特性を有する（１Ｓ，２Ｒ）体と（１Ｒ，２Ｓ）体を得た。
【００３８】
（１Ｓ，２Ｒ）体
無色結晶；
ｍ．ｐ．：１９９．０−２０２．０℃（酢酸エチル−ヘキサン）；
[α]_Ｄ ^２９＝＋１９．２（ｃ０．５１，ＣＨＣｌ_３ ）；
^１ Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：８．３７（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９９（ｓ，１Ｈ），６．９１（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３３（ｄ，Ｊ＝４．４Ｈｚ，１Ｈ），５．２２（ｔｄ，Ｊ＝１０．７ and ４．３Ｈｚ，１Ｈ），４．５８（ｍ，１Ｈ），２．８６（ｔｄ，Ｊ＝１１．４ and３．４Ｈｚ，１Ｈ），２．３０−０．８４（ｍ，２８Ｈ），２．３０（ｓ，３Ｈ），２．０３（ｓ，３Ｈ），０．９５（ｓ，３Ｈ），０．１０（ｓ，３Ｈ）；
ＩＲ（ＫＢｒ）：１７３２，１７２１ｃｍ^−１；
ＭＳ ＥＩ（＋）ｍ／ｚ：５３４［（Ｍ＋Ｈ）^＋，４］，５３３（Ｍ^＋，１０），４７４（３６），４７３（１００），３００（９），１９０（３４），１７５（１２），１７４（７１），１７３（１４）；
ＨＲＭＳ：Ｃ_３４Ｈ_４７ＮＯ_４（Ｍ^＋）としての計算値：５３３．３５０５、実測値：５３３．３４９９；
元素分析：Ｃ_３４Ｈ_４７ＮＯ_４としての計算値：Ｃ，７６．５１；Ｈ，８．８８；Ｎ，２．６２ 、実測値：Ｃ，７６．３３；Ｈ，８．７４；Ｎ，２．６２；
【００３９】
（１Ｒ，２Ｓ）体
白色結晶；
ｍ．ｐ．：１４９．０−１５１．０℃（酢酸エチル−ヘキサン）；
^１ Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：８．３６（ｄ，Ｊ＝４．７Ｈｚ，１Ｈ），６．９４（ｓ，１Ｈ），６．９０（ｄ，Ｊ＝４．７Ｈｚ，１Ｈ），５．３５（ｄ，Ｊ＝４．８Ｈｚ，１Ｈ），５．１１（ｔｄ，Ｊ＝１０．３ and ４．３Ｈｚ，１Ｈ），４．５９（ｍ，１Ｈ），２．８６（ｔｄ，Ｊ＝１１．４ and３．３Ｈｚ，１Ｈ），２．３０（ｓ，３Ｈ），２．２１−０．８８（ｍ，２８Ｈ），２．０３（ｓ，３Ｈ），１．００（ｓ，３Ｈ），０．４６（ｓ，３Ｈ）；
ＩＲ（ＫＢｒ）：１７３２ｃｍ^−１;
元素分析：Ｃ_３４Ｈ_４７ＮＯ_４としての計算値：Ｃ，７６．５１；Ｈ，８．８８；Ｎ，２．６２ 、実測値：Ｃ，７６．３３；Ｈ，８．８７；Ｎ，２．５８；
【００４０】
このジアステレオマー混合物（３０７ｍｇ）をジエチルエーテル（５１ｍＬ）に溶解し、得られた有機溶液を２％塩酸水溶液（２１ｍＬ）で洗浄した。有機層と水層を分離した後、有機層は炭酸ナトリウムで乾燥し、ジエチルエーテルを留去することにより一方のジアステレオマーを１７２ｍｇ（５６％，６７％ｄｅ）得た。水層は炭酸水素ナトリウムでｐＨ８に調整した後、吸引ろ過により他方のジアステレオマーを１３６ｍｇ（４４％，８２％ｄｅ）回収した。
【００４１】
有機層より得られた一方のジアステレオマー（６７％ｄｅ，８５ｍｇ，０．１６ｍｍｏｌ）のＴＨＦ溶液（１ｍＬ）を水素化アルミニウムリチウム（６０ｍｇ，１．６０ｍｍｏｌ）のＴＨＦ懸濁液（１ｍＬ）に氷冷下でゆっくり滴下し、ＴＨＦ（３ｍＬ）を追加した後、全体を室温で２時間撹拌した。反応液を氷冷した後、飽和硫酸ナトリウム水溶液を滴下してしばらく撹拌した後、反応液を炭酸カリウムで乾燥した。乾燥剤を除去し、塩化メチレンで洗浄した後溶液を濃縮し、残渣を再度塩化メチレンに溶解し、得られた有機溶液を５％塩酸水溶液で洗浄した。塩酸水溶液層を炭酸カリウムでアルカリ性（ｐＨ１２）とし、塩化メチレンで抽出し、有機層を炭酸ナトリウムで乾燥し、乾燥剤を除去し、塩化メチレンを留去した。得られた残渣をカラムクロマトグラフィー（溶離剤：ヘキサン／酢酸エチル＝１／１）により精製し、(＋)−（１Ｓ，２Ｒ）−２−（４−メチル−２−ピリジル）シクロヘキサン−１−オールを２５ｍｇ（８３％，６４％ｅｅ）得た。
【００４２】
水層より得られた他方のジアステレオマー（８２％ｄｅ，８０ｍｇ，０．１５ｍｍｏｌ）も上記と同様の操作で処理することによって(−)−（１Ｒ，２Ｓ）−２−（４−メチル−２−ピリジル）シクロヘキサン−１−オールを２６ｍｇ（９０％，７９％ｅｅ）得た。
【００４３】
(＋)−（１Ｓ，２Ｒ）−２−（４−メチル−２−ピリジル）シクロヘキサン−１−オール
白色結晶；
ｍ．ｐ．：１００．０−１０２．０℃；
[α]_Ｄ ^２７：＋１７．０（ｃ０．５３，ＣＨＣｌ_３ ）；
光学純度：６４％ｅｅ［ＨＰＬＣ分析（ダイセル社製、「Chiralcel OD」；ヘキサン／イソプロパノール＝９５／５；流量：１．０ｍＬ／分；２５℃；保持時間：８．９分）により測定した。］
【００４４】
(−)−（１Ｒ，２Ｓ）−２−（４−メチル−２−ピリジル）シクロヘキサン−１−オール
白色結晶；
ｍ．ｐ．：９３．５−９５．０℃;
[α]_Ｄ ^２９：−２４．８（ｃ０．５６，ＣＨＣｌ_３ ）；
光学純度：８０％ｅｅ［ＨＰＬＣ分析（ダイセル社製、「Chiralcel OD」；ヘキサン／イソプロパノール＝９５／５；流量：１．０ｍＬ／分；２５℃；保持時間：１１．０分）により測定した。］
【００４５】
実施例３
３β−アセトキシ−Δ５−エチオコレン酸クロライド（１．３７ｇ，３．６１ｍｍｏｌ）を塩化メチレン（８ｍＬ）に溶解し、これにトリエチルアミン（０．４０ｍｌ，２．８８ｍｍｏｌ）と、(±)−trans −２−（４−クロロ−２−ピリジル）シクロヘキサン−１−オール（５０９ｍｇ，２．４０ｍｍｏｌ）の塩化メチレン溶液（２ｍｌ）を氷冷下で加え、さらに塩化メチレン（５ｍＬ）を追加した後、全体を室温で１８．５時間撹拌した。反応液を水洗した後、塩化メチレンを留去し、得られた残渣をカラムクロマトグラフィー（溶離剤：ヘキサン／酢酸エチル＝７／１）により精製し、化学式[Ｘ]で示される縮合体（trans −２−［（４−クロロ−２−ピリジル）シクロヘキシル］−Δ５−３β−アセトキシエチオコレン酸エステル）をジアステレオマー混合物として１．２２ｇ（９６％）を得た。
【００４６】
【化２０】

【００４７】
（１Ｓ，２Ｒ）体と（１Ｒ，２Ｓ）体の混合物
白色結晶；
ｍ．ｐ．：６１．０−６３．０℃；
^１ Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ：８．４３（ｄ，Ｊ＝５．３Ｈｚ，１Ｈ），８．４２（ｄ，Ｊ＝５．１Ｈｚ，１Ｈ），７．２０（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．１５（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．１２（ｄｄ，Ｊ＝５．３ and ２．０Ｈｚ，１Ｈ），７．１２（ｄｄ，Ｊ＝５．１ and ２．１Ｈｚ，１Ｈ），５．３４（ｍ，１Ｈ），５．１９（ｔｄ，Ｊ＝１０．６ and ４．２Ｈｚ，１Ｈ），５．０８（ｔｄ，Ｊ＝１０．４ and ４．２Ｈｚ，１Ｈ），４．５８（ｍ，１Ｈ），２．８６（ｍ，１Ｈ），２．３１−０．８４（ｍ，２８Ｈ），２．０３（ｓ，３Ｈ），１．００（ｓ，３Ｈ），０．９６（ｓ，３Ｈ），０．４８（ｓ，３Ｈ），０．１３（ｓ，３Ｈ）；
ＩＲ（ＫＢｒ）：１７３２ｃｍ^−１；
【００４８】
このジアステレオマー混合物（３１９ｍｇ）をジエチルエーテル（５３ｍＬ）に溶解し、得られた有機溶液を１５％塩酸水溶液（２１ｍＬ）で洗浄した。有機層と水層を分離した後、有機層は炭酸ナトリウム乾燥し、ジエチルエーテルを留去することにより一方のジアステレオマーを１３４ｍｇ（４２％，８２％ｄｅ）得た。水層は炭酸水素ナトリウムでｐＨ８に調整した後、吸引ろ過により他方のジアステレオマーを１７９ｍｇ（５６％，５４％ｄｅ）回収した。
【００４９】
有機層より得られた一方のジアステレオマー（８２％ｄｅ，６０ｍｇ，０．１１ｍｍｏｌ）の塩化メチレン溶液（１．５ｍＬ）に水素化ジイソブチルアルミニウムのヘキサン溶液（０．９５Ｍ，０．５７ｍＬ，０．５４ｍｍｏｌ）を−２０℃下でゆっくり滴下し、塩化メチレン（１ｍＬ）を追加した後、徐々に温度を上げ、全体を２時間撹拌した。反応液を氷冷した後、精製水を滴下してしばらく撹拌し、セライトろ過により白色沈殿物を除去し、濾液を濃縮した。残渣を再度塩化メチレンに溶解し、得られた有機溶液を５％塩酸水溶液で洗浄した。塩酸水溶液層を炭酸カリウムでアルカリ性（ｐＨ１２）とし、塩化メチレンで抽出し、有機層を炭酸ナトリウムで乾燥し、乾燥剤を除去し、塩化メチレンを留去した。得られた残渣をカラムクロマトグラフィー（溶離剤：ヘキサン／酢酸エチル＝２／１）により精製し、(＋)−trans −２−（４−クロロ−２−ピリジル）シクロヘキサン−１−オールを１６ｍｇ（７０％，７９％ｅｅ）得た。
【００５０】
水層より得られた他方のジアステレオマー（５４％ｄｅ，４６ｍｇ，０．０８ｍｍｏｌ）も上記と同様の操作で処理することにより(−)−trans −２−（４−クロロ−２−ピリジル）シクロヘキサン−１−オールを１６ｍｇ（８９％，５０％ｅｅ）得た。
【００５１】
(＋)−trans −２−（４−クロロ−２−ピリジル）シクロヘキサン−１−オール白色結晶；
ｍ．ｐ．：８４．５−８６．０℃;
[α]_Ｄ ^２８：＋３０．６（ｃ０．９２，ＣＨＣｌ_３ ）；
光学純度：７９％ｅｅ［ＨＰＬＣ分析（ダイセル社製、「Chiralcel OD」；ヘキサン／イソプロパノール＝９５／５；流量：１．０ｍＬ／分；２５℃；保持時間：８．４分）により測定した。］
【００５２】
(−)−trans −２−（４−クロロ−２−ピリジル）シクロヘキサン−１−オール白色結晶；
ｍ．ｐ．：８２．５−８５．０℃;
[α]_Ｄ ^２８：−２０．５（ｃ０．７２，ＣＨＣｌ_３ ）；
光学純度：５０％ｅｅ［ＨＰＬＣ分析（ダイセル社製、「Chiralcel OD」；ヘキサン／イソプロパノール＝９５／５；流量：１．０ｍＬ／分；２５℃；保持時間：９．７分）により測定した。］[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing optically active trans-2- (2-pyridyl) cycloalkane-1-ols (hereinafter sometimes abbreviated as pyridyl alcohols), and more specifically, a specific optically active carboxylic acid. It relates to a method for optically resolving (±) -trans-2- (2-pyridyl) cycloalkane-1-ols using According to the present invention, optically active pyridyl alcohols having high optical purity useful as pharmaceuticals, agricultural chemicals, and synthetic intermediates thereof can be obtained. The present invention also relates to an ester of a novel pyridyl alcohol containing a diastereomer of a condensate obtained during the optical resolution step, and a method for producing the same.
[0002]
[Prior art]
In general, techniques such as recrystallization, column chromatography, and high performance liquid chromatography have been used to isolate and purify two kinds of diastereomers derived from a racemate as a separation target.
[0003]
[Problems to be solved by the invention]
However, when two diastereomers are to be isolated and purified by recrystallization, the compound of interest is required to be a crystalline substance. Therefore, it is difficult to isolate and purify diastereomers that do not exhibit crystallinity. On the other hand, in the case of column chromatography or high-performance liquid chromatography, it is necessary to search for conditions for isolating two kinds of diastereomers, and if these conditions are not found, it is difficult to adopt these methods. Become.
[0004]
[Means for Solving the Problems]
The present invention relates to an optical resolution method that can be performed using extraction that is easier to operate than conventional methods as a method for isolating two diastereomers. The principle is that in the diastereomeric pair represented by the general formula [III], the intramolecular carbon CH / π interaction between the methyl group at the 2-position of the condensed ring and the pyridine ring in the same formula was derived from one enantiomer. This is thought to be due to expression only in diastereomers. This intramolecular CH / π interaction affects the basicity of the pyridine ring, thereby creating a difference between the solubilities of the two diastereomers, which makes it possible to isolate each diastereomer. It is thought that there is.
[0005]
That is, the method for producing optically active pyridyl alcohols according to the present invention includes:
Formula [I]
[Chemical Formula 10]

[0006]
(In the formula, R ¹ represents a lower alkyl group which may have a substituent or a halogen atom, and n represents an integer of 3 to 5.)
(±) -trans-2- (2-pyridyl) cycloalkane-1-ols represented by general formula [II]
Embedded image

[0007]
(In the formula, the configuration of the carboxyl group at position 1 or a derivative thereof and the methyl group at position 2 adjacent thereto is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ² and R ³ are R ² and R ³ are the same or different and each represents an optionally substituted alkyl group, and R ² and R ³ are bonded to each other to form a single ring or condensed ring optionally having a carbon-carbon double bond. And an optically active carboxylic acid having a known absolute configuration or a derivative thereof represented by the general formula [III].
Embedded image

[0008]
(Wherein R ¹ , R ² , R ³ and n have the same meaning as in the above formula), a diastereomeric pair of the condensate is obtained, and then dissolved in a water-insoluble organic solvent. The obtained organic solution is washed with an acidic aqueous solution to partition one diastereomer into the organic layer and the other diastereomer into the aqueous layer, and reduce the ester bond of each diastereomer obtained. Or hydrolysis to obtain the corresponding optically active trans-2- (2-pyridyl) cycloalkane-1-ol.
[0009]
The present invention also relates to a general formula [VII]
Embedded image

[0010]
(In the formula, R ¹ represents a lower alkyl group which may have a substituent or a halogen atom. R ² and R ³ are the same or different and represent an alkyl group which may have a substituent. R ² and R ³ may be bonded to each other to form a hydrocarbon group that forms a monocyclic ring or a condensed ring which may have a carbon-carbon double bond, and n is an integer of 3 to 5. Represents.)
The novel pyridyl alcohol ester shown by these is provided.
[0011]
The ester [VII] of the pyridyl alcohol is represented by the general formula [I]
Embedded image

[0012]
(In the formula, R ¹ represents a lower alkyl group which may have a substituent or a halogen atom, and n represents an integer of 3 to 5.)
2- (2-pyridyl) cycloalkane-1-ols represented by:
Formula [VI]
Embedded image

[0013]
(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ² and R ³ are the same or different and each represents an alkyl group which may have a substituent. R ² and R ³ are It may be a hydrocarbon group that is bonded to form a monocyclic ring or condensed ring optionally having a carbon-carbon double bond.
It can obtain by condensing with the carboxylic acid or its derivative shown by esterification reaction.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Racemates to be resolved by the method of the present invention are (±) -trans-2- (2-pyridyl) cycloalkane-1-ols represented by the general formula [I]. Here, n represents an integer of 3 to 5, and 4 is particularly preferable. R ¹ represents a lower alkyl group which may have a substituent or a halogen atom, and the lower alkyl group is preferably an alkyl group having 1 to 3 carbon atoms such as a methyl group or an ethyl group. Is preferably chlorine or bromine. R ¹ is preferably a hydrogen atom, a methyl group or a chlorine atom. The position of R ¹ on the pyridine ring is preferably the 4-position.
[0015]
On the other hand, the optically active substance used for forming a diastereomer is an optically active carboxylic acid having a known absolute configuration represented by the above general formula [II] or a derivative thereof, preferably the general formula [IV]
Embedded image

[0016]
(In the formula, the configuration of the methyl group at the 13-position and the carboxyl group at the 17-position or its derivative group is cis, and the ring-forming carbon atoms other than the 13- and 17-positions may have a substituent and adjacent carbon atoms. (It may have a double bond between them. X represents a hydroxyl group, an alkoxy group or a halogen atom.)
An optically active carboxylic acid having a steroid skeleton represented by the above known absolute configuration or a derivative thereof, and more preferably a general formula [V]
Embedded image

[0017]
(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom.)
3β-acetoxy-Δ5-etiocholenic acid or a derivative thereof.
[0018]
A method of condensing (±) -trans-2- (2-pyridyl) cycloalkane-1-ols represented by the general formula [I] with the optically active carboxylic acid represented by the general formula [II] or a derivative thereof No particular limitation, for example, a method of condensing the former compound [I] with an acid chloride of a carboxylic acid by conducting an esterification reaction under basic conditions or in the presence of a dehydration condensing agent such as carbodiimides, etc. There is.
[0019]
The organic solvent for dissolving the diastereomer of the condensate [III] obtained by the condensation is not particularly limited as long as it is not mixed with water, and aliphatic hydrocarbons such as hexane and heptane, diethyl ether, diesters, and the like. Ethers such as butyl ether, diisopropyl ether, tert-butyl methyl ether and dibutyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane, n -Alcohols, such as butyl alcohol, n-hexanol, cyclohexanol, or these mixed solvents are mentioned, Ethers are preferable and diethyl ether is especially preferable.
[0020]
The acidic aqueous solution used for washing the organic solution is preferably an aqueous solution of a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid, and particularly preferably an aqueous hydrochloric acid solution.
[0021]
Examples of the method for converting each diastereomer distributed in the organic layer and the aqueous layer into optically active trans-2- (2-pyridyl) cycloalkane-1-ol include lithium aluminum hydride and diisobutylaluminum hydride, Examples thereof include a method of reducing an ester bond using a reducing agent such as lithium borohydride and a method of hydrolyzing an ester bond in the presence of an acid or a base. The former method is preferable, and a method using lithium aluminum hydride or diisobutylaluminum hydride as the reducing agent is particularly preferable.
[0022]
Further, R ¹ , R ² , R ³ , X and n in the carboxylic acid or its derivative [VI] and the pyridyl alcohol ester [VII] may be the same as those described above. As described above, the esterification reaction of 2- (2-pyridyl) cycloalkane-1-ols [I] and a carboxylic acid or a derivative thereof [VI] is performed by, for example, acidification of the former compound [I] and a carboxylic acid. It may be a method of condensing a product with an esterification reaction under basic conditions or in the presence of a dehydrating condensing agent such as carbodiimides.
[0023]
Pyridyl alcohol esters [VII] are novel compounds. Of these, the hydroxyl group and pyridyl group of the pyridyl alcohol moiety are located at trans, and the configuration of the carboxyl group at the 1-position of the carboxylic acid (or its derivative) moiety or its derivative group and the methyl group at the 2-position adjacent thereto is The compound which is cis is useful as a diastereomer of a condensate obtained during the optical resolution step of (±) -trans-2- (2-pyridyl) cycloalkane-1-ols as described above. In particular, (±) -trans-2- (2-pyridyl) cycloalkane-1-ols [I] and an ester of a compound [IV] having a steroid skeleton are preferable, and (±) -trans-2- ( 2-pyridyl) cycloalkane-1-ols [I] and esters of 3β-acetoxy-Δ5-ethiocholenoic acid or its derivatives [V] are most preferred.
[0024]
【Example】
The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
[0025]
Example 1
3β-Acetoxy-Δ5-ethiocholenic acid chloride (2.19 g, 5.77 mmol) was dissolved in methylene chloride (10 mL), and triethylamine (0.64 mL, 4.62 mmol) was added to (±) -trans -2- A solution of (2-pyridyl) cyclohexane-1-ol (682 mg, 3.85 mmol) in methylene chloride (2 mL) was added under ice cooling, and further methylene chloride (8 mL) was added, and the whole was stirred at room temperature for 68 hours. . After washing the reaction solution with water, methylene chloride was distilled off, and the resulting residue was purified by column chromatography (eluent: hexane / ethyl acetate = 5/1) to give a condensate represented by the chemical formula [VIII]. 1.84 g (90%) of (trans-2-[(2-pyridyl) cyclohexyl] -Δ5-3β-acetoxyethiocholenate) was obtained as a mixture of diastereomers.
[0026]
Embedded image

[0027]
This diastereomer mixture was isolated and purified to obtain (1S, 2R) and (1R, 2S) isomers having the following characteristics.
[0028]
(1S, 2R) body white crystals;
m. p. : 126.0-129.0 ° C (diethyl ether-hexane);
[α] _D ²⁸ : +22.3 (c 0.63, CHCl ₃ );
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.52 (d, J = 4.5 Hz, 1H), 7.57 (td, J = 7.7 and 1.8 Hz, 1H), 7.18 (d , J = 7.7 Hz, 1H), 7.09 (ddd, J = 7.7, 4.5 and 0.8 Hz, 1H), 5.33 (d, J = 4.2 Hz, 1H), 5. 24 (td, J = 10.8 and 4.3 Hz, 1H), 4.58 (m, 1H), 2.91 (td, J = 11.5 and 3.5 Hz, 1H), 2.31-0 .84 (m, 28H), 2.03 (s, 3H), 0.95 (s, 3H), 0.11 (s, 3H);
IR (KBr): 1732 cm ⁻¹ ;
MS EI (+) m / z: 520 [(M + H) ⁺ , 3], 519 (M ⁺ , 3), 460 (22), 459 (59), 300 (9), 176 (56), 175 (32 ), 161 (19), 160 (100), 159 (20), 93 (18), 81 (26);
HRMS: Calculated as C ₃₃ H ₄₅ NO ₄ (M ⁺ ): 519.3348, found: 519.3367;
Elemental _analysis: calculated for _{C 33 H 45 NO 4: C} , 76.26; H, 8.73; N, 2.70, Found: C, 76.06; H, 8.72 ; N, 2 .62;
[0029]
(1R, 2S) body white crystals;
m. p. 149.5-150.0 ° C. (diethyl ether-hexane);
[α] _D ²⁸ : -70.7 (c 0.59, CHCl ₃ );
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.51 (d, J = 4.4 Hz, 1H), 7.56 (td, J = 7.7 and 1.8 Hz, 1H), 7.13 (d , J = 7.7 Hz, 1H), 7.09 (ddd, J = 7.7, 4.4 and 0.9 Hz, 1H), 5.34 (d, J = 4.4 Hz, 1H), 5. 13 (td, J = 11.0 and 4.2 Hz, 1H), 4.59 (m, 1H), 2.88 (td, J = 11.0 and 3.6 Hz, 1H), 2.32-0 .88 (m, 28H), 2.03 (s, 3H), 0.99 (s, 3H), 0.46 (s, 3H);
IR (KBr): 1732 cm ⁻¹ ;
MS EI (+) m / z: 520 [(M + H) ⁺ , 1], 519 (M ⁺ , 1), 460 (35), 459 (100), 300 (6), 176 (40), 161 (16 ), 160 (97), 159 (15), 93 (11), 81 (8);
HRMS: Calculated as C ₃₃ H ₄₅ NO ₄ (M ⁺ ): 519.3348, found: 519.3358;
Elemental _analysis: calculated for _{C 33 H 45 NO 4: C} , 76.26; H, 8.73; N, 2.70, Found: C, 75.96; H, 8.62 ; N, 2 .70;
[0030]
This diastereomer mixture (300 mg) was dissolved in diethyl ether (50 mL), and the resulting organic solution was washed with 3% aqueous hydrochloric acid (20 mL). The organic layer and the aqueous layer were separated, the organic layer was dried over sodium carbonate, diethyl ether was distilled off, the residue was dissolved again in diethyl ether (37 mL), and the resulting organic solution was diluted with 7% hydrochloric acid (15 mL). Washed. Thereafter, the organic layer was treated in the same manner as above to obtain 57 mg (44%, 81% de) of one diastereomer. The aqueous layer was adjusted to pH 8 with sodium hydrogen carbonate, and 75 mg (23%, 93% de) of the other diastereomer was recovered by suction filtration.
[0031]
A THF solution (1 mL) of one diastereomer (81% de, 57 mg, 0.11 mmol) obtained from the organic layer was added to a THF suspension (1 mL) of lithium aluminum hydride (42 mg, 1.10 mmol) on ice. The solution was slowly added dropwise under cooling, and further THF (3 mL) was added, and the whole was stirred at room temperature for 2 hours. The reaction solution was ice-cooled, saturated aqueous sodium sulfate solution was added dropwise and stirred for a while, and then the reaction solution was dried over potassium carbonate. After removing the desiccant and washing with methylene chloride, the washing solution was concentrated, the residue was again dissolved in methylene chloride, and the resulting organic solution was washed with 5% aqueous hydrochloric acid. The aqueous hydrochloric acid layer was made alkaline (pH 12) with potassium carbonate, extracted with methylene chloride, the organic layer was dried over sodium carbonate, the desiccant was removed, and methylene chloride was distilled off. The resulting residue was purified by column chromatography (eluent: hexane / ethyl acetate = 1/1), and 13 mg (68%, 68%, +)-trans-2- (2-pyridyl) cyclohexane-1-ol was obtained. 77% ee).
[0032]
The other diastereomer (93% de, 60 mg, 0.12 mmol) obtained from the aqueous layer was treated in the same manner as above to give (−)-trans-2- (2-pyridyl) cyclohexane-1- 18 mg (90%, 93% ee) of oals were obtained.
[0033]
(+)-Trans-2- (2-pyridyl) cyclohexane-1-ol white crystals;
m. p. : 62.5-65.0 ° C;
[α] _D ²⁸ : +20.4 (c0.49, CHCl ₃ );
Optical purity: 77% ee [Measured by HPLC analysis (manufactured by Daicel, “Chiralcel OD”; hexane / isopropanol = 95/5; flow rate: 1.0 mL / min; 25 ° C .; retention time: 9.9 min). ]
[0034]
(−)-Trans-2- (2-pyridyl) cyclohexane-1-ol white crystals;
m. p. : 81.0-82.5 ° C;
[α] _D ²⁷ : -23.5 (c 0.53, CHCl ₃ );
Optical purity: 93% ee [Measured by HPLC analysis (manufactured by Daicel, “Chiralcel OD”; hexane / isopropanol = 95/5; flow rate: 1.0 mL / min; 25 ° C .; retention time: 14.2 min). ]
[0035]
Example 2
3β-acetoxy-Δ5-ethiocholenic acid chloride (1.16 g, 3.05 mmol) was dissolved in methylene chloride (8 mL), and triethylamine (0.34 mL, 2.44 mmol) was added to (±) -trans -2- A solution of (4-methyl-2-pyridyl) cyclohexane-1-ol (389 mg, 2.03 mmol) in methylene chloride (2 mL) was added under ice cooling, and further methylene chloride (6 mL) was added. Stir for 19 hours. After the reaction solution was washed with water, methylene chloride was distilled off, and the resulting residue was purified by column chromatography (eluent: hexane / ethyl acetate = 5/1) to give a condensate represented by the chemical formula [IX] (trans 934 mg (86%) of 2-[(4-methyl-2-pyridyl) cyclohexyl] -Δ5-3β-acetoxyethiocholenate) as a diastereomeric mixture was obtained.
[0036]
Embedded image

[0037]
This diastereomer mixture was isolated and purified to obtain (1S, 2R) and (1R, 2S) isomers having the following characteristics.
[0038]
(1S, 2R) body colorless crystals;
m. p. 199.0-202.0 ° C. (ethyl acetate-hexane);
[α] _D ²⁹ = + 19.2 (c0.51, CHCl ₃ );
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.37 (d, J = 5.0 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J = 5.0 Hz, 1H), 5.33 (d, J = 4.4 Hz, 1H), 5.22 (td, J = 10.7 and 4.3 Hz, 1H), 4.58 (m, 1H), 2.86 (td, J = 11.4 and 3.4 Hz, 1H), 2.30-0.84 (m, 28H), 2.30 (s, 3H), 2.03 (s, 3H), 0.95 (s, 3H) , 0.10 (s, 3H);
IR (KBr): 1732, 1721 cm ⁻¹ ;
MS EI (+) m / z: 534 [(M + H) ⁺ , 4], 533 (M ⁺ , 10), 474 (36), 473 (100), 300 (9), 190 (34), 175 (12 ), 174 (71), 173 (14);
HRMS: Calculated as C ₃₄ H ₄₇ NO ₄ (M ⁺ ): 533.3505, found: 533.3499;
Elemental _analysis: calculated for _{C 34 H 47 NO 4: C} , 76.51; H, 8.88; N, 2.62, Found: C, 76.33; H, 8.74 ; N, 2 .62;
[0039]
(1R, 2S) body white crystals;
m. p. 149.0-151.0 ° C. (ethyl acetate-hexane);
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.36 (d, J = 4.7 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 4.7 Hz, 1H), 5.35 (d, J = 4.8 Hz, 1H), 5.11 (td, J = 10.3 and 4.3 Hz, 1H), 4.59 (m, 1H), 2.86 (td, J = 11.4 and 3.3 Hz, 1H), 2.30 (s, 3H), 2.21-0.88 (m, 28H), 2.03 (s, 3H), 1.00 (s, 3H) , 0.46 (s, 3H);
IR (KBr): 1732 cm ⁻¹ ;
Elemental _analysis: calculated for _{C 34 H 47 NO 4: C} , 76.51; H, 8.88; N, 2.62, Found: C, 76.33; H, 8.87 ; N, 2 .58;
[0040]
This diastereomeric mixture (307 mg) was dissolved in diethyl ether (51 mL), and the resulting organic solution was washed with 2% aqueous hydrochloric acid (21 mL). After the organic layer and the aqueous layer were separated, the organic layer was dried over sodium carbonate, and diethyl ether was distilled off to obtain 172 mg (56%, 67% de) of one diastereomer. The aqueous layer was adjusted to pH 8 with sodium bicarbonate, and then 136 mg (44%, 82% de) of the other diastereomer was recovered by suction filtration.
[0041]
A THF solution (1 mL) of one diastereomer (67% de, 85 mg, 0.16 mmol) obtained from the organic layer was added to a THF suspension (1 mL) of lithium aluminum hydride (60 mg, 1.60 mmol) on ice. The solution was slowly added dropwise under cooling, THF (3 mL) was added, and the whole was stirred at room temperature for 2 hours. The reaction solution was ice-cooled, saturated aqueous sodium sulfate solution was added dropwise and stirred for a while, and then the reaction solution was dried over potassium carbonate. The desiccant was removed, the solution was concentrated after washing with methylene chloride, the residue was dissolved again in methylene chloride, and the resulting organic solution was washed with 5% aqueous hydrochloric acid. The aqueous hydrochloric acid layer was made alkaline (pH 12) with potassium carbonate, extracted with methylene chloride, the organic layer was dried over sodium carbonate, the desiccant was removed, and methylene chloride was distilled off. The obtained residue was purified by column chromatography (eluent: hexane / ethyl acetate = 1/1) and (+)-(1S, 2R) -2- (4-methyl-2-pyridyl) cyclohexane-1- 25 mg (83%, 64% ee) of oals were obtained.
[0042]
The other diastereomer (82% de, 80 mg, 0.15 mmol) obtained from the aqueous layer was treated in the same manner as above to obtain (−)-(1R, 2S) -2- (4-methyl- 26 mg (90%, 79% ee) of 2-pyridyl) cyclohexane-1-ol were obtained.
[0043]
(+)-(1S, 2R) -2- (4-methyl-2-pyridyl) cyclohexane-1-ol white crystals;
m. p. : 100.0-102.0 ° C;
[α] _D ²⁷ : +17.0 (c0.53, CHCl ₃ );
Optical purity: 64% ee [Measured by HPLC analysis (manufactured by Daicel, “Chiralcel OD”; hexane / isopropanol = 95/5; flow rate: 1.0 mL / min; 25 ° C .; retention time: 8.9 min). ]
[0044]
(−)-(1R, 2S) -2- (4-methyl-2-pyridyl) cyclohexane-1-ol white crystals;
m. p. : 93.5-95.0 ° C;
[α] _D ²⁹ : -24.8 (c 0.56, CHCl ₃ );
Optical purity: 80% ee [Measured by HPLC analysis (Daicel, “Chiralcel OD”; hexane / isopropanol = 95/5; flow rate: 1.0 mL / min; 25 ° C .; retention time: 11.0 min). ]
[0045]
Example 3
3β-acetoxy-Δ5-ethiocholenic acid chloride (1.37 g, 3.61 mmol) was dissolved in methylene chloride (8 mL), and triethylamine (0.40 ml, 2.88 mmol) was added to (±) -trans -2- A solution of (4-chloro-2-pyridyl) cyclohexane-1-ol (509 mg, 2.40 mmol) in methylene chloride (2 ml) was added under ice-cooling, and further methylene chloride (5 mL) was added. Stir for 18.5 hours. After the reaction solution was washed with water, methylene chloride was distilled off, and the resulting residue was purified by column chromatography (eluent: hexane / ethyl acetate = 7/1) to give a condensate represented by the chemical formula [X] (trans -2-[(4-Chloro-2-pyridyl) cyclohexyl] -Δ5-3β-acetoxyethiocholenate) was obtained as a diastereomeric mixture to give 1.22 g (96%).
[0046]
Embedded image

[0047]
A mixture of (1S, 2R) and (1R, 2S) isomers, white crystals;
m. p. : 61.0-63.0 ° C;
¹ H NMR (300 MHz, CDCl ₃ ) δ: 8.43 (d, J = 5.3 Hz, 1H), 8.42 (d, J = 5.1 Hz, 1H), 7.20 (d, J = 2) 0.0 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.12 (dd, J = 5.3 and 2.0 Hz, 1H), 7.12 (dd, J = 5. 1 and 2.1 Hz, 1H), 5.34 (m, 1H), 5.19 (td, J = 10.6 and 4.2 Hz, 1H), 5.08 (td, J = 10.4 and 4) .2 Hz, 1 H), 4.58 (m, 1 H), 2.86 (m, 1 H), 2.31-0.84 (m, 28 H), 2.03 (s, 3 H), 1.00 ( s, 3H), 0.96 (s, 3H), 0.48 (s, 3H), 0.13 (s, 3H);
IR (KBr): 1732 cm ⁻¹ ;
[0048]
This diastereomeric mixture (319 mg) was dissolved in diethyl ether (53 mL), and the resulting organic solution was washed with 15% aqueous hydrochloric acid (21 mL). After the organic layer and the aqueous layer were separated, the organic layer was dried over sodium carbonate, and diethyl ether was distilled off to obtain 134 mg (42%, 82% de) of one diastereomer. The aqueous layer was adjusted to pH 8 with sodium bicarbonate, and then 179 mg (56%, 54% de) of the other diastereomer was recovered by suction filtration.
[0049]
One diastereomer obtained from the organic layer (82% de, 60 mg, 0.11 mmol) in methylene chloride solution (1.5 mL) and hexane solution of diisobutylaluminum hydride (0.95 M, 0.57 mL,. 54 mmol) was slowly added dropwise at −20 ° C., methylene chloride (1 mL) was added, the temperature was gradually raised, and the whole was stirred for 2 hours. The reaction mixture was ice-cooled, purified water was added dropwise and stirred for a while, white precipitate was removed by celite filtration, and the filtrate was concentrated. The residue was dissolved again in methylene chloride, and the resulting organic solution was washed with 5% aqueous hydrochloric acid. The aqueous hydrochloric acid layer was made alkaline (pH 12) with potassium carbonate, extracted with methylene chloride, the organic layer was dried over sodium carbonate, the desiccant was removed, and methylene chloride was distilled off. The obtained residue was purified by column chromatography (eluent: hexane / ethyl acetate = 2/1), and 16 mg (+)-trans-2- (4-chloro-2-pyridyl) cyclohexane-1-ol was obtained. 70%, 79% ee).
[0050]
The other diastereomer (54% de, 46 mg, 0.08 mmol) obtained from the aqueous layer was treated in the same manner as above to obtain (−)-trans-2- (4-chloro-2-pyridyl). 16 mg (89%, 50% ee) of cyclohexane-1-ol was obtained.
[0051]
(+)-Trans-2- (4-chloro-2-pyridyl) cyclohexane-1-ol white crystals;
m. p. : 84.5-86.0 ° C;
[α] _D ²⁸ : +30.6 (c0.92, CHCl ₃ );
Optical purity: 79% ee [Measured by HPLC analysis (manufactured by Daicel, “Chiralcel OD”; hexane / isopropanol = 95/5; flow rate: 1.0 mL / min; 25 ° C .; retention time: 8.4 min). ]
[0052]
(−)-Trans-2- (4-chloro-2-pyridyl) cyclohexane-1-ol white crystals;
m. p. : 82.5-85.0 ° C;
[α] _D ²⁸ : -20.5 (c0.72, CHCl ₃ );
Optical purity: 50% ee [Measured by HPLC analysis (manufactured by Daicel, “Chiralcel OD”; hexane / isopropanol = 95/5; flow rate: 1.0 mL / min; 25 ° C .; retention time: 9.7 min). ]

Claims (10)

Formula [I]

(In the formula, R ¹ represents a lower alkyl group which may have a substituent or a halogen atom, and n represents an integer of 3 to 5.)
(±) -trans-2- (2-pyridyl) cycloalkane-1-ols represented by general formula [II]

(In the formula, the configuration of the carboxyl group at the 1-position or the derivative group thereof and the methyl group at the 2-position is cis, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ² and R ³ are the same or different. Represents an optionally substituted alkyl group, and R ² and R ³ are bonded to each other to form a hydrocarbon ring that may have a carbon-carbon double bond or a single ring or a condensed ring. It may be a group.)
Is condensed with an optically active carboxylic acid of known absolute configuration or a derivative thereof by an esterification reaction, to form a compound represented by the general formula [III]

(Wherein R ¹ , R ² , R ³ and n have the same meaning as in the above formula), a diastereomer pair of the condensate is obtained, and then dissolved in a water-insoluble organic solvent. The obtained organic solution is washed with an acidic aqueous solution to partition one diastereomer into the organic layer and the other diastereomer into the aqueous layer, and reduce the ester bond of each diastereomer obtained. Or producing the corresponding optically active trans-2- (2-pyridyl) cycloalkane-1-ol by hydrolysis. An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [IV]

(In the formula, the configuration of the methyl group at the 13-position and the carboxyl group at the 17-position or its derivative group is cis, and the ring-forming carbon atoms other than the 13- and 17-positions may have a substituent and adjacent carbon atoms. (It may have a double bond between them. X represents a hydroxyl group, an alkoxy group or a halogen atom.)
The method for producing an optically active pyridyl alcohol according to claim 1, wherein the compound has a steroid skeleton represented by formula (1). An optically active carboxylic acid having a known absolute configuration represented by the general formula [II] or a derivative thereof is represented by the general formula [V].

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom.)
The method for producing an optically active pyridyl alcohol according to claim 1, which is 3β-acetoxy-Δ5-ethiocholenoic acid or a derivative thereof represented by the formula: The method for producing optically active pyridyl alcohols according to any one of claims 1 to 3, wherein n in the general formula [I] is 4. R < ¹ > in general formula [I] is a hydrogen atom, a methyl group, or a chlorine atom, The manufacturing method of optically active pyridyl alcohol in any one of Claims 1-4. The method for producing an optically active pyridyl alcohol according to any one of claims 1 to 5, wherein R ¹ in the general formula [I] is located at the 4-position of the 2-pyridyl group. The method for producing an optically active pyridyl alcohol according to any one of claims 1 to 6, wherein the organic solvent is an ether. The method for producing optically active pyridyl alcohols according to any one of claims 1 to 7, wherein the acidic aqueous solution is an aqueous hydrochloric acid solution. Formula [VII]

(In the formula, R ¹ represents a lower alkyl group which may have a substituent or a halogen atom. R ² and R ³ are the same or different and represent an alkyl group which may have a substituent. R ² and R ³ may be bonded to each other to form a hydrocarbon group that forms a monocyclic ring or a condensed ring which may have a carbon-carbon double bond, and n is an integer of 3 to 5. Represents.)
Ester of pyridyl alcohol characterized by being shown by these. Formula [I]

(In the formula, R ¹ represents an optionally substituted lower alkyl group or a halogen atom, and n represents an integer of 3 to 5.)
2- (2-pyridyl) cycloalkane-1-ols represented by:
Formula [VI]

(In the formula, X represents a hydroxyl group, an alkoxy group or a halogen atom, and R ² and R ³ are the same or different and each represents an alkyl group which may have a substituent. R ² and R ³ are It may be a hydrocarbon group that is bonded to form a monocyclic ring or a condensed ring which may have a carbon-carbon double bond.
Is condensed with an esterification reaction to produce a compound of the general formula [VII]

(Wherein R ¹ , R ² , R ³ and n represent the same meaning as in the above formula). A method for producing an ester of pyridyl alcohol, characterized in that a condensate is obtained.