JPWO2002064553A1 - Method for producing halogeno alcohol derivative - Google Patents

Abstract

A method for producing a halogeno alcohol derivative represented by the following general formula (1), and a novel useful intermediate compound. Starting from the known compound N-Cbz-S-phenyl-L-cysteine as a starting material, novel active ester derivatives and novel ylide compounds of formulas (4) and (5), a halomethylketone intermediate of formula (6) , A halogeno alcohol represented by the formula (1), that is, a (2S, 3R) N-Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative is efficiently produced.

Description

背景技術
上記式（７）で表される化合物の製造方法としては、例えば、次のような方法が知られている。すなわち、
１）セリンを出発原料としてアジド化合物を経て製造する方法（国際公開番号ＷＯ９５／０９８４３号公報）。
２）２−ブテン−１，４−ジオールを出発原料としてキラルアミンを経て製造する方法（国際公開番号ＷＯ９７／１１９３７、ＷＯ９７／１１９３８号公報）。
３）１，３−オキサゾリジン−２−オン誘導体からジアミノアルコールを経て製造する方法（特開平１１−２７９１５４号公報）。
上記の方法による上記式（７）で表わされる化合物の製造においては、いずれの方法も中間体として式（１）で表わされるハロゲノアルコール」を経て製造される。しかし、このハロゲノアルコール、すなわち（２Ｓ，３Ｒ）Ｎ−Ｃｂｚ−３−アミノ−１−ハロゲノ−４−フェニルスルファニルブタン−２−オール誘導体を製造する場合に、１）の方法は、途中の工程で、爆発性を有するジアゾメタンを使用したり、反応条件に一定の低温条件を必要とする等、工程に非効率な点がある、２）の方法は工業的に使用が規制される塩化メチレンを大量に使用すること、３）の方法は工程数が長いなど、従来行われている製造方法はいずれも問題を内包している。したがって、ＨＩＶプロテアーゼ阻害剤として極めて有用な化合物である上記式（７）の化合物を安全にかつ安価に製造する方法が望まれている。
本発明の目的は上記のような現状に鑑み、ＨＩＶプロテアーゼ阻害剤［３Ｓ−（３α，４ａβ，８ａβ）］−２−［２’−ヒドロキシ−３’−フェニルチオメチル−４’−アザ−５’−オキソ−５’−（２”−メチル−３”−ヒドロキシフェニル）ペンチル］デカヒドロイソキノリン−３−Ｎ−ｔ−ブチルカルボキシアミド（上記式（７））の製造中間体で、製造工程に種々問題のあった（２Ｓ，３Ｒ）Ｎ−Ｃｂｚ−３−アミノ−１−ハロゲノ−４−フェニルスルファニルブタン−２−オール誘導体（上記式（１））の製造を改良された新規な方法により効率よく行う製造方法を提供することである。
また、本発明の他の目的は、当該化合物を製造するために有用な新規中間体化合物及びその製造方法を提供することである。
発明の開示
本発明者等は、上記目的に従って鋭意検討した結果、下記式（２）で表わされる公知の化合物Ｎ−Ｃｂｚ−Ｓ−フェニル−Ｌ−システインを出発原料として、新規な活性エステル誘導体（下記式（４））及び新規なイリド化合物（下記式（５））、ハロメチルケトン中間体（下記式（６））を経て、式（１）で表されるハロゲノアルコール、すなわち、（２Ｓ，３Ｒ）Ｎ−Ｃｂｚ−３−アミノ−１−ハロゲノ−４−フェニルスルファニルブタン−２−オール誘導体を効率よく製造する方法を見出し、本発明を完成した。
本発明方法によれば、従来の方法における問題点を解消し、温和な反応条件で短い工程で目的の化合物を収率よく製造することができる。
即ち、本発明の要旨は、
下記式（２）で表される化合物（２）を、

一般式（３）で表される化合物（化合物（３））と縮合剤の存在下に反応させて、

（式（３）中、Ｚは直鎖または分岐したＣ_１〜Ｃ_４アルコキシ基、Ｃ_１〜Ｃ_４アルキルチオ基、フェノキシ基あるいは、ハロゲン原子、ニトロ基、アルキル基、アルコキシ基または、ヒドロキシ基置換フェノキシ基、フェニルチオ基あるいは、ハロゲン原子、ニトロ基、アルキル基、アルコキシ基または、ヒドロキシ基置換フェニルチオ基、ベンジルオキシ基あるいは、ハロゲン原子、ニトロ基、アルキル基または、アルコキシ基置換ベンジルオキシ基、ベンジルチオ基あるいはハロゲン原子、ニトロ基、アルキル基またはアルコキシ基置換ベンジルチオ基、ピリジルオキシ基、ピリジルチオ基、エトキシビニルオキシ基、直鎖または分岐したＣ_１〜Ｃ_４アルキルカルボニルオキシ基、置換リン酸エステル基、置換硫酸エステル基、イミダゾリル基、アジド基、アルコキシカルボニルオキシ基、シクロヘキシルカルボジイミドキシ基、スクシンイミドキシ基、フタルイミドキシ基、ベンゾトリアゾリルオキシ基、ピペリジノオキシ基及びハロゲン原子を表し、Ｒは水素原子を表す。ただし、下記一般式（４）においてＺがハロゲン原子である場合には、Ｚ−Ｒは一緒になって、塩化チオニル、塩化スルフリル、五塩化リン、三塩化リン、臭化チオニル、またはオキザルクロリドを表す。）
下記一般式（４）

（式（４）中、Ｚは前述のとおり。）
で示される化合物（４）に変換する工程、
得られた化合物（４）をメチリド化合物と反応させて、下記式（５）で表されるイリド化合物（化合物（５））を生成する工程、

得られたイリド化合物をハロゲン化水素で処理して下記一般式（６）で表されるハロメチルケトン（化合物（６））とし、

（式中、Ｘはハロゲン原子を表す）、
ついで、これを還元して一般式（１）で表されるハロゲノアルコール誘導体を製造する方法である。

（式中、Ｘはハロゲン原子を表す）
さらに、本発明は、前記一般式（４）で表される新規な活性エステル化合物及び前記式（５）で表される新規なイリド化合物を提供する。
本発明方法は、公知の化合物である上記一般式（２）で表されるＮ−カルボベンゾキシ−Ｓ−フェニル−Ｌ−システイン（化合物（２））を出発原料とし、この化合物のカルボキシル基をエステル化して上記一般式（４）で表される活性エステル化合物（化合物（４））に変換する工程、得られた活性エステル化合物をメチリド化合物と反応させて、上記式（５）で表されるイリド化合物（化合物（５））を生成する工程、得られたイリド化合物をハロゲン化水素で処理して下記一般式（６）で表されるハロメチルケトン（化合物（６））とする工程、ついで、これを還元して一般式（１）で表されるハロゲノアルコール誘導体を製造する工程よりなる。
（ｉ）活性エステル化合物生成工程
この工程では、出発化合物Ｎ−ベンジルオキシ−Ｓ−フェニル−Ｌ−システイン（化合物（２））を適当な有機溶媒中で、エステルを形成するもう一方の一般式（３）Ｚ−Ｒ（式中Ｒ，Ｚは前記と同じ）で表される化合物（３）と反応させる。このような化合物としては、好ましくはアルコール類、フェノール類、Ｎ−ヒドロキシイミド類またはＮ−ヒドロキシ複素環化合物等を用いることができ、これら化合物は種々の置換基を有していてよく、前記化合物（３）の定義中のＺとして定義した基を導入できるものであればよい。特に好ましいＺとしてはｐ−ニトロフェノキシ基、スクシンイミドキシ基等を挙げることができる。
反応は、例えば、ｐ−ニトロフェノールまたはＮ−ヒドロキシスクシンイミド等と、縮合剤、例えばＮ，Ｎ’−ジシクロヘキシルカルボイミド（ＤＣＣ）、または、塩化チオニル及び塩基の存在下に、−２０℃〜１５０℃、好ましくは−１０℃〜８０℃の温度で反応させることにより一般式（４）の活性エステル化合物を得ることができる。
また、ｐ−ニトロフェノールやＮ−ヒドロキシスクシンイミド等を不活性溶媒中で、塩化チオニルと２倍量の塩基、例えばトリエチルアミン等を用いて０℃から５０℃で反応することにより、ｐ−ニトロフェニル亜硫酸エステルあるいはスクシンイミド亜硫酸エステルが得られる。このものは単離あるいは単離することなく、化合物（２）と反応させることにより、一般式（４）の活性エステル化合物を得ることができる。適当な有機溶媒としては、ジオキサン、ジエチルエーテル、テトラヒドロフラン、１，２−ジエトキシエタン等のエーテル系溶媒、ベンゼン、トルエン、キシレン等の芳香族溶媒が好ましく、更に好ましくは、ジオキサン、トルエンが挙げられる。反応温度は−１０℃〜６０℃、好ましくは０℃〜３０℃である。反応時間は３０分〜２日間、好ましくは１時間〜２４時間である。
なお、一般式（４）のＺがハロゲン原子の化合物はそのままコーリー試薬と反応させてイリド化合物（５）とすることができるが、エステル化合物に変換させてからコーリー試薬と反応させてもよい。一般式（４）のＺがハロゲン原子の化合物を用いてエステル化合物を得るには、不活性溶媒中、化合物（２）とハロゲン化剤、例えば、塩化チオニル、塩化スルフリル、五塩化リン、三塩化リン、臭化チオニル、オギザリルクロリド等と−１０℃〜８０℃、好ましくは、０℃〜５０℃で、酸ハロゲン化物とした後、アルコール類、チオール類、フェノール類等と反応することにより、活性エステル化合物を得ることができる。
（ｉｉ）イリド化合物を生成させる工程（以下において、イリド化工程と記載する）
この工程では、（ｉ）で得られた活性エステル化合物とジメチルスルホキソメチリド（以下において、メチリド化合物と記載する。このメチリド化合物はコーリー試薬と称されることもある）とを反応させて、イリド化合物（化合物（５））を生成させる。
このイリド化工程では、通常トリメチルスルホキソニウムハライドから生成させたメチリド化合物を含有する混合物（以下において、メチリド含有混合物と記載する）とイリド化合物とを反応させる。
メチリド含有混合物を調製する工程（以下において、メチリド調製工程と記載する）は、トリメチルスルホキソニウムハライド（好ましいハライドは、ブロマイド、ヨーダイドであり、特に好ましくは、ブロマイドである）と塩基（好ましい塩基として、水素化ナトリウム、カリウム ｔｅｒｔ−ブトキシド、ナトリウム ｔｅｒｔ−ブトキシドをあげることができる）とを反応させる。
通常、メチリド調製工程とイリド化工程とを一連の工程で行う。
したがって、メチリド調製工程で使用する溶媒は、イリド化工程に悪影響を及ぼさない溶媒から選択して使用する。好ましい有機溶媒としては、ｔｅｒｔ−ブタノール、ジメチルスルホキシド、ジメチルホルムアミド、２−メチルピロリドン、トルエン、テトラヒドロフランをあげることができる。これらの溶媒の１種または、２種以上を混合して使用する。
２種類の溶媒混合物として、テトラヒドロフランとジメチルスルホキシド、テトラヒドロフランとｔｅｒｔ−ブタノール及び、ｔｅｒｔ−ブタノールとトルエンとの組み合わせをあげることができる。
メチリド調製工程の反応温度は、５〜１５０℃、好ましくは、２０〜１００℃、特に好ましくは、４０〜８５℃である。
メチリド調製工程の反応時間は、１０分〜２０時間、好ましくは、３０分〜５時間である。
イリド化工程の反応温度は、−７０〜１００℃、好ましくは、−５０〜７０℃、特に好ましくは、−２０〜４０℃である。
イリド化工程の反応時間は、１０分〜２０時間、好ましくは、３０分〜５時間である。
なお、上述の活性エステル化合物生成工程で得られるエステル化合物を分離精製することなく、イリド化工程で使用することもできる。すなわち、エステル化反応液中に析出した結晶を濾別した濾液を別途調製したメチリド含有混合物中に添加することにより、イリド化合物を生成させることができる。反応溶媒としてはエステル化反応に適した溶媒とメチリド調製工程に適した溶媒の混合溶媒がよく、適当な混合溶媒としては、テトラヒドロフランとジメチルスルホキシド、テトラヒドロフランとｔｅｒｔ−ブタノールが好ましい。この場合は、エステル化合物を分離するためのエステル化反応溶媒の濃縮、エステル化合物の精製などの操作が省略できて有利である。
（ｉｉｉ）ハロメチルケトンを生成する工程
イリド化合物（５）からハロメチルケトン（６）への変換は適当な有機溶媒中、ハロゲン化水素と−５０℃〜１００℃、好ましくは、−２０℃〜８０℃で反応を行うことにより、化合物（６）のハロメチルケトンを得ることができる。
適当な有機溶媒としては、酢酸エチル、テトラヒドロフラン、ジクロロエタン、トルエン等があげられ、反応時間は１０分〜１０時間、好ましくは３０分〜５時間である。
ハロゲン化水素としては、塩化水素、臭化水素等があげられ、またこれらを有機溶媒に溶解して使用してもよい。特に好ましくは塩化水素を酢酸エチル、テトラヒドロフラン、ジエチルエーテル、トルエン等に溶解して使用するのが良い。
（ｉｖ）ハロメチルケトンを還元する工程（以下において、ケトン還元工程と記載する）
このケトン還元工程はメーヤワイン−ポンドルフ−バーリー（Ｍｅｅｒｗｅｉｎ−Ｐｏｎｎｄｏｒｆ−Ｖｅｒｌｅｙ）還元による方法もしくは、水素化ホウ素ナトリウムを用いる方法で有利に行うことができる。
メーヤワイン−ポンドルフ−バーリー（Ｍｅｅｒｗｅｉｎ−Ｐｏｎｎｄｏｒｆ−Ｖｅｒｌｅｙ）還元においては、−３０〜１００℃、好ましくは−１０〜７０℃で、イソプロパノール、ｓｅｃ−ブタノール等のアルコールを溶媒として、アルミニウムイソプロポキシド、アルミニウムｓｅｃ−ブトキシド等のアルミニウムアルコキシドを用いて還元を行う。
化合物（６）に対するアルミニウムアルコキシドの使用量は、反応条件によって適宜に選ぶことが可能であり、通常、好ましくは、０．５〜３当量、より好ましくは、１〜１．５当量を使用する。反応に悪影響を及ぼさない溶媒を併用しても差し支えなく、例えば、トルエン、テトラヒドロフランをあげることができる。また、水素化ホウ素ナトリウムを用いる方法においては、エーテル系溶媒または、エーテル系溶媒と水との混合溶媒中で行われる。好ましくは、テトラヒドロフラン、テトラヒドロフランと水との混合溶媒があげられる。混合溶媒の比は、１０００／１〜１／１０、好ましくは、１００／１〜１／１、より好ましくは、１０／１〜５／１である。反応温度は−２０〜１００℃、好ましくは−１０〜６０℃である。
化合物（６）に対する水素化ホウ素ナトリウムの使用量は、好ましくは、０．５〜３当量、より好ましくは、１〜１．５当量を使用する。
なお、上記のようにして製造される化合物（１）及び各種中間体化合物は、工程に応じた分離・精製手段、例えば、濃縮、抽出、クロマトグラフィー、再結晶等の手段を適宜施すことにより、任意の純度のものとして単離することができる。
発明を実施するための最良の形態
以下、実施例により本発明を具体的に述べるが、本発明はこれらによって限定されるものではない。
実施例
［実施例 １］
Ｎ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン Ｎ’−オキシスクシンイミドエステル（化合物４：Ｚ＝スクシンイミドキシ基：以下の実施例において「イミドエステル」と記す）の合成
温度計、冷却器、撹拌装置を付した１００ｍｌの四つ口フラスコにＮ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン（化合物２：光学純度９８．６％ｅｅ）９．９４ｇ（０．０３ｍｏｌ）を取り、ジオキサン６０ｍｌに溶解した。Ｎ−ヒドロキシコハク酸イミド３．４６ｇ（０．０３１ｍｏｌ）を加え、氷水で４℃まで冷却した後、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド（ＤＣＣ）６．４ｇ（０．０３ｍｏｌ）を添加した。
結晶の析出と若干の発熱（７℃）が見られた。３０分撹拌後、反応フラスコを冷蔵庫に入れ、一夜放置した。析出結晶を濾別し、ジオキサンで洗浄した。
濾液を減圧濃縮して半固体物１３．２ｇを得た。これを結晶化させた後、ｎ−ヘキサン／酢酸エチル＝５／１で再結晶してｍ．ｐ １０６−１０９℃の白色結晶のイミドエステルを１２．６５ｇ（収率：９８．４％：ＨＰＬＣ；９７．１％）得た。
^１Ｈ ＮＭＲ（６０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：２．７０（４Ｈ，ｓ）、３．４０（２Ｈ，ｄ，Ｊ＝５Ｈｚ）、４．６０−４．９７（１Ｈ，ｍ）、５．０２（２Ｈ，ｓ）、５．４５（１Ｈ，ｄ，Ｊ＝８Ｈｚ）、７．０３−７．４３（１０Ｈ，ｍ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３４８，３０４４，２９５２，１８１８，１７９０，１７４６，１６９６，１６３６，１５７８，１５３８，１４７２，１４５８，１４４２，１４３０，１４１８，１３６８，１３０８，１２８０，１２１０，１１６０，１０９４，１０６６，１０４２，１０２４，１００４，９９４，９２２，８４８，８１４，７７６，７５０，６９８，６６０，６４２，６１８，５８４，５００，４８０，４２４．
［実施例 ２］
Ｎ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン ４’−ニトロフェニルエステル（化合物４：Ｚ＝４−ニトロフェノキシ基：以下の実施例において「ｐ−ニトロフェニルエステル」と記す）の合成
実施例２−１
縮合剤Ｎ，Ｎ’−ジシクロヘキシルカルボジイミドを用いるｐ−ニトロフェニルエステルの合成
温度計、撹拌装置、窒素導入管、滴下ロートを付した１００ｍｌ四ツ口フラスコに、Ｎ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン（化合物２：光学純度９８．６％ｅｅ）３．３１ｇ（０．０１ｍｏｌ）、ｐ−ニトロフェノール１．３９ｇ（０．０１ｍｏｌ）を取り、１，４−ジオキサン１５ｍｌで希釈した。
次いで、Ｎ，Ｎ’−ジシクロヘキシルカルボジイミド（ＤＣＣ）２．１７ｇ（０．０１０５ｍｏｌ）を１，４−ジオキサン５ｍｌで希釈した溶液を滴下ロートより、窒素気流下、内温６℃〜１０℃の範囲で１０分間で滴下した。同温度で５時間撹拌し、冷蔵庫中に一夜放置した。得られた黄色懸濁溶液を濾過して白色固体を除き、濾液を減圧濃縮した。黄色粘調液体５．２４ｇを得た。ＨＰＬＣ；９６．４％
これをｎ−ヘキサン／酢酸エチル＝５／１で固化させ、ｍ．ｐ ９３−９５℃の白色結晶のｐ−ニトロフェニルエステルを４．３ｇ（収率：９５．１％）得た。
^１Ｈ ＮＭＲ（２５０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：３．５４（２Ｈ，ｄ，Ｊ＝５．０Ｈｚ）、４．８５−４．８９（１Ｈ，ｍ）、５．１１（２Ｈ，ｓ）、５．６３（１Ｈ，ｄ，Ｊ＝７．０Ｈｚ）、７．０４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）、７．２０−７．５０（１０Ｈ，ｍ）、８．２０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３３５６，１７７４，１７５４，１６８２，１６５６，１６２４，１５９８，１５６０，１５２８，１４９０，１４５８，１４４２，１４２２，１３５０，１３２８，１３１２，１２７８，１２３４，１２０６，１１７０，１１４４，１１１２，１０９０，１０４２，１０２８，１０１６，９９０，９７４，９２８，９１０，８８８，８６４，８５０，７８２，７５８，７４２，７１４，６９４，６５８，６３２，６１８，６００，５８２，５４２，４７０，４４２，４１８．
実施例２−２
ビス−ｐ−ニトロフェニル亜硫酸を用いるｐ−ニトロフェニルエステルの合成 温度計、冷却器、撹拌装置を付した１００ｍｌの四つ口フラスコにｐ−ニトロフェノール１３．９ｇ（０．１ｍｏｌ）を取り、乾燥ジエチルエーテル５０ｍｌに溶解し、塩化チオニル６．０ｇ（０．０５ｍｏｌ）を加えた後、０℃に冷却した。撹拌下にトリエチルアミン１０．１ｇ（０．１ｍｏｌ）を乾燥ジエチルエーテル１０ｍｌに溶解した溶液を徐々に滴下した。滴下と同時に、白煙、発熱を伴って結晶が析出してきた。滴下終了後、冷却下に１時間、室温で１時間撹拌した。再度５℃に冷却して反応液を濾別し、残渣を乾燥冷ジエチルエーテルで洗浄した。この残渣を約５０ｍｌの水に懸濁し、濾別して冷水で洗浄した。
更に、５０ｍｌの冷エタノールに懸濁し、濾別し、冷エタノール次いで冷ジエチルエールで洗浄して乾燥してｍ．ｐ １０５−１０６℃の類白色結晶のビス−ｐ−ニトロフェニル亜硫酸を１２．７ｇ（収率：７８．３％）を得た。
ＩＲ（ＫＢｒ，ｃｍ−１）：３４７２，３１２８，３０９２，１６１８，１５９２，１５１８，１４８８，１４６０，１３５２，１３２４，１２９６，１２３８，１１９８，１１８０，１１６４，１１５４，１１１２，１１０２，１０１０，８６２，８３２，８２４，７５８，７１８，７００，６５０，６２６，５３２，４８０，４１８．
温度計、冷却器、撹拌装置を付した５０ｍｌの三つ口フラスコにＮ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン（化合物２：光学純度９８．６％ｅｅ）１．０ｇ（０．００３ｍｏｌ）をジメチルホルムアミド５ｍｌとピリジン５ｍｌに溶解し、室温でビス−ｐ−ニトロフェニル亜硫酸２．９ｇ（０．００９ｍｏｌ）を添加した。その後、室温で３．５時間反応した後、２００ｍｌの氷水中に投入し希塩酸でｐＨ＝２とした。酢酸エチル１５０ｍｌで抽出し、酢酸エチル層を水洗した。更に、酢酸エチル層を１０％水酸化ナトリウム水溶液で洗浄、水洗後、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。酢酸エチル層を減圧濃縮して白色固体のｐ−ニトロフェニルエステルを１．２５ｇ（収率：９１％）得た。ＨＰＬＣ；９６％
^１Ｈ ＮＭＲ（６０ＭＨｚ：ＣＤＣｌ_３，δ，ｐｐｍ）：３．６２（２Ｈ，ｄ，Ｊ＝５Ｈｚ）、４．７０−４．９８（１Ｈ，ｍ）、５．２２（２Ｈ，ｓ）、５．７７（１Ｈ，ｄ，Ｊ＝８Ｈｚ）、７．２２（２Ｈ，ｄ，Ｊ＝９Ｈｚ）、７．２８−７．７３（１０Ｈ，ｍ）、８．４３（２Ｈ，ｄ，Ｊ＝９Ｈｚ）．
実施例 ２−３
ビス−ｐ−ニトロ亜硫酸を単離しないで、ｐ−ニトロフェニルエステルを合成する方法
温度計、冷却器、攪拌機、窒素導入管を付した１０ＬのセパラブルフラスコにＮ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン（化合物２：光学純度９８．６％ｅｅ）４９７．０ｇ（１．５ｍｏｌ：１．０ｅｑ）、ｐ−ニトロフェノール２３０．９ｇ（１．６５ｍｏｌ；１．１ｅｑ）をトルエン７．０Ｌに懸濁し、トリエチルアミン３３３．９ｇ（３．３ｍｏｌ；２．２ｅｑ）を加えた。添加後、懸濁溶液が溶解し黄色溶液となった。黄色溶液をドライアイス−アセトンバスで−７℃前後に冷却し、塩化チオニル１９６．３ｇ（１．６５ｍｏｌ；１．１ｅｑ）をトルエン０．５Ｌに溶解した液を、−５℃で０．５時間で滴下した。
滴下終了後、０℃で３時間攪拌し、ドライアイス−アセトンバスをはずし、５０℃±２℃でさらに３時間攪拌した。ＨＰＬＣで化合物（２）が０．２％以下になったことを確認し、反応を止めた、２Ｌの水で２回洗浄し、５％炭酸水素ナトリウム水溶液２Ｌで２回洗浄し、さらに２Ｌの水で２回洗浄しｐ−ニトロフェニルエステルを含むトルエン溶液を得た。無水硫酸ナトリウムで乾燥した後、トルエンを減圧留去して残渣を得た。この残渣を酢酸エチル２Ｌで加熱溶解後、攪拌下にｎ−ヘキサン１０Ｌを加え、結晶を析出させた。この結晶を濾過し、ｎ−ヘキサン／酢酸エチル＝５／１２Ｌで洗浄後乾燥し、類白色結晶状のｐ−ニトロフェニルエステルを得た。
収量：６５０ｇ（収率：９５．７％）
ｍ．ｐ ９１−９４℃、ＨＰＬＣ；９８．５％
［実施例 ３］
３−ベンジルオキシカルボニルアミノ−１−（１’，１’−ジメチルオキシスルフラニル）−４−フェニルスルファニルブタン−２−オン（化合物５：以下の実施例において「イリド化合物」と記す）の合成
実施例３−１
水素化ナトリウムとトリメチルスルホキソニウムヨーダイドから生成させたコーリー試薬（ジメチルスルホキソニウムメチリド）とイミドエステルとを用いるイリド化合物の合成
温度計、冷却器、撹拌機を付した１００ｍｌ四ツ口フラスコにＮａＨ（６０％）０．１８６ｇ（４．６６ｍｍｏｌ；２．０ｅｑ）を取り、ｎ−ヘキサン５ｍｌで２回洗浄した後、乾燥ＤＭＳＯ１０ｍｌに懸濁した。窒素気流下にトリメチルスルホキソニウムヨーダイド（ＴＭＳＯＩ）１．０３ｇ（４．６６ｍｍｏｌ；２．０ｅｑ）を少量ずつ添加した。発泡、発熱を伴いＮａＨが溶解する。
添加終了後、１０分間撹拌した後、油浴中で５５℃に３０分加熱撹拌し、コーリー試薬を調製した。
その後、ＴＨＦ１０ｍｌを加えてドライアイス−アセトンバスで−１２℃に冷却した。−１２℃でイミドエステル１．０ｇ（２．３３ｍｍｏｌ）を乾燥ＴＨＦ５ｍｌに溶解してコーリー試薬中に滴下し、５ｍｌのＴＨＦで洗浄した。滴下と同時に白濁し若干発熱した。滴下終了後、同温度で１．７５時間反応した。
反応液を氷水中にあけＡｃＯＥｔ １００ｍｌで抽出した。水層を更にＡｃＯＥｔ １００ｍｌで抽出し、ＡｃＯＥｔ層を合わせＮａＣｌａｑで洗浄後、無水Ｎａ２ＳＯ４で乾燥後、濃縮して微黄色油状物１．０ｇを得た。ＨＰＬＣ；９４％。これをシリカゲルカラムクロマトグラフィー（ワコーゲルＣ３００：１５０ｍｌ；ベンゼン／アセトン＝２／１）にて分離精製し、微黄色油状物のイリド化合物を０．７９ｇ（収率：８３．６％：ＨＰＬＣ；９８．８％）得た。
^１Ｈ ＮＭＲ（６０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：３．０７（６Ｈ，ｓ）、３．１３（２Ｈ，ｄ，Ｊ＝５Ｈｚ）、３．８７−４．３３（２Ｈ，ｍ）、４．８７（２Ｈ，ｓ）、５．８０（１Ｈ，ｄ，Ｊ＝８Ｈｚ）、６．７７−７．１８（１０Ｈ，ｍ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３０４０，２９３２，１７１８，１６４０，１５６２，１５４４，１５１０，１４８２，１４６０，１４４２，１３９８，１３３４，１２４８，１１９２，１１３８，１０８８，１０２６，９４２，８９８，８５６，７４２，６８２，４２０．
実施例３−２
水素化ナトリウムとトリメチルスルホキソニウムブロミドから生成させたコーリー試薬とイミドエステルとを用いるイリド化合物の合成
温度計、冷却器、窒素導入管、滴下ロート、撹拌機を付した１００ｍｌ四ツ口フラスコにＮａＨ（６０％）０．７４７ｇ（１８．６４ｍｍｏｌ；２．０ｅｑ）を取り、ｎ−ヘキサン１０ｍｌで２回洗浄した後、乾燥ＤＭＳＯ４０ｍｌに懸濁した。窒素気流下にトリメチルスルホキソニウムブロミド（ＴＭＳＯＢ）３．２３ｇ（１８．６４ｍｍｏｌ；２．０ｅｑ）を少量ずつ添加した。発泡、発熱を伴いＮａＨが溶解する。添加終了後、１０分間撹拌した後、油浴中で５５℃に６０分加熱撹拌し、コーリー試薬を調製した。
調製したコーリー試薬を室温まで戻し、ＴＨＦ４０ｍｌを加えた後、ドライアイス−アセトンバスにより−１２℃に冷却した。イミドエステル４．０ｇ（９．３４ｍｍｏｌ）を乾燥ＴＨＦ２０ｍｌに溶解した溶液を滴下ロートに仕込み、内温が−１０℃以上にならないようにして１０分間でコーリー試薬中に滴下し、５ｍｌのＴＨＦで洗浄した。滴下終了後、同温度で１時間撹拌し、２時間かけて０℃まで昇温させて反応を停止した。反応液を氷水２００ｍｌにあけＡｃＯＥｔ２５０ｍｌで抽出した。水層を更にＡｃＯＥｔ１００ｍｌ×２で抽出して有機層を合わせ、飽和食塩水２００ｍｌ×２で有機層を洗浄し、無水Ｎａ２ＳＯ４で乾燥後、濃縮して茶褐色油状物のイリド化合物を３．８９ｇ得た。ＨＰＬＣ；９０％
^１Ｈ ＮＭＲ（６０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：３．０７（６Ｈ，ｓ）、３．１３（２Ｈ，ｄ，Ｊ＝５Ｈｚ）、３．８７−４．３３（２Ｈ，ｍ）、４．８７（２Ｈ，ｓ）、５．８０（１Ｈ，ｄ，Ｊ＝８Ｈｚ）、６．７７−７．１８（１０Ｈ，ｍ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３０４０，２９３２，１７１８，１６４０，１５６２，１５４４，１５１０，１４８２，１４６０，１４４２，１３９８，１３３４，１２４８，１１９２，１１３８，１０８８，１０２６，９４２，８９８，８５６，７４２，６８２，４２０．
実施例３−３
水素化ナトリウムとトリメチルスルホキソニウムブロミドから生成させたコーリー試薬とｐ−ニトロフェニルエステルとを用いるイリド化合物の合成
温度計、冷却器、窒素導入管、滴下ロート、撹拌機を付した１００ｍｌ四ツ口フラスコにＮａＨ（６０％）０．３５４ｇ（８．８４ｍｍｏｌ；２．０ｅｑ）を取り、ｎ−ヘキサン５ｍｌで２回洗浄した後、乾燥ＤＭＳＯ２０ｍｌに懸濁した。
窒素気流下にトリメチルスルホキソニウムブロミド（ＴＭＳＯＢ）１．５３ｇ（８．８４ｍｍｏｌ；２．０ｅｑ）を少量ずつ添加した。発泡、発熱を伴いＮａＨが溶解する。添加終了後、１０分間撹拌した後、油浴中で５５℃に６０分加熱撹拌し、コーリー試薬を調製した。
調製したコーリー試薬を室温まで戻し、ＴＨＦ２０ｍｌを加えた後、ドライアイス−アセトンバスにより−１２℃に冷却した。
ｐ−ニトロフェニルエステル２．０ｇ（４．４２ｍｍｏｌ）を乾燥ＴＨＦ２０ｍｌに溶解した溶液を滴下ロートに仕込み、内温が−１０℃以上にならないようにして１０分間でコーリー試薬中に滴下し、５ｍｌのＴＨＦで洗浄した。滴下終了後、同温度で２時間撹拌した。
反応液を氷水１００ｍｌにあけＡｃＯＥｔ１５０ｍｌで抽出した。水層を更にＡｃＯＥｔ５０ｍｌ×２で抽出して有機層を合わせ、飽和食塩水５０ｍｌ×５で有機層を洗浄し、無水Ｎａ２ＳＯ４で乾燥後、濃縮して茶褐色油状物のイリド化合物を１．５８ｇ（収率：８８．２％：ＨＰＬＣ；８１．２％）得た。
^１Ｈ ＮＭＲ（６０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：３．０７（６Ｈ，ｓ）、３．１３（２Ｈ，ｄ，Ｊ＝５Ｈｚ）、３．８７−４．３３（２Ｈ，ｍ）、４．８７（２Ｈ，ｓ）、５．８０（１Ｈ，ｄ，Ｊ＝８Ｈｚ）、６．７７−７．１８（１０Ｈ，ｍ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３０４０，２９３２，１７１８，１６４０，１５６２，１５４４，１５１０，１４８２，１４６０，１４４２，１３９８，１３３４，１２４８，１１９２，１１３８，１０８８，１０２６，９４２，８９８，８５６，７４２，６８２，４２０．
実施例３−４
イミドエステル合成反応液と、トリメチルスルホキソニウムブロミドと水素化ナトリウムとから生成させたコーリー試薬とを用いるイリド化合物の合成
温度計、冷却器、撹拌機を付した１００ｍｌ四ツ口フラスコにＮ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン（化合物２：光学純度９８．６％ｅｅ）３．３１ｇ（０．０１ｍｏｌ）およびＮ−ヒドロキシコハク酸イミド１．３８ｇ（０．０１２ｍｏｌ）を取り、テトラヒドロフラン５０ｍｌに懸濁し、トリエチルアミン２．４３ｇ（０．０２４ｍｏｌ）を添加してドライアイス−アセトンバスで−２℃に冷却した。塩化チオニル１．４３ｇ（０．０１２ｍｏｌ）をテトラヒドロフラン３ｍｌと混合し、−１℃でゆっくり滴下した。その後、−５℃で１時間、室温で１時間攪拌した。反応の終点は、ＴＬＣ，ＨＰＬＣで確認した。
別に以下の方法でコーリー試薬（ジメチルスルホキソニウムメチリド）を調製した。
温度計、冷却器、撹拌機を付した１００ｍｌ四ツ口フラスコに窒素気流中、ＮａＨ（６０％）０．８ｇ（０．０２ｍｏｌ）を。乾燥ＤＭＳＯ３０ｍｌに懸濁し、トリメチルスルホキソニウムブロミド（ＴＭＳＯＢ）３．４６ｇ（０．０２ＭＯＬ）を少量ずつ添加した。発泡、発熱を伴いＮａＨが溶解する。添加終了後、１０分間攪拌した後、油浴中で５５℃に３０分加熱攪拌し、コーリー試薬を調製した。この溶液にテトラヒドロフラン１０ｍｌを加え、ドライアイス−アセトンバスで−５℃に冷却した。
このコーリー試薬の溶液に、先に合成したイミドエステル反応液から析出した結晶を濾別し、濾液を−４℃で滴下した。滴下終了後、５℃以下で１時間攪拌した後、反応液を３００ｍｌの氷水に投入した。５０ｍｌのｎ−ヘキサンを加えて攪拌すると結晶が析出した。この結晶を濾別しよく水洗乾燥してｍ．ｐ．１０６−１１２℃の微黄色結晶のイリド化合物を２．８５ｇ（収率：７０．４％）得た。
実施例３−５
ｐ−ニトロフェニルエステル合成反応液と、トリメチルスルホキソニウムブロミドとカリウム ｔｅｒｔ−ブトキシドとから生成させたコーリー試薬とを用いるイリド化合物の合成
温度計、冷却器、撹拌機を付した１００ｍｌ四ツ口フラスコにＮ−ベンジルオキシカルボニル−Ｓ−フェニル−Ｌ−システイン（化合物２：光学純度９８．６％ｅｅ）３．３１ｇ（０．０１ｍｏｌ）およびｐ−ニトロフェノール１．６７ｇ（０．０１２ｍｏｌ）を取り、テトラヒドロフラン３０ｍｌに懸濁し、トリエチルアミン２．４３ｇ（０．０２４ｍｏｌ）を添加してドライアイス−アセトンバスで−５℃に冷却した。塩化チオニル１．４３ｇ（０．０１２ｍｏｌ）をテトラヒドロフラン３ｍｌと混合し、−５℃でゆっくり滴下した。その後、−５℃で１．５時間、室温で２昼夜攪拌した。反応の終点は、ＴＬＣ，ＨＰＬＣで確認した。別に以下の方法でコーリー試薬（ジメチルスルホキソニウムメチリド）を調製した。
温度計、冷却器、撹拌機を付した１００ｍｌ四ツ口フラスコに窒素気流中、カリウム−ｔｅｒｔ−ブトキシド２．８ｇ（０．０２５ｍｏｌ）を乾燥ｔ−ブタノール６０ｍｌに懸濁し、トリメチルスルホキソニウムブロミド（ＴＭＳＯＢ）４．３３ｇ（０．０２５ｍｏｌ）を少量ずつ添加した。添加終了後、１０分間攪拌した後、油浴中で６５℃〜７５℃に３０分加熱攪拌し、コーリー試薬を調製した。この溶液にテトラヒドロフラン４０ｍｌを加え、ドライアイス−アセトンバスで−５℃に冷却した。
このコーリー試薬の溶液に、先に合成したｐ−ニトロフェニルエステル反応液から析出した結晶を濾別し、濾液を−４℃で滴下した。滴下終了後、５℃以下で３時間攪拌した後、反応液を３００ｍｌの氷水に投入した。酢酸エチルで抽出し、酢酸エチル層を２％水酸化ナトリウム水溶液、次いで水洗、飽和食塩水でよく洗浄した。無水硫酸ナトリウムで乾燥後、酢酸エチルを濃縮して油状物のイリド化合物を３．５１ｇ（収率：８６．６％）得た。
実施例３−６
ｐ−ニトロフェニルエステルと、トリメチルスルホキソニウムブロミドとカリウム ｔｅｒｔ−ブトキシドとから生成させたコーリー試薬とを用いるイリド化合物の合成
温度計、冷却器、撹拌機を付した２００ｍｌの四ツ口フラスコに窒素気流中、乾燥したｔ−ブタノール５０ｍｌを取り、カリウム ｔｅｒｔ−ブトキシド２．２４ｇ（０．０２ｍｏｌ；４．０ｅｑ）を加えた。室温（２５℃）でトリメチルスルホキソニウムブロミド（ＴＭＳＯＢ）３．４６ｇ（０．０２ｍｏｌ；４．０ｅｑ）を少量づつ添加した。ＴＭＳＯＢ添加後、７０−７５℃に３０分間加熱攪拌し、メチリドを調製した。
室温まで冷却し、ＴＨＦ５０ｍｌを加え、更にドライアイス−アセトンバスで−１２℃に冷却した。−１２℃でｐ−ニトロフェニルエステル（ＨＰＬＣ；９９．６ａｒｅａ％）２．２６ｇ（０．００５ｍｏｌ）を固体のまま添加した。０．５時間後にＨＰＬＣでモニターし、１時間で反応を止めて、反応液を６００ｍｌの氷水中に投入した。一部結晶の析出が見られたが、酢酸エチルで抽出した。酢酸エチル層は水洗、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥後、濃縮して油状物２．１９ｇを得た。水層は１００ｍｌの酢酸エチル抽出し、同様の処理をして油状物０．１９ｇを得た。
両油状物を合わせ、シリカゲルクロマト（シリカゲル６０Ｎ，１５０ｍｌ、ベンゼン／アセトン＝１／１展開）精製して微黄色結晶１．９１ｇを得た。ｍ．ｐ．８９−９５℃
これをＨＰＬＣで４，４’−ジメチルベンゾフェノンを内部標準物質として内部標準法で定量すると純度９５．８％を示すイリド化合物を１．８３ｇ（収率：９０．３％）得た。
実施例３−７
ｐ−ニトロフェニルエステルとトリメチルスルホキソニウムブロミドとナトリウム ｔｅｒｔ−ブトキシドから生成させたコーリー試薬とを用いたトルエン溶媒でのイリド化合物の合成
温度計、冷却器、攪拌機、窒素導入管を付した１Ｌの四つ口フラスコにナトリウム ｔｅｒｔ−ブトキシド２２．１ｇ（０．２３ｍｏｌ；２．３ｅｑ）、ｔｅｒｔ−ブタノール２５ｍｌ、トルエン２２５ｍｌを仕込み、４５℃で攪拌した。この混合物に、トリメチルスルホキソニウムブロミド３９．８１ｇ（０．２３ｍｏｌ；２．３ｅｑ）を加え、１時間攪拌して、コーリー試薬を調製した。
このコーリー試薬を−１０℃に冷却し、攪拌下、この中にｐ−ニトロフェニルエステル［４６．１７ｇ（０．１ｍｏｌ；１．０ｅｑ）］をトルエン４５０ｍｌに溶解した液を２０分かけて滴下した。滴下後、同温度で２．５時間攪拌を続けた。ついでこの反応混合物を３５℃に加温後、温水２５０ｍｌを加え３５℃で２０分攪拌した。反応液を分液ロートに移し分液し、得られたトルエン液を２Ｌフラスコに移し、バス温５０℃で共沸脱水し、さらにトルエン液を１Ｌフラスコに移し、減圧濃縮して液量を２００ｇとした。得られたトルエン液を温め、攪拌しながらｎ−ヘキサン２０ｍｌを加え攪拌下自然冷却し、結晶を析出させた。この結晶を濾取し、トルエン７０ｍｌで洗浄後、乾燥し、白色結晶状のイリド化合物を得た。
収量：３８．５２ｇ（収率：９４．９％）、ｍ．ｐ ９２−９６℃、ＨＰＬＣ：９８．８％
［α］＝−２２．７°（ｃ１．０アセトニトリル、２３．５℃）
［実施例 ４］
３−ベンジルオキシカルボニルアミノ−１−クロロ−４−フェニルスルファニルブタン−２−オン（化合物６、以下の実施例において「クロロメチルケトン」と記す）の合成
実施例 ４−１
ＨＣｌ／酢酸エチル溶液を用いたクロロメチルケトンの合成
イリド化合物０．７８ｇ（１．９２ｍｍｏｌ）を温度計、冷却器、撹拌機を付した１００ｍｌ四ツ口フラスコに取り、酢酸エチル３０ｍｌに溶解し、ドライアイス−アセトンバスで−２０℃に冷却した。−２０℃で２．１８Ｎ ＨＣｌ／ＡｃＯＥｔ１．０６ｍｌ（１．２ｅｑ）を滴下した。反応液は白濁した。その後、１時間自然昇温で撹拌した。（−１０℃まで）。ドライアイス−アセトンバスをはずし、室温に戻した後、オイルバスで７８℃で２０分加熱した。冷却後、反応液に酢酸エチル１００ｍｌと水１００ｍｌを加え抽出した。酢酸エチル層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。
水層を１００ｍｌの酢酸エチルで抽出し、同様に乾燥した。酢酸エチル層を合わせ減圧濃縮して微黄色固体のクロロメチルケトンを０．６６ｇ（収率：９２．８％：ＨＰＬＣ；９１．０％）得た。
^１Ｈ ＮＭＲ（６０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：３．１３（２Ｈ，ｄ，Ｊ＝６Ｈｚ）、３．９４（２Ｈ，ｓ）、４．２７−４．６２（１Ｈ，ｍ）、４．８５（２Ｈ，ｓ）、５．４０（１Ｈ，ｄ，Ｊ＝８Ｈｚ）、６．８３−７．２０（１０Ｈ，ｍ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３３６８，１７３６，１７１２，１６８４，１６４６，１６３６，１５１６，１４８６，１４７０，１４５８，１４４４，１４１２，１３９６，１３１６，１２７０，１２３４，１１８０，１１５２，１０８４，１０３６，９７２，８５４，７７８，７４８，７３６，６９８，６２８，５８６，５０８，４９２，４３６．
旋光度：［α］−８７．０°（ｃ１．０ ｉｎ ＭｅＯＨ）
実施例 ４−２
ＨＣｌ／テトラヒドロフラン溶液を用いたクロロメチルケトンの合成
イリド化合物２．０３ｇ（５．０ｍｍｏｌ）を温度計、冷却器、撹拌機を付した２００ｍｌ四つ口フラスコに取り、トルエン６０ｍｌを加えて懸濁させ、０℃に冷却した。この白色懸濁液に、塩化水素ガスをテトラヒドロフランに吹き込んで調製した、６．１％塩化水素／テトラヒドロフラン溶液３．０ｇ（５ｍｍｏｌ）を５分で滴下し、同温度で２時間撹拌した。オイルバスにより、６５℃に昇温し、４時間反応させた。反応混合物は黄色透明溶液になった。原料消失を確認後、冷却し、トルエン１００ｍｌを加え、飽和食塩水３０ｍｌで２回洗浄し、さらに水３０ｍｌで２回洗浄した。このトルエン溶液を無水硫酸ナトリウムで乾燥し、減圧濃縮し、茶白色結晶状のクロロメチルケトンを得た。収量１．６９ｇ（収率９２．９％，ＨＰＬＣ９３．８％，ｍ．ｐ．８７−９１℃）
比旋光度：［α］＝−７６．９°（ｃ１．０，２５．０℃，ＭｅＯＨ）
実施例 ４−３
ＨＣｌ／ジエチルエーテル溶液を用いたクロロメチルケトンの合成
イリド化合物１２．３ｇ（３０．４ｍｍｏｌ）を温度計、冷却器、撹拌機を付した１Ｌの四つ口フラスコに取り、トルエン４９８ｍｌを加えて懸濁させ、０℃に冷却した。この白色懸濁液に、塩化水素ガスをジエチルエーテルに吹き込んで調製した、１Ｍ塩化水素／ジエチルエーテル溶液３１ｍｌ（３１ｍｍｏｌ）を３０分で滴下し、同温度で１時間撹拌した。オイルバスにより、６５℃に昇温し、３時間反応させた。この反応混合物は黄色透明溶液になった。この反応混合物の原料消失を確認後、冷却して水１００ｍｌで５回洗浄した。このトルエン液を無水硫酸ナトリウムで乾燥し、減圧濃縮して、茶白色結晶状のクロロメチルケトンを得た。収量１０．４ｇ（収率９３．９％，ＨＰＬＣ９４．２％，ｍ．ｐ．８６−９１℃）得られた。
比旋光度：［α］＝−８０．０°（ｃ１．０，２４．０℃，ＭｅＯＨ）
［実施例 ５］
（２Ｓ，３Ｒ）３−ベンジルオキシカルボニルアミノ−１−クロロ−４−フェニルスルファニルブタン−２−オール（化合物１：以下の実施例において「クロロアルコール」と記す）の合成
実施例 ５−１
アルミニウムイソプロポキシドを用いたクロロアルコールの合成
温度計、冷却器、撹拌機を付した５０ｍｌ三ツ口フラスコに、クロロメチルケトン０．４ｇ（１．１ｍｍｏｌ）及びアルミニウムイソプロポキシド［Ａｌ（ＰｒＯ−ｉ）_３］０．２２５ｇ（１．１ｍｍｏｌ）を取り、イソプロパノール１０ｍｌを加えた後、６０℃〜７０℃で加熱撹拌した。ＴＬＣ及びＨＰＬＣモニターで原料クロロメチルケトンの消失を確認し、１．５時間で反応を停止した。冷却後、反応液を氷水中に投入した後、希塩酸でｐＨ＝２−３とした。析出した白色結晶を濾別、良く水洗し乾燥した。
白色結晶、収量：０．３２４ｇ（収率：８１％）ＨＰＬＣ；９７．４６％、ｓｙｎ／ａｎｔｉ＝９０．４４／７．０２
これをｎ−ヘキサン／酢酸エチル＝６／２ｍｌより再結晶して、ｍ．ｐ １１５−１１６℃のクロロアルコールを０．１９４ｇ（収率：４８．５％）得た。
ＨＰＬＣ；９８．９９％、ｓｙｎ／ａｎｔｉ＝９８．２２／０．７７
^１Ｈ ＮＭＲ（２５０ＭＨｚ；ＣＤＣｌ_３，δ，ｐｐｍ）：２．７９（１Ｈ．ｄ，Ｊ＝１．９５Ｈｚ）、３．２９（２Ｈ，ｄ，Ｊ＝３．９１Ｈｚ）、３．５９−３．７０（２Ｈ，ｍ）、３．９２（２Ｈ，ｔ，ｔ，Ｊ＝０．９８Ｈｚ，３．４２Ｈｚ）、５．０７（２Ｈ，ｓ）、５．１４（１Ｈ，ｄ，Ｊ＝２．４４Ｈｚ）、７．１９−７．３９（１０Ｈ，ｍ）．
ＩＲ（ＫＢｒ，ｃｍ−１）：３３５６，３０７２，２９７６，２９５２，１６９０，１６４６，１５８８，１５３６，１５０６，１４８４，１４７０，１４５６，１４４０，１３４０，１２９４，１２５０，１２２６，１１３６，１１１０，１０９０，１０６８，１０２８，９７０，９３６，９１０，８７４，８３６，７７８，７４２，７３０，６９４，６５８，６１４，５８０，４７６．
旋光度［α］−７７．９°（ｃ１．０ ｉｎ ＭｅＯＨ）
実施例 ５−２
アルミニウム−ｓｅｃ−ブチレートを用いたクロロアルコールの合成
温度計、冷却器、攪拌機、シリカゲル乾燥管を付した２００ｍｌの四つ口フラスコにアルミニウムｓｅｃ−ブチレート［Ａｌ（ＯＢｕ−ｓ）３］３．０８ｇ（１２．５ｍｍｏｌ；０．５ｅｑ）を２−ブタノール１５ｍｌ及びトルエン５０ｍｌをよく混合して溶液にした。次いで、室温（１７℃）で攪拌しながら、この混合物に粉状のクロロメチルケトン９．１ｇ（２５ｍｍｏｌ；１．０ｅｑ）を加え、さらにトルエン２５ｍｌを加えた。室温で攪拌しながらＨＰＬＣモニターで原料クロロメチルケトンの消失を確認し、４．５時間で攪拌を止めた。この反応物を分液ロートに移し、酢酸エチル１５０ｍｌを加え、５％塩酸水溶液７５ｍｌで１回、ついで１％塩酸水溶液７５ｍｌで１回、ついで水７５ｍｌで２回洗浄した後、有機層を取り出し、無水硫酸ナトリウムで乾燥した。洗浄に使用した５％塩酸水溶液、１％塩酸水溶液及び水層を合わせて酢酸エチル液３０ｍｌで再抽出し、酢酸エチル液を無水硫酸ナトリウムで乾燥した。３Ｇグラスフィルターを使用して濾過、溶媒を留去して白色結晶状のクロロアルコールを得た。収量８．８５ｇ（収率：９６．６９％）。
ＨＰＬＣ；９８．６７％
ｓｙｎ／ａｎｔｉ＝９５．１２／３．５０
この白色結晶８．８５ｇにトルエン８８ｍｌを加え、バス温７０−７５℃で溶解後、３００ｍｌのビーカーに移し、攪拌下にｎ−ヘキサン４４ｍｌを滴下して再度結晶させた。再結晶物を濾取し、トルエン／ｎ−ヘキサン＝２／１ ３０ｍｌで洗浄後、乾燥し白色結晶状のクロロアルコールを得た。白色結晶、収量：８．３２ｇ（収率：９２．１１％）
ｍ．ｐ １１６−１１７℃
ＨＰＬＣ；９９．７２％、ｓｙｎ／ａｎｔｉ＝９９．３３／０．３９
産業上の利用可能性
本発明方法は、従来法におけるように危険な試薬の使用を必要とせず、また工程も短く、３−ベンジルオキシカルボニルアミノ−１−ハロゲノ−４−フェニルチオブタン−２−オールを有利に製造する方法を提供する。従って、これより誘導することができるＨＩＶプロテアーゼ阻害剤として有用な［３Ｓ−（３α，４ａβ，８ａβ）］−２−［２’−ヒドロキシ−３’−フェニルチオメチル−４’−アザ−５’−オキソ−５’−（２”−メチル−３”−ヒドロキシフェニル）ペンチル］デカヒドロイソキノリン−３−Ｎ−ｔ−ブチルカルボキシアミドを工業的に有利に製造し提供することができる。Technical field
The present invention relates to a halogeno alcohol represented by the formula (1), a (2S, 3R) N-benzyloxycarbonyl 3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative (Compound No. 1, hereinafter referred to as halogeno alcohol). (May be referred to as alcohol). This halogeno alcohol is [3S- (3α, 4aβ, 8aβ)]-2- [2′-hydroxy-3′-phenylthio represented by the following formula (7), which is a compound extremely useful as an HIV protease inhibitor. Methyl-4'-aza-5'-oxo-5 '-(2 "-methyl-3" -hydroxyphenyl) pentyl] as an intermediate for the preparation of decahydroisoquinoline-3-Nt-butylcarboxamide Useful. The present invention further relates to a novel active ester compound and an ylide compound for producing the halogeno alcohol.
In addition, in description of a compound name, "benzyloxycarbonyl" may be abbreviated as "Cbz" below.

Background art
As a method for producing the compound represented by the above formula (7), for example, the following method is known. That is,
1) A method in which serine is used as a starting material and is produced via an azide compound (WO95 / 09843).
2) A method of producing 2-butene-1,4-diol as a starting material via a chiral amine (WO 97/11937, WO 97/11938).
3) A method of producing from a 1,3-oxazolidin-2-one derivative via diamino alcohol (JP-A-11-279154).
In the production of the compound represented by the above formula (7) by the above method, any of the methods is produced via a halogeno alcohol represented by the formula (1) as an intermediate. However, when producing this halogeno alcohol, that is, (2S, 3R) N-Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative, the method 1) is an intermediate step. There is an inefficiency in the process, such as the use of explosive diazomethane and the need for constant low-temperature reaction conditions. The method 2) uses a large amount of methylene chloride, whose use is regulated industrially. Each of the conventional manufacturing methods has a problem, for example, the method of 3) requires a long number of steps. Therefore, a method for safely and inexpensively producing the compound of the above formula (7), which is a compound extremely useful as an HIV protease inhibitor, is desired.
In view of the above situation, an object of the present invention is to provide an HIV protease inhibitor [3S- (3α, 4aβ, 8aβ)]-2- [2′-hydroxy-3′-phenylthiomethyl-4′-aza-5. '-Oxo-5'-(2 "-methyl-3" -hydroxyphenyl) pentyl] is an intermediate for the production of decahydroisoquinoline-3-N-t-butylcarboxamide (formula (7)). The production of the (2S, 3R) N-Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative (formula (1)), which had various problems, was efficiently carried out by an improved novel method. An object of the present invention is to provide a manufacturing method which is frequently performed.
Another object of the present invention is to provide a novel intermediate compound useful for producing the compound and a method for producing the same.
Disclosure of the invention
The present inventors have conducted intensive studies in accordance with the above-mentioned object, and as a result, using a known compound N-Cbz-S-phenyl-L-cysteine represented by the following formula (2) as a starting material, a novel active ester derivative (the following formula ( 4)) and a novel ylide compound (following formula (5)) and a halomethylketone intermediate (following formula (6)) to obtain a halogeno alcohol represented by formula (1), ie, (2S, 3R) N The present inventors have found a method for efficiently producing a -Cbz-3-amino-1-halogeno-4-phenylsulfanylbutan-2-ol derivative, and have completed the present invention.
ADVANTAGE OF THE INVENTION According to the method of this invention, the problem in the conventional method is solved and the target compound can be manufactured with a mild reaction condition and a short process with a good yield.
That is, the gist of the present invention is:
A compound (2) represented by the following formula (2):

Reacting the compound represented by the general formula (3) (compound (3)) with a condensing agent,

(In the formula (3), Z represents a linear or branched C ₁ ~ C ₄ Alkoxy group, C ₁ ~ C ₄ Alkylthio group, phenoxy group, or halogen atom, nitro group, alkyl group, alkoxy group, or hydroxy-substituted phenoxy group, phenylthio group, or halogen atom, nitro group, alkyl group, alkoxy group, or hydroxy-substituted phenylthio group, benzyl Oxy group or halogen atom, nitro group, alkyl group or benzyloxy group substituted with alkoxy group, benzylthio group or halogen atom, nitro group, alkyl or alkoxy group substituted benzylthio group, pyridyloxy group, pyridylthio group, ethoxyvinyloxy group , Linear or branched C ₁ ~ C ₄ Alkylcarbonyloxy group, substituted phosphate group, substituted sulfate group, imidazolyl group, azide group, alkoxycarbonyloxy group, cyclohexylcarbodiimidoxy group, succinimidoxy group, phthalimidoxy group, benzotriazolyloxy group, piperidinooxy group and R represents a halogen atom, and R represents a hydrogen atom. However, when Z is a halogen atom in the following general formula (4), ZR together form thionyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl bromide, or oxal chloride. Represents )
The following general formula (4)

(In the formula (4), Z is as described above.)
A step of converting into a compound (4) represented by
Reacting the obtained compound (4) with a methylide compound to produce an ylide compound (compound (5)) represented by the following formula (5):

The obtained ylide compound is treated with hydrogen halide to give a halomethyl ketone (compound (6)) represented by the following general formula (6):

(Wherein X represents a halogen atom),
Next, this is a method for producing a halogeno alcohol derivative represented by the general formula (1) by reducing the same.

(Wherein, X represents a halogen atom)
Furthermore, the present invention provides a novel active ester compound represented by the general formula (4) and a novel ylide compound represented by the formula (5).
The method of the present invention uses N-carbobenzoxy-S-phenyl-L-cysteine (compound (2)) represented by the above general formula (2), which is a known compound, as a starting material, and uses the carboxyl group of this compound as a starting material. A step of converting into an active ester compound (compound (4)) represented by the above general formula (4) by esterification, and reacting the obtained active ester compound with a methylide compound to give a compound represented by the above formula (5) A step of producing an ylide compound (compound (5)), a step of treating the obtained ylide compound with hydrogen halide to give a halomethylketone (compound (6)) represented by the following general formula (6), And reducing this to produce a halogeno alcohol derivative represented by the general formula (1).
(I) Active ester compound formation step
In this step, the starting compound N-benzyloxy-S-phenyl-L-cysteine (compound (2)) is converted into another ester of the general formula (3) ZR (formula (3)) in a suitable organic solvent to form an ester. R and Z are the same as described above). As such a compound, preferably, alcohols, phenols, N-hydroxyimides, N-hydroxy heterocyclic compounds and the like can be used, and these compounds may have various substituents. What is necessary is just to be able to introduce the group defined as Z in the definition of (3). Particularly preferred examples of Z include a p-nitrophenoxy group and a succinimidoxy group.
The reaction is carried out, for example, at -20 ° C to 150 ° C in the presence of p-nitrophenol or N-hydroxysuccinimide or the like and a condensing agent such as N, N'-dicyclohexylcarbimide (DCC) or thionyl chloride and a base. The active ester compound of the general formula (4) can be obtained by reacting at a temperature of preferably -10 ° C to 80 ° C.
Further, p-nitrophenol, N-hydroxysuccinimide, or the like is reacted with thionyl chloride in an inert solvent at a temperature of 0 ° C to 50 ° C using twice the amount of a base, for example, triethylamine, to give p-nitrophenylsulfite. Ester or succinimide sulfite is obtained. This is isolated or reacted without isolation with the compound (2) to obtain an active ester compound of the general formula (4). Suitable organic solvents include ether solvents such as dioxane, diethyl ether, tetrahydrofuran and 1,2-diethoxyethane, and aromatic solvents such as benzene, toluene and xylene, and more preferably dioxane and toluene. . The reaction temperature is from -10C to 60C, preferably from 0C to 30C. The reaction time is 30 minutes to 2 days, preferably 1 hour to 24 hours.
The compound of the general formula (4) in which Z is a halogen atom can be directly reacted with a Corey reagent to obtain an ylide compound (5). However, the compound may be converted into an ester compound and then reacted with the Corey reagent. In order to obtain an ester compound using a compound in which Z in the general formula (4) is a halogen atom, compound (2) and a halogenating agent such as thionyl chloride, sulfuryl chloride, phosphorus pentachloride, and trichloride are used in an inert solvent. By reacting with phosphorus, thionyl bromide, oxalyl chloride and the like at -10 ° C to 80 ° C, preferably at 0 ° C to 50 ° C, and then reacting with alcohols, thiols, phenols and the like, An active ester compound can be obtained.
(Ii) a step of producing an ylide compound (hereinafter referred to as an ylide-forming step)
In this step, the active ester compound obtained in (i) is reacted with dimethyl sulfoxomethylide (hereinafter, referred to as a methylide compound. This methylide compound may be referred to as a Corey reagent), An ylide compound (compound (5)) is produced.
In the ylidation step, a mixture containing a methylide compound (hereinafter, referred to as a methylide-containing mixture) usually produced from trimethylsulfoxonium halide is reacted with the ylide compound.
The step of preparing a methylide-containing mixture (hereinafter, referred to as a methylide preparation step) includes a trimethylsulfoxonium halide (preferred halides are bromide and iodide, and particularly preferably bromide) and a base (as a preferable base). , Sodium hydride, potassium tert-butoxide, and sodium tert-butoxide).
Usually, a methylide preparation step and an ylidation step are performed in a series of steps.
Therefore, the solvent used in the step of preparing methylide is selected from solvents that do not adversely affect the step of iridation. Preferred organic solvents include tert-butanol, dimethylsulfoxide, dimethylformamide, 2-methylpyrrolidone, toluene and tetrahydrofuran. One of these solvents or a mixture of two or more thereof is used.
Examples of the two types of solvent mixtures include tetrahydrofuran and dimethyl sulfoxide, tetrahydrofuran and tert-butanol, and tert-butanol and toluene.
The reaction temperature in the process for preparing methylide is 5 to 150 ° C, preferably 20 to 100 ° C, particularly preferably 40 to 85 ° C.
The reaction time of the methylide preparation step is 10 minutes to 20 hours, preferably 30 minutes to 5 hours.
The reaction temperature in the ylidation step is -70 to 100C, preferably -50 to 70C, and particularly preferably -20 to 40C.
The reaction time of the ylidation step is 10 minutes to 20 hours, preferably 30 minutes to 5 hours.
The ester compound obtained in the above-mentioned active ester compound producing step can be used in the ylidation step without separation and purification. That is, an ylide compound can be produced by adding a filtrate obtained by filtering out crystals precipitated in the esterification reaction solution to a separately prepared methylide-containing mixture. As the reaction solvent, a mixed solvent of a solvent suitable for the esterification reaction and a solvent suitable for the methylide preparation step is preferable, and as the suitable mixed solvent, tetrahydrofuran and dimethyl sulfoxide, and tetrahydrofuran and tert-butanol are preferable. In this case, operations such as concentration of the esterification reaction solvent for separating the ester compound and purification of the ester compound can be advantageously omitted.
(Iii) Step of producing halomethyl ketone
The conversion of the ylide compound (5) into the halomethylketone (6) is carried out by reacting the compound with a hydrogen halide at -50 ° C to 100 ° C, preferably -20 ° C to 80 ° C in a suitable organic solvent. Halomethyl ketone (6) can be obtained.
Suitable organic solvents include ethyl acetate, tetrahydrofuran, dichloroethane, toluene and the like, and the reaction time is 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
Examples of the hydrogen halide include hydrogen chloride and hydrogen bromide, and these may be used by dissolving them in an organic solvent. Particularly preferably, hydrogen chloride is used after being dissolved in ethyl acetate, tetrahydrofuran, diethyl ether, toluene or the like.
(Iv) a step of reducing halomethyl ketone (hereinafter referred to as a ketone reduction step)
This ketone reduction step can be advantageously performed by a method based on Meerwein-Pondorf-Verley reduction or a method using sodium borohydride.
In Meerwein-Pondorf-Verley reduction, aluminum isopropoxide, aluminum sec. Is used at a temperature of -30 to 100 ° C, preferably -10 to 70 ° C, using an alcohol such as isopropanol or sec-butanol as a solvent. -Reduction is carried out using an aluminum alkoxide such as butoxide.
The amount of the aluminum alkoxide to be used for the compound (6) can be appropriately selected depending on the reaction conditions, and is usually preferably 0.5 to 3 equivalents, more preferably 1 to 1.5 equivalents. A solvent that does not adversely affect the reaction may be used in combination, and examples thereof include toluene and tetrahydrofuran. The method using sodium borohydride is carried out in an ether solvent or a mixed solvent of an ether solvent and water. Preferably, tetrahydrofuran or a mixed solvent of tetrahydrofuran and water is used. The ratio of the mixed solvent is 1000/1 to 1/10, preferably 100/1 to 1/1, more preferably 10/1 to 5/1. The reaction temperature is -20 to 100C, preferably -10 to 60C.
The amount of sodium borohydride to be used relative to compound (6) is preferably 0.5 to 3 equivalents, more preferably 1 to 1.5 equivalents.
In addition, the compound (1) and various intermediate compounds produced as described above are appropriately subjected to separation / purification means according to the step, for example, means such as concentration, extraction, chromatography, and recrystallization. It can be isolated as of any purity.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
Example
[Example 1]
Synthesis of N-benzyloxycarbonyl-S-phenyl-L-cysteine N'-oxysuccinimide ester (Compound 4: Z = succinimidoxy group: referred to as "imide ester" in the following Examples)
9.94 g (0.03 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) was placed in a 100 ml four-necked flask equipped with a thermometer, a condenser, and a stirrer. ) Was dissolved in 60 ml of dioxane. After adding 3.46 g (0.031 mol) of N-hydroxysuccinimide and cooling to 4 ° C. with ice water, 6.4 g (0.03 mol) of N, N′-dicyclohexylcarbodiimide (DCC) was added.
Crystal precipitation and slight heat generation (7 ° C.) were observed. After stirring for 30 minutes, the reaction flask was placed in a refrigerator and left overnight. The precipitated crystals were separated by filtration and washed with dioxane.
The filtrate was concentrated under reduced pressure to obtain 13.2 g of a semi-solid substance. After crystallizing this, it was recrystallized with n-hexane / ethyl acetate = 5/1 to give m.p. 12.65 g (yield: 98.4%: HPLC; 97.1%) of white crystalline imide ester having a p of 106-109 ° C was obtained.
¹ 1 H NMR (60 MHz; CDCl ₃ , Δ, ppm): 2.70 (4H, s), 3.40 (2H, d, J = 5 Hz), 4.60-4.97 (1H, m), 5.02 (2H, s), 5.45 (1H, d, J = 8 Hz), 7.03-7.43 (10H, m).
IR (KBr, cm-1): 348, 3044, 2952, 1818, 1790, 1746, 1696, 1636, 1578, 1538, 1472, 1458, 1442, 1430, 1418, 1368, 1308, 1280, 1210, 1160, 1094. , 1066,1042,1024,1004,994,922,848,814,776,750,698,660,642,618,584,500,480,424.
[Example 2]
Synthesis of N-benzyloxycarbonyl-S-phenyl-L-cysteine 4′-nitrophenyl ester (compound 4: Z = 4-nitrophenoxy group: referred to as “p-nitrophenyl ester” in the following examples)
Example 2-1
Synthesis of p-nitrophenyl ester using condensing agent N, N'-dicyclohexylcarbodiimide
3.31 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) was placed in a 100 ml four-necked flask equipped with a thermometer, a stirrer, a nitrogen inlet tube, and a dropping funnel. (0.01 mol) and 1.39 g (0.01 mol) of p-nitrophenol were taken and diluted with 15 ml of 1,4-dioxane.
Next, a solution obtained by diluting 2.17 g (0.0105 mol) of N, N′-dicyclohexylcarbodiimide (DCC) with 5 ml of 1,4-dioxane was dropped from the dropping funnel under a nitrogen stream at an internal temperature of 6 ° C. to 10 ° C. It was dropped in 10 minutes. The mixture was stirred at the same temperature for 5 hours and left in a refrigerator overnight. The obtained yellow suspension was filtered to remove a white solid, and the filtrate was concentrated under reduced pressure. 5.24 g of a yellow viscous liquid was obtained. HPLC; 96.4%
This was solidified with n-hexane / ethyl acetate = 5/1, and m.p. 4.3 g (yield: 95.1%) of p-nitrophenyl ester as a white crystal having a p of 93 to 95 ° C. was obtained.
¹ 1 H NMR (250 MHz; CDCl ₃ , Δ, ppm): 3.54 (2H, d, J = 5.0 Hz), 4.85-4.89 (1H, m), 5.11 (2H, s), 5.63 (1H, d) , J = 7.0 Hz), 7.04 (2H, d, J = 9.0 Hz), 7.20-7.50 (10H, m), 8.20 (2H, d, J = 9.0 Hz) .
IR (KBr, cm-1): 3356, 1774, 1754, 1682, 1656, 1624, 1598, 1560, 1528, 1490, 1458, 1442, 1422, 1350, 1328, 1312, 1278, 1234, 1206, 1170, 1144. , 1112,1090,1042,1028,1016,990,974,928,910,888,864,850,782,758,742,714,694,658,632,618,600,582,542,470,442 , 418.
Example 2-2
Synthesis of p-nitrophenyl ester using bis-p-nitrophenyl sulfite 13.9 g (0.1 mol) of p-nitrophenol was placed in a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, and dried. It was dissolved in 50 ml of diethyl ether, added with 6.0 g (0.05 mol) of thionyl chloride, and then cooled to 0 ° C. Under stirring, a solution of 10.1 g (0.1 mol) of triethylamine dissolved in 10 ml of dry diethyl ether was gradually added dropwise. At the same time as the dropping, crystals were precipitated with white smoke and heat generation. After completion of the dropwise addition, the mixture was stirred under cooling for 1 hour and at room temperature for 1 hour. After cooling to 5 ° C. again, the reaction solution was separated by filtration, and the residue was washed with dry cold diethyl ether. This residue was suspended in about 50 ml of water, filtered and washed with cold water.
Further, the suspension was suspended in 50 ml of cold ethanol, separated by filtration, washed with cold ethanol and then with cold diethyl ale, dried and dried. 12.7 g (yield: 78.3%) of bis-p-nitrophenylsulfite as a white crystal having a p of 105 to 106 ° C. was obtained.
IR (KBr, cm-1): 3472, 3128, 3092, 1618, 1592, 1518, 1488, 1460, 1352, 1324, 1296, 1238, 1198, 1180, 1164, 1154, 1112, 1102, 1010, 862, 832 , 824, 758, 718, 700, 650, 626, 532, 480, 418.
1.0 g (0.003 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) in a 50 ml three-necked flask equipped with a thermometer, a condenser and a stirrer. ) Was dissolved in 5 ml of dimethylformamide and 5 ml of pyridine, and 2.9 g (0.009 mol) of bis-p-nitrophenylsulfite was added at room temperature. Then, after reacting at room temperature for 3.5 hours, the reaction mixture was poured into 200 ml of ice water and adjusted to pH = 2 with dilute hydrochloric acid. The mixture was extracted with 150 ml of ethyl acetate, and the ethyl acetate layer was washed with water. Furthermore, the ethyl acetate layer was washed with a 10% aqueous sodium hydroxide solution, washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure to obtain 1.25 g (yield: 91%) of p-nitrophenyl ester as a white solid. HPLC; 96%
¹ 1 H NMR (60 MHz: CDCl ₃ , Δ, ppm): 3.62 (2H, d, J = 5 Hz), 4.70-4.98 (1H, m), 5.22 (2H, s), 5.77 (1H, d, J) = 8 Hz), 7.22 (2H, d, J = 9 Hz), 7.28-7.73 (10 H, m), 8.43 (2H, d, J = 9 Hz).
Example 2-3
Method for synthesizing p-nitrophenyl ester without isolating bis-p-nitrosulfite
497.0 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) was placed in a 10 L separable flask equipped with a thermometer, a condenser, a stirrer, and a nitrogen inlet tube. 0.5 mol: 1.0 eq) and 230.9 g (1.65 mol; 1.1 eq) of p-nitrophenol were suspended in 7.0 L of toluene, and 333.9 g (3.3 mol; 2.2 eq) of triethylamine was added. After the addition, the suspension dissolved and became a yellow solution. The yellow solution was cooled to about −7 ° C. in a dry ice-acetone bath, and a solution of 196.3 g (1.65 mol; 1.1 eq) of thionyl chloride dissolved in 0.5 L of toluene was added at −5 ° C. for 0.5 hour Was dropped.
After completion of the dropwise addition, the mixture was stirred at 0 ° C. for 3 hours, the dry ice-acetone bath was removed, and the mixture was further stirred at 50 ° C. ± 2 ° C. for 3 hours. The compound (2) was confirmed to be 0.2% or less by HPLC, and the reaction was stopped. The reaction was washed twice with 2 L of water, twice with 2 L of 5% aqueous sodium hydrogen carbonate solution, and further washed with 2 L of water. After washing twice with water, a toluene solution containing p-nitrophenyl ester was obtained. After drying over anhydrous sodium sulfate, toluene was distilled off under reduced pressure to obtain a residue. The residue was heated and dissolved in 2 L of ethyl acetate, and 10 L of n-hexane was added with stirring to precipitate crystals. The crystals were collected by filtration, washed with n-hexane / ethyl acetate = 5/12 L, and dried to obtain p-nitrophenyl ester as a white crystal.
Yield: 650 g (Yield: 95.7%)
m. p 91-94 ° C, HPLC; 98.5%
[Example 3]
Synthesis of 3-benzyloxycarbonylamino-1- (1 ′, 1′-dimethyloxysulfuranyl) -4-phenylsulfanylbutan-2-one (compound 5: referred to as “ylide compound” in the following Examples)
Example 3-1
Synthesis of Ylide Compounds Using Cory Reagent (Dimethylsulfoxonium Methylide) Generated from Sodium Hydride and Trimethylsulfoxonium Iodide and Imide Esters
0.186 g (4.66 mmol; 2.0 eq) of NaH (60%) was placed in a 100 ml four-necked flask equipped with a thermometer, a condenser, and a stirrer, washed twice with 5 ml of n-hexane, and then dried 10 ml of DMSO. Suspended in water. Under a nitrogen stream, 1.03 g (4.66 mmol; 2.0 eq) of trimethylsulfoxonium iodide (TMSOI) was added little by little. NaH dissolves with foaming and heat generation.
After the addition was completed, the mixture was stirred for 10 minutes and then heated and stirred at 55 ° C. for 30 minutes in an oil bath to prepare a Corey reagent.
Thereafter, 10 ml of THF was added, and the mixture was cooled to -12 ° C in a dry ice-acetone bath. At −12 ° C., 1.0 g (2.33 mmol) of imide ester was dissolved in 5 ml of dry THF, added dropwise to the Cory reagent, and washed with 5 ml of THF. At the same time as the dropwise addition, the mixture became cloudy and slightly heated. After the completion of the dropwise addition, the mixture was reacted at the same temperature for 1.75 hours.
The reaction solution was poured into ice water and extracted with 100 ml of AcOEt. The aqueous layer was further extracted with 100 ml of AcOEt, and the AcOEt layers were combined, washed with NaClaq, dried over anhydrous Na2SO4, and concentrated to obtain a pale yellow oil (1.0 g). HPLC; 94%. This was separated and purified by silica gel column chromatography (Wako gel C300: 150 ml; benzene / acetone = 2/1), and 0.79 g (yield: 83.6%: HPLC; 98.9 g) of a slightly yellow oily ylide compound was obtained. 8%).
¹ 1 H NMR (60 MHz; CDCl ₃ , Δ, ppm): 3.07 (6H, s), 3.13 (2H, d, J = 5 Hz), 3.87-4.33 (2H, m), 4.87 (2H, s), 5.80 (1H, d, J = 8 Hz), 6.77-7.18 (10H, m).
IR (KBr, cm-1): 3040, 2932, 1718, 1640, 1562, 1544, 1510, 1482, 1460, 1442, 1398, 1334, 1248, 1192, 1138, 1088, 1026, 942, 898, 856, 742. , 682, 420.
Example 3-2
Synthesis of ylide compounds using Cory reagents and imide esters formed from sodium hydride and trimethylsulfoxonium bromide.
0.747 g (18.64 mmol; 2.0 eq) of NaH (60%) was placed in a 100 ml four-necked flask equipped with a thermometer, a cooler, a nitrogen introducing tube, a dropping funnel, and a stirrer, and the mixture was treated with 10 ml of n-hexane. After washing twice, it was suspended in 40 ml of dry DMSO. Under a nitrogen stream, 3.23 g (18.64 mmol; 2.0 eq) of trimethylsulfoxonium bromide (TMSOB) was added little by little. NaH dissolves with foaming and heat generation. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 55 ° C. for 60 minutes in an oil bath to prepare a Corey reagent.
The prepared Corey reagent was returned to room temperature, and after adding 40 ml of THF, the solution was cooled to -12 ° C with a dry ice-acetone bath. A solution prepared by dissolving 4.0 g (9.34 mmol) of imide ester in 20 ml of dry THF was charged into a dropping funnel, dropped into the Cory reagent in 10 minutes while keeping the internal temperature from -10 ° C or higher, and washed with 5 ml of THF. did. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour, and heated to 0 ° C. over 2 hours to stop the reaction. The reaction solution was poured into 200 ml of ice water and extracted with 250 ml of AcOEt. The aqueous layer was further extracted with AcOEt 100 ml × 2, and the organic layers were combined. The organic layer was washed with saturated saline 200 ml × 2, dried over anhydrous Na 2 SO 4 and concentrated to obtain 3.89 g of a brown oily ylide compound. . HPLC; 90%
¹ 1 H NMR (60 MHz; CDCl ₃ , Δ, ppm): 3.07 (6H, s), 3.13 (2H, d, J = 5 Hz), 3.87-4.33 (2H, m), 4.87 (2H, s), 5.80 (1H, d, J = 8 Hz), 6.77-7.18 (10H, m).
IR (KBr, cm-1): 3040, 2932, 1718, 1640, 1562, 1544, 1510, 1482, 1460, 1442, 1398, 1334, 1248, 1192, 1138, 1088, 1026, 942, 898, 856, 742. , 682, 420.
Example 3-3
Synthesis of ylide compounds using p-nitrophenyl ester and Cory reagent formed from sodium hydride and trimethylsulfoxonium bromide
0.354 g (8.84 mmol; 2.0 eq) of NaH (60%) was placed in a 100 ml four-necked flask equipped with a thermometer, a cooler, a nitrogen introducing tube, a dropping funnel, and a stirrer, and the mixture was treated with 5 ml of n-hexane. After washing twice, it was suspended in 20 ml of dry DMSO.
Under a nitrogen stream, 1.53 g (8.84 mmol; 2.0 eq) of trimethylsulfoxonium bromide (TMSOB) was added little by little. NaH dissolves with foaming and heat generation. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 55 ° C. for 60 minutes in an oil bath to prepare a Corey reagent.
The prepared Corey reagent was returned to room temperature, and after adding 20 ml of THF, the solution was cooled to -12 ° C with a dry ice-acetone bath.
A solution prepared by dissolving 2.0 g (4.42 mmol) of p-nitrophenyl ester in 20 ml of dry THF was charged into a dropping funnel, and the solution was dropped into the Cory reagent in 10 minutes while keeping the internal temperature from -10 ° C or higher. Washed with THF. After the addition, the mixture was stirred at the same temperature for 2 hours.
The reaction solution was poured into 100 ml of ice water and extracted with 150 ml of AcOEt. The aqueous layer was further extracted with AcOEt (50 ml × 2), and the organic layers were combined. The organic layer was washed with saturated saline (50 ml × 5), dried over anhydrous Na 2 SO 4, and concentrated to obtain 1.58 g (yield) of a brown oily ylide compound. %: 88.2%: HPLC; 81.2%).
¹ 1 H NMR (60 MHz; CDCl ₃ , Δ, ppm): 3.07 (6H, s), 3.13 (2H, d, J = 5 Hz), 3.87-4.33 (2H, m), 4.87 (2H, s), 5.80 (1H, d, J = 8 Hz), 6.77-7.18 (10H, m).
IR (KBr, cm-1): 3040, 2932, 1718, 1640, 1562, 1544, 1510, 1482, 1460, 1442, 1398, 1334, 1248, 1192, 1138, 1088, 1026, 942, 898, 856, 742. , 682, 420.
Example 3-4
Synthesis of ylide compounds using imide ester synthesis reaction solution and Corey reagent formed from trimethylsulfoxonium bromide and sodium hydride
3.31 g (0.01 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) in a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer. Then, 1.38 g (0.012 mol) of N-hydroxysuccinimide was taken, suspended in 50 ml of tetrahydrofuran, added with 2.43 g (0.024 mol) of triethylamine, and cooled to −2 ° C. in a dry ice-acetone bath. 1.43 g (0.012 mol) of thionyl chloride was mixed with 3 ml of tetrahydrofuran, and slowly added dropwise at -1 ° C. Thereafter, the mixture was stirred at -5 ° C for 1 hour and at room temperature for 1 hour. The end point of the reaction was confirmed by TLC and HPLC.
Separately, a Corey reagent (dimethylsulfoxonium methylide) was prepared by the following method.
In a nitrogen stream, 0.8 g (0.02 mol) of NaH (60%) was placed in a 100 ml four-necked flask equipped with a thermometer, a condenser, and a stirrer. The suspension was suspended in 30 ml of dry DMSO, and 3.46 g (0.02 MOL) of trimethylsulfoxonium bromide (TMSOB) was added little by little. NaH dissolves with foaming and heat generation. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 55 ° C. for 30 minutes in an oil bath to prepare a Corey reagent. 10 ml of tetrahydrofuran was added to this solution, and the mixture was cooled to -5 ° C in a dry ice-acetone bath.
Crystals precipitated from the previously synthesized imide ester reaction solution were separated by filtration into the solution of the Cory reagent, and the filtrate was added dropwise at -4 ° C. After completion of the dropwise addition, the mixture was stirred at 5 ° C. or lower for 1 hour, and then the reaction solution was poured into 300 ml of ice water. When 50 ml of n-hexane was added and stirred, crystals were precipitated. The crystals were separated by filtration, washed well with water and dried. p. 2.85 g (yield: 70.4%) of an ylide compound as pale yellow crystals at 106 to 112 ° C. was obtained.
Example 3-5
Synthesis of ylide compound using p-nitrophenyl ester synthesis reaction solution and Corey reagent formed from trimethylsulfoxonium bromide and potassium tert-butoxide
3.31 g (0.01 mol) of N-benzyloxycarbonyl-S-phenyl-L-cysteine (compound 2: optical purity 98.6% ee) in a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer. Then, 1.67 g (0.012 mol) of p-nitrophenol was taken, suspended in 30 ml of tetrahydrofuran, added with 2.43 g (0.024 mol) of triethylamine, and cooled to −5 ° C. in a dry ice-acetone bath. 1.43 g (0.012 mol) of thionyl chloride was mixed with 3 ml of tetrahydrofuran, and slowly added dropwise at -5 ° C. Thereafter, the mixture was stirred at -5 ° C for 1.5 hours and at room temperature for 2 days and nights. The end point of the reaction was confirmed by TLC and HPLC. Separately, a Corey reagent (dimethylsulfoxonium methylide) was prepared by the following method.
In a 100 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, 2.8 g (0.025 mol) of potassium tert-butoxide was suspended in 60 ml of dry t-butanol in a nitrogen stream, and trimethylsulfoxonium bromide ( TMSOB) (4.33 g, 0.025 mol) was added in small portions. After completion of the addition, the mixture was stirred for 10 minutes, and then heated and stirred at 65 ° C. to 75 ° C. for 30 minutes in an oil bath to prepare a Corey reagent. To this solution was added 40 ml of tetrahydrofuran, and the mixture was cooled to -5 ° C in a dry ice-acetone bath.
Crystals precipitated from the previously synthesized p-nitrophenyl ester reaction solution were separated by filtration into the solution of the Cory reagent, and the filtrate was added dropwise at -4 ° C. After completion of the dropwise addition, the mixture was stirred at 5 ° C. or lower for 3 hours, and then the reaction solution was poured into 300 ml of ice water. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a 2% aqueous sodium hydroxide solution, then with water, and washed well with saturated saline. After drying over anhydrous sodium sulfate, ethyl acetate was concentrated to obtain 3.51 g (yield: 86.6%) of an ylide compound as an oil.
Example 3-6
Synthesis of ylide compounds using p-nitrophenyl ester and Corey reagent formed from trimethylsulfoxonium bromide and potassium tert-butoxide
In a nitrogen stream, 50 ml of dried t-butanol was placed in a 200 ml four-necked flask equipped with a thermometer, a condenser and a stirrer, and 2.24 g (0.02 mol; 4.0 eq) of potassium tert-butoxide was added. . At room temperature (25 ° C.), 3.46 g (0.02 mol; 4.0 eq) of trimethylsulfoxonium bromide (TMSOB) was added little by little. After TMSOB addition, the mixture was heated and stirred at 70-75 ° C. for 30 minutes to prepare methylide.
After cooling to room temperature, 50 ml of THF was added, and the mixture was further cooled to -12 ° C in a dry ice-acetone bath. At −12 ° C., 2.26 g (0.005 mol) of p-nitrophenyl ester (HPLC; 99.6 area%) was added as a solid. After 0.5 hour, the reaction was monitored by HPLC, the reaction was stopped after 1 hour, and the reaction solution was poured into 600 ml of ice water. Some crystals were precipitated, but extracted with ethyl acetate. The ethyl acetate layer was washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give 2.19 g of an oil. The aqueous layer was extracted with 100 ml of ethyl acetate and subjected to the same treatment to obtain 0.19 g of an oily substance.
The two oils were combined and purified by silica gel chromatography (silica gel 60N, 150 ml, benzene / acetone = 1/1 development) to obtain 1.91 g of pale yellow crystals. m. p. 89-95 ° C
When this was quantified by HPLC using 4,4′-dimethylbenzophenone as an internal standard substance by an internal standard method, 1.83 g (yield: 90.3%) of an ylide compound having a purity of 95.8% was obtained.
Example 3-7
Synthesis of ylide compounds in toluene solvent using p-nitrophenyl ester, trimethylsulfoxonium bromide and Corey reagent formed from sodium tert-butoxide
A 1 L four-necked flask equipped with a thermometer, a condenser, a stirrer, and a nitrogen inlet tube was charged with 22.1 g (0.23 mol; 2.3 eq) of sodium tert-butoxide, 25 ml of tert-butanol, and 225 ml of toluene. With stirring. To this mixture, 39.81 g (0.23 mol; 2.3 eq) of trimethylsulfoxonium bromide was added, and the mixture was stirred for 1 hour to prepare a Corey reagent.
This Corey reagent was cooled to -10 ° C, and a solution in which p-nitrophenyl ester [46.17 g (0.1 mol; 1.0 eq)] was dissolved in 450 ml of toluene was added dropwise thereto over 20 minutes with stirring. . After dropping, stirring was continued at the same temperature for 2.5 hours. Then, the reaction mixture was heated to 35 ° C, 250 ml of warm water was added, and the mixture was stirred at 35 ° C for 20 minutes. The reaction solution was transferred to a separating funnel and separated, and the obtained toluene solution was transferred to a 2 L flask, azeotropically dehydrated at a bath temperature of 50 ° C., further transferred to a 1 L flask, and concentrated under reduced pressure to a liquid volume of 200 g. And The obtained toluene solution was warmed, 20 ml of n-hexane was added with stirring, and the mixture was naturally cooled with stirring to precipitate crystals. The crystals were collected by filtration, washed with 70 ml of toluene, and dried to obtain a white crystalline ylide compound.
Yield: 38.52 g (yield: 94.9%), m.p. p 92-96 ° C, HPLC: 98.8%
[Α] = − 22.7 ° (c1.0 acetonitrile, 23.5 ° C.)
[Example 4]
Synthesis of 3-benzyloxycarbonylamino-1-chloro-4-phenylsulfanylbutan-2-one (compound 6, referred to as "chloromethyl ketone" in the following examples)
Example 4-1
Synthesis of chloromethyl ketone using HCl / ethyl acetate solution
0.78 g (1.92 mmol) of the ylide compound was placed in a 100 ml four-necked flask equipped with a thermometer, a condenser, and a stirrer, dissolved in 30 ml of ethyl acetate, and cooled to −20 ° C. in a dry ice-acetone bath. At −20 ° C., 1.06 ml (1.2 eq) of 2.18N HCl / AcOEt was added dropwise. The reaction solution became cloudy. Thereafter, the mixture was stirred at a natural temperature for 1 hour. (Up to -10 ° C). After removing the dry ice-acetone bath and returning to room temperature, the mixture was heated in an oil bath at 78 ° C for 20 minutes. After cooling, 100 ml of ethyl acetate and 100 ml of water were added to the reaction solution for extraction. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate.
The aqueous layer was extracted with 100 ml of ethyl acetate and dried similarly. The ethyl acetate layers were combined and concentrated under reduced pressure to obtain 0.66 g (yield: 92.8%: HPLC; 91.0%) of slightly yellow solid chloromethyl ketone.
¹ 1 H NMR (60 MHz; CDCl ₃ , Δ, ppm): 3.13 (2H, d, J = 6 Hz), 3.94 (2H, s), 4.27-4.62 (1H, m), 4.85 (2H, s), 5.40 (1H, d, J = 8 Hz), 6.83-7.20 (10H, m).
IR (KBr, cm-1): 3368, 1736, 1712, 1684, 1646, 1636, 1516, 1486, 1470, 1458, 1444, 1412, 1396, 1316, 1270, 1234, 1180, 1152, 1084, 1036, 972. , 854, 778, 748, 736, 698, 628, 586, 508, 492, 436.
Optical rotation: [α] -87.0 ° (c1.0 in MeOH)
Example 4-2
Synthesis of chloromethyl ketone using HCl / tetrahydrofuran solution
2.03 g (5.0 mmol) of the ylide compound was placed in a 200 ml four-necked flask equipped with a thermometer, a cooler and a stirrer, suspended in 60 ml of toluene, and cooled to 0 ° C. To this white suspension, 3.0 g (5 mmol) of a 6.1% hydrogen chloride / tetrahydrofuran solution prepared by blowing hydrogen chloride gas into tetrahydrofuran was added dropwise over 5 minutes, followed by stirring at the same temperature for 2 hours. The temperature was raised to 65 ° C. by an oil bath, and the reaction was performed for 4 hours. The reaction mixture became a clear yellow solution. After confirming the disappearance of the raw materials, the mixture was cooled, 100 ml of toluene was added, and the mixture was washed twice with 30 ml of saturated saline and twice with 30 ml of water. The toluene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain brown white crystalline chloromethyl ketone. Yield 1.69 g (Yield 92.9%, HPLC 93.8%, mp 87-91 ° C)
Specific rotation: [α] =-76.9 ° (c1.0, 25.0 ° C, MeOH)
Example 4-3
Synthesis of chloromethyl ketone using HCl / diethyl ether solution
12.3 g (30.4 mmol) of the ylide compound was placed in a 1-L four-necked flask equipped with a thermometer, a condenser, and a stirrer, suspended in 498 ml of toluene, and cooled to 0 ° C. To this white suspension, 31 ml (31 mmol) of a 1 M hydrogen chloride / diethyl ether solution prepared by blowing hydrogen chloride gas into diethyl ether was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 1 hour. The temperature was raised to 65 ° C. by an oil bath, and the reaction was performed for 3 hours. The reaction mixture became a clear yellow solution. After confirming the disappearance of the raw material of the reaction mixture, the mixture was cooled and washed five times with 100 ml of water. The toluene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain chloromethyl ketone as brown white crystals. The yield was 10.4 g (93.9% yield, 94.2% HPLC, mp 86-91 ° C).
Specific rotation: [α] =-80.0 ° (c1.0, 24.0 ° C, MeOH)
[Example 5]
Synthesis of (2S, 3R) 3-benzyloxycarbonylamino-1-chloro-4-phenylsulfanylbutan-2-ol (Compound 1: described as "chloroalcohol" in the following Examples)
Example 5-1
Synthesis of chloroalcohol using aluminum isopropoxide
In a 50 ml three-necked flask equipped with a thermometer, a condenser and a stirrer, 0.4 g (1.1 mmol) of chloromethyl ketone and aluminum isopropoxide [Al (PrO-i) ₃ 0.225 g (1.1 mmol), 10 ml of isopropanol was added, and the mixture was heated and stirred at 60 to 70 ° C. The disappearance of the raw material chloromethyl ketone was confirmed by TLC and HPLC monitor, and the reaction was stopped in 1.5 hours. After cooling, the reaction solution was poured into ice water and adjusted to pH = 2-3 with dilute hydrochloric acid. The precipitated white crystals were separated by filtration, washed well with water, and dried.
White crystals, yield: 0.324 g (yield: 81%) HPLC; 97.46%, syn / anti = 90.44 / 7.02
This was recrystallized from n-hexane / ethyl acetate = 6/2 ml to give m.p. 0.194 g (yield: 48.5%) of chloroalcohol at p 115-116 ° C was obtained.
HPLC; 99.99%, syn / anti = 98.22 / 0.77
¹ 1 H NMR (250 MHz; CDCl ₃ , Δ, ppm): 2.79 (1 Hd, J = 1.95 Hz), 3.29 (2H, d, J = 3.91 Hz), 3.59-3.70 (2H, m), 3 .92 (2H, t, t, J = 0.98 Hz, 3.42 Hz), 5.07 (2H, s), 5.14 (1H, d, J = 2.44 Hz), 7.19-7. 39 (10H, m).
IR (KBr, cm-1): 3356, 3072, 2976, 2952, 1690, 1646, 1588, 1536, 1506, 1484, 1470, 1456, 1440, 1340, 1294, 1250, 1226, 1136, 1110, 1090, 1068. , 1028, 970, 936, 910, 874, 736, 778, 742, 730, 694, 658, 614, 580, 476.
Optical rotation [α] -77.9 ° (c1.0 in MeOH)
Example 5-2
Synthesis of chloroalcohol using aluminum-sec-butylate
In a 200 ml four-necked flask equipped with a thermometer, a cooler, a stirrer, and a silica gel drying tube, 3.08 g (12.5 mmol; 0.5 eq) of aluminum sec-butylate [Al (OBu-s) 3] was added to 2-butanol. 15 ml and 50 ml of toluene were mixed well to form a solution. Then, 9.1 g (25 mmol; 1.0 eq) of powdery chloromethyl ketone was added to this mixture while stirring at room temperature (17 ° C.), and further 25 ml of toluene were added. While stirring at room temperature, disappearance of the raw material chloromethyl ketone was confirmed by an HPLC monitor, and the stirring was stopped in 4.5 hours. The reaction product was transferred to a separatory funnel, 150 ml of ethyl acetate was added, and the mixture was washed once with 75 ml of a 5% aqueous hydrochloric acid solution, once with 75 ml of a 1% aqueous hydrochloric acid solution, and twice with 75 ml of water. It was dried over anhydrous sodium sulfate. The 5% aqueous hydrochloric acid solution, the 1% aqueous hydrochloric acid solution, and the aqueous layer used for washing were combined and re-extracted with 30 ml of ethyl acetate solution, and the ethyl acetate solution was dried over anhydrous sodium sulfate. Filtration was performed using a 3G glass filter, and the solvent was distilled off to obtain chloroalcohol as white crystals. 8.85 g (yield: 96.69%).
HPLC; 98.67%
syn / anti = 95.12 / 3.50
To 8.85 g of the white crystals, 88 ml of toluene was added and dissolved at a bath temperature of 70 to 75 ° C., then transferred to a 300 ml beaker, and 44 ml of n-hexane was added dropwise with stirring to recrystallize. The recrystallized product was collected by filtration, washed with 30 ml of toluene / n-hexane = 2/130 ml, and dried to obtain chloroalcohol as white crystals. White crystals, yield: 8.32 g (yield: 92.11%)
m. p 116-117 ° C
HPLC; 99.72%, syn / anti = 99.33 / 0.39.
Industrial applicability
The process of the present invention does not require the use of hazardous reagents as in the prior art, is short in process, and advantageously produces 3-benzyloxycarbonylamino-1-halogeno-4-phenylthiobutan-2-ol. Provide a method. Therefore, [3S- (3α, 4aβ, 8aβ)]-2- [2′-hydroxy-3′-phenylthiomethyl-4′-aza-5 ′ is useful as an HIV protease inhibitor that can be derived therefrom. -Oxo-5 '-(2 "-methyl-3" -hydroxyphenyl) pentyl] decahydroisoquinoline-3-N-t-butylcarboxamide can be industrially advantageously produced and provided.

Claims (7)

i) a compound represented by the following formula (2):

By reacting the compound represented by the general formula (3) with a condensing agent,

(In the formula (3), Z represents a linear or branched C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ alkylthio group, a phenoxy group, or a halogen atom, a nitro group, an alkyl group, an alkoxy group, or a hydroxy group. Phenoxy group, phenylthio group, or halogen atom, nitro group, alkyl group, alkoxy group, or hydroxy group-substituted phenylthio group, benzyloxy group, or halogen atom, nitro group, alkyl group, or alkoxy group-substituted benzyloxy group, benzylthio group Or a halogen atom, a nitro group, an alkyl group or an alkoxy group, a substituted benzylthio group, a pyridyloxy group, a pyridylthio group, an ethoxyvinyloxy group, a linear or branched C ₁ -C ₄ alkylcarbonyloxy group, a substituted phosphate group, Sulfate group, a A dazolyl group, an azide group, an alkoxycarbonyloxy group, a cyclohexylcarbodiimidoxy group, a succinimidoxy group, a phthalimidoxy group, a benzotriazolyloxy group, a piperidinooxy group, and a halogen atom, and R represents a hydrogen atom, provided that: When Z is a halogen atom in the formula (4), ZR together represent thionyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus trichloride, thionyl bromide, or oxal chloride.)
The following general formula (4)

(In the formula (4), Z is as described above.)
In the step of converting to an active ester compound represented by
ii) reacting the obtained compound represented by the general formula (4) with a methylide compound to produce an ylide compound represented by the following formula (5);

iii) treating the obtained ylide compound with hydrogen halide to obtain a halomethyl ketone represented by the following general formula (6);

(Wherein X represents a halogen atom),
iv) Next, a method of producing the halogeno alcohol derivative represented by the general formula (1) by reducing the same.

(Wherein, X represents a halogen atom) A compound represented by the following formula (2):

General formula ZR (3)
And a compound represented by the following formula (4)

(Wherein, R and Z are the same as described above). An active ester compound represented by the following general formula (4) (where Z is the same as described above) is reacted with trimethylsulfoxonium halide in the presence of a base to give an ylide represented by the following formula (5) A method for producing a compound.

The ylide compound represented by the following formula (5) is reacted with hydrogen halide in an inert solvent to give a compound represented by the following formula (6).

(Wherein X is as defined above). A method for producing a halogeno alcohol derivative represented by the following general formula (1) by reducing a halomethyl ketone compound represented by the following general formula (6) (where X is the same as described above).

The following general formula (4)

(Wherein Z is the same as described above, except that Z = methoxy group). An ylide compound represented by the following formula (5):