JP3875315B2 - Process for producing optically active acylsulfonamides - Google Patents

Description

（式中、＊は不斉炭素原子の存在位置を示し、Ｒ¹は置換基を有していてもよいフェニルを示し、Ｒ²は置換されていてもよい低級アルキル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールを示す）
で表わされる光学活性なカルボン酸に、塩素化剤１〜２当量を不活性溶媒中、塩基の不存在下−３０℃〜室温で反応させ、一般式（ＩＩ）：
【化６】

（式中、Ｒ¹とＲ²は前記と同意義である）
で表わされる酸塩化物とした後、さらに一般式（ＩＶ）：
【化７】

（式中、Ｒ³は置換されていてもよいアリールを示し、Ｒ⁴は水素原子または低級アルキルを示す）
で表わされる化合物１〜２当量を−３０℃〜室温で、不活性溶媒中２〜８当量の無機塩基の存在下に反応させるか、または一般式（ＩＶ）で表される化合物の金属塩１〜２当量を不活性溶媒中塩基不存在下に反応させることを特徴とする、一般式（Ｉ）：
【化８】

（式中、＊、Ｒ¹、Ｒ²、Ｒ³およびＲ⁴は前記と同意義である）
で表わされる、９５％以上の光学純度を持つアシルスルホンアミド類の製造法に関する。
【００１８】
本明細書中、「低級アルキル」とは、直鎖状または分枝状のＣ₁〜Ｃ₆アルキル、例えば、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、ｓｅｃ−ブチル、およびｔｅｒｔ−ブチルを意味する。
本明細書中、「低級アルケニル」とは、Ｃ₂〜Ｃ₆直鎖状または分枝状のアルケニル、例えば、ビニル、アリル、プロペニル、およびブテニルを意味する。
本明細書中、「アリール」とは、単環状または縮合環状芳香族炭化水素、例えば、フェニル、ナフチル、およびインデニルを意味する。
本明細書中、「ヘテロアリール」とは、５〜７員環でＮ、ＯまたはＳ原子を環内に1個以上含み、炭素環もしくは他の複素環と縮合していてもよいヘテロ芳香族、例えば、ピリジル、キノリル、チエニル、フリル、インドリル、もしくはベンゾフリルを意味する。
本明細書中、「アルキルオキシ」とは、アルキル部分が低級アルキルであるアルキルオキシ、例えば、メチルオキシ、エチルオキシ、ｎ−プロピルオキシ、イソプロピルオキシ、ｎ−ブチルオキシ、イソブチルオキシ、ｓｅｃ−ブチルオキシ、およびｔｅｒｔ−ブチルオキシを意味する。
本明細書中、「アルキルオキシカルボニル」とは、アルキル部分が低級アルキルであるアルキルオキシカルボニル、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、およびブトキシカルボニルを意味する。
本明細書中、「アラルキル」とは、低級アルキルにアリールが置換したもので、例えば、ベンジル、フェネチル、フェニルプロピル、およびナフチルメチルを意味する。
【００１９】
本明細書中、「置換基を有していてもよいフェニル」とは、低級アルキル基、低級アルケニル基、アルキルオキシ基、ニトロ基、水酸基、アルキルオキシカルボニル基、アラルキル基、カルボキシル基、アミド基またはハロゲンで１ケ所以上置換されていてもよいフェニルを意味する。例えば、１，３−ジベンゾオキソリル、メトキシフェニル、フルオロフェニル、およびカルボキシフェニルが挙げられる。
【００２０】
本明細書中、「置換されていてもよい低級アルキル」における置換基としては、アルキルオキシ基、アリール部分がニトロ基もしくはハロゲンで置換されていてもよいアリールオキシ基、アラルキル基、ニトロ基およびハロゲンが挙げられる。
【００２１】
本明細書中、「置換されていてもよいアリール」とは、低級アルキル基、低級アルケニル基、アルキルオキシ基、カルボキシル基、アルコキシカルボニル基、アラルキル基、アルキル部分が低級アルキル基もしくは低級アルケニル基であるアシルオキシ基、ニトロ基またはハロゲンにより１ケ所以上置換されていてもよいアリールを意味する。例えば、トリル、クメニル、メシチル、イソプロピルフェニル、tert-ブチルフェニル、ビフェニル、ダンシル、シクロヘキシルフェニル、カルボキシフェニル、インダニル、およびテトラヒドロナフチルが挙げられる。
【００２２】
本明細書中、「置換されていてもよいヘテロアリール」とは、低級アルキル基、低級アルケニル基、アルキルオキシ基、カルボキシル基、アルコキシカルボニル基、アラルキル基、ニトロ基またはハロゲンにより１ケ所以上置換されていてもよいヘテロアリールを意味する。例えば、２−メチル−４−プロピル−３―ピリジル、および４−プロピル−３―ピリジルが挙げられる。
【００２３】
【発明の実施の形態】
本発明は、二工程からなる。
第一工程では、本発明法の出発原料である光学活性カルボン酸（ＩＩＩ）１当量を、塩化メチレン、１，２−ジクロロエタン、クロロホルム、アセトニトリル、テトラヒドロフラン、１，４−ジオキサン、ジメトキシエタン、ベンゼン、またはトルエンなどの溶媒、好ましくは塩化メチレンまたはアセトニトリルに溶解し、１〜２当量、好ましくは１．０５〜１．２０当量の塩素化剤、好ましくは塩化オキザリルまたは塩化チオニルを、−３０℃〜室温条件下、好ましくは氷冷下で滴下し、5分〜5時間、好ましくは１５分間攪拌した後、揮発物をすべて減圧下留去し目的とする酸塩化物とする。触媒として少量のジメチルホルムアミドを適宜加えてもよい。
【００２４】
第二工程は、上記酸塩化物とスルホンアミドを無機塩基存在下縮合する工程であり、以下に示す試薬を加える順序が異なる２種類の方法およびスルホンアミドの金属塩を使用する方法が挙げられるが、いずれの方法を用いても結果に相違はない。
【００２５】
第一の方法では、スルホンアミド（ＩＶ）１〜２当量、好ましくは１．０５当量と、水酸化ナトリウム、水酸化カリウム、リン酸三ナトリウム、もしくはリン酸三カリウムなどの無機塩基を粉末状、または４０〜５０％水溶液として２〜８当量、好ましくは２．２〜３．３当量を塩化メチレン、アセトニトリル、テトラヒドロフラン、１，４−ジオキサンなどの溶媒中に、好ましくは塩化メチレンまたはテトラヒドロフラン中に加えておき、−３０℃〜室温条件下、好ましくは氷冷下〜室温下にて、上記有機溶媒に溶解した該塩化物１当量を含む溶液を滴下し、引き続き同温で１５分〜５時間、好ましくは1時間攪拌する。その後水、１規定塩酸を順次加え、有機溶媒で抽出後、有機層を無水硫酸マグネシウムなどの乾燥剤で乾燥する。溶媒を減圧留去することにより光学活性なアシルスルホンアミドを得ることができる。
【００２６】
第二の方法では、該塩化物１当量を塩化メチレン、アセトニトリル、テトラヒドロフラン、または１，４−ジオキサンなどの溶媒、好ましくは塩化メチレンまたはテトラヒドロフランに溶解し、これに−３０℃〜室温条件下、好ましくは氷冷下〜室温下にて水酸化ナトリウム、水酸化カリウム、リン酸三ナトリウム、もしくはリン酸三カリウムなどの無機塩基を粉末状、または４０〜５０％水溶液として２〜８当量、好ましくは２．２〜３．３当量加え、さらに上記の溶媒に溶解したスルホンアミド１〜２当量、好ましくは１．０５当量をゆっくり滴下し、１５分〜５時間、好ましくは1時間攪拌する。その後、水、１規定塩酸を順次加え、有機溶媒で抽出後、有機層を無水硫酸マグネシウムなどの乾燥剤で乾燥する。溶媒を減圧留去することにより光学活性なアシルスルホンアミドを得ることができる。
【００２７】
第三の方法では、スルホンアミド（ＩＶ）１〜２当量、好ましくは１．１０当量と、２〜５当量、好ましくは２〜３．５当量の水素化ナトリウムをテトラヒドロフラン、１，４−ジオキサンなどの溶媒、好ましくはテトラヒドロフランに懸濁し、−３０℃〜室温条件下、好ましくは氷冷下にて、上記有機溶媒に溶解した酸塩化物１当量を含む溶液を滴下し、引き続き同温で１５分〜５時間、好ましくは1時間攪拌する。その後水、１規定塩酸を順次加え攪拌後、有機溶媒で抽出する。有機層を無水硫酸マグネシウムなどの乾燥剤で乾燥し、溶媒を減圧留去することにより光学活性なアシルスルホンアミドを得る。
ただし、反応に支障をきたす置換基が存在する場合は、適当な保護基によりその置換基を保護し、適当な段階にて脱保護を行う。
上記のようにして得られた光学活性な粗製アシルスルホンアミド類は、直接再結晶することにより、または適当な塩を形成したのち再結晶精製することにより、光学純度をさらに上げることができる。
【００２８】
反応がラセミ化せずに進行したかどうか、あるいは反応の過程でどの程度ラセミ化したのかを正確に定量する方法として、出発原料と反応生成物のそれぞれの鏡像異性体比を別個に定量し、比較する方法がある。本明細書では、その鏡像異性体比を光学純度として表しているが、光学純度は両鏡像体の存在比から以下の式に従って決定することができる。
【式１】
光学純度（％）＝１００Ｘ（Ａ−Ｂ）／（Ａ＋Ｂ） （１）
（式中、ＡおよびＢはそれぞれの鏡像異性体の存在比を示す）
両鏡像異性体の存在比は、光学活性な物質を担体とするカラムを用いた高速液体クロマトグラフィー（ＨＰＬＣ）法で決定することができる。
ＨＰＬＣ法で光学純度を決定するためには、両鏡像異性体の保持時間を正確に決定することができ、かつピークがベースライン上で分離していなくてはならない。そこで、まず出発原料に該化合物のラセミ体を用いて同様の反応を行い、反応生成物をラセミ体として得た後に、化合物個々の至適分析条件を決定しなければならない。
本分析法で得られる保持時間は、分析時における環境変化によって変動する可能性がある。そこで、検体を分析する直前に該ラセミ検体をあらかじめ分析し、保持時間の較正を行うのが望ましい。以下の実施例にあげる保持時間は、あくまでも平均的な保持時間であり、恒常的に保持時間が正確に再現されるとは限らない。
また、実施例に示した３種の分析条件は、すべての化合物に汎用的に適用されるものではない。
【００２９】
【実施例】
以下に本発明の実施例を示して本発明を更に詳しく説明するが、本発明はこれらに限定されるものではない。
まず、本実施例にあげた各化合物の光学純度を決定するための、ＨＰＬＣの分析条件３種類を以下に示す。
Ａ）カラム：住友化学製SumichiralOA4900(4.6x250mm)；移動層：２０mM酢酸アンモニウム含有メタノール；流速：１．０ｍｌ／分；検出：ＵＶ（２４０ｎｍ）
Ｂ）カラム：住友化学製SumichiralOA4900(4.6x250mm)；移動層：２０mM酢酸アンモニウム含有メタノール；流速：１．０ｍｌ／分；検出：ＵＶ（２８６ｎｍ）
Ｃ）カラム：ダイセル化学製CHIRALPAC OD(4.6x250mm)；移動層：ヘキサン：エタノール：トリフルオロ酢酸（８５０：１５０：１）；流速：０．５ｍｌ／分；検出：ＵＶ（２８６ｎｍ）
以上の分析条件での測定結果について、両鏡像異性体に由来するピークの面積比より存在比を求め、光学純度を式（１）により決定した。
【００３０】
参考例１
（−）−α−メトキシフェニル酢酸の調製
市販の（ラセミ）−α−メトキシフェニル酢酸をＪ．Ｃｈｅｍ．Ｓｏｃ．，１９６２，１５１９記載の方法により、エフェドリンで光学分割して合成した。
融点：１８７−１８９℃
［α］_D＝−７４．６°（ｃ＝１．１６，メタノール，２３℃）
光学純度：１００％（Ａ法による）（ただしラセミ体の保持時間は１６．８分および１８．０分）
【００３１】
参考例２
（＋）−α−（４−メチルフェノキシ）フェニル酢酸の調製
６０％水素化ナトリウム１．１７ｇ（２９．３mmol）のジメチルホルムアミド懸濁液（１０ｍｌ）中に、室温下ｐ−クレゾール１．５１ｇ（１３．９５mmol）のジメチルホルムアミド溶液（２０ｍｌ）を加えた。３０分間攪拌した後、同温度でα−ブロモフェニル酢酸３．０ｇ（１３．９５mmol）のジメチルホルムアミド溶液（３０ｍｌ）を滴下した。１時間後、ｐ−クレゾール０．１５ｇ（１．４０mmol）、６０％水素化ナトリウム０．１２ｇ（２．９３mmol）を加えさらに室温で１６時間攪拌した。氷水を反応液に加え、１規定塩酸水溶液でｐＨ３にした後エーテルで３回抽出した。エーテル層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られる固形残渣を酢酸エチル−ｎ-ヘキサンで再結晶して無色結晶のラセミ酸１．９９ｇ（５９％）を得た。
融点：１１１−１１２℃
上記で得られた（±）−α−（４−メチルフェノキシ）フェニル酢酸１．５０ｇ（６．１９mmol）、（１Ｓ，２Ｓ）−（＋）−２−アミノ−１−フェニル−１，３−プロパンジオール１．０４ｇ（６．１９mmol）を９５％エタノール９ｍｌに溶かし、室温で３時間放置した後、析出する結晶を濾取した。この操作を２回繰り返し、白色結晶７１７ｍｇを得た。得られた結晶のうち５４７ｍｇ（１．３４mmol）に水を加え、１規定塩酸水溶液でｐＨ３にして酢酸エチルで抽出した。酢酸エチル層は水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣を酢酸エチル−ｎ-ヘキサンで再結晶して無色結晶の（＋）−体２９６ｍｇを得た。
融点：１０９．５−１１０．５℃
［α］_D＝＋１２６．２°（ｃ＝１．００，メタノール，２５℃）
ＮＭＲ（ＣＤＣｌ３）：２．２７（３Ｈ，ｓ），５．６０（１Ｈ，ｓ），６．８４（２Ｈ，ｄ），７．０６（２Ｈ，ｄ，Ｊ＝８．６），７．３６−７．４４（３Ｈ，ｍ），７．５４−７．５９（２Ｈ，ｍ）
元素分析：Ｃ１５Ｈ１４Ｏ３
計算値：Ｃ；７４．３６， Ｈ；５．８２
実測値：Ｃ；７４．５２， Ｈ；５．８４
光学純度：１００％（Ａ法による）（ただしラセミ体の保持時間は１７．７分および１９．３分）
【００３２】
参考例３
（−）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸の調製
特願平７−２６２３３７記載の方法で製造した（±）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸１０００ｇ、（１Ｓ，２Ｒ）−（＋）−ノルエフェドリン４５９ｇを、アセトニトリル（１０Ｌ）−イソプロパノール（１Ｌ）に溶解した。室温で放置後、析出した結晶を濾取し、アセトニトリル２．５Ｌで洗浄し粗結晶１０３６ｇ（７１．０％）を得た。この粗結晶をアセトニトリル：イソプロパノール＝１：１の混液に溶解した後、アセトニトリル８Ｌを加えて再結晶し、濾過後、アセトニトリル２Ｌで２回洗浄し、乾燥して有機塩９２３ｇ（６３．３％）を得た。
融点：１８０−１８２℃
［α］_D＝−５０．２°（ｃ＝１．００，メタノール，２５℃）
得られた有機塩９２２ｇを水３．７Ｌに懸濁し、２規定塩酸水溶液９５９ｍｌを加えた後、氷冷し、生じた結晶を濾取し、冷水２Ｌで洗浄した。さらにこの結晶をメタノール２．４６Ｌに溶解し、酢酸エチル２．４６Ｌを加え減圧濃縮して（−）−酸５７２ｇ（９０．６％）を得た。
融点：１５６−１５８℃
［α］_D＝−１１２．０°（ｃ＝１．００，メタノール，２３℃）
光学純度：１００％（Ｃ法による）（ただしラセミ体の保持時間は２４．８分および２８．４分）
元素分析：Ｃ１８Ｈ１９ＮＯ５
計算値：Ｃ；６５．６４， Ｈ；５．８２， Ｎ；４．２５
実測値：Ｃ；６５．５５， Ｈ；５．８２， Ｎ；４．４６
【００３３】
参考例４
（＋）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸の調製
参考例３で得た再結晶母液を濃縮し、氷冷下１規定塩酸水溶液でｐＨ４とし、クロロホルム：メタノール＝９：１で抽出した。有機層を水、飽和食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残渣を９５％エタノールで再結晶して、無色結晶の（＋）−酸を得た。
融点：１５５−１５７℃
［α］_D＝＋１１１．２°（ｃ＝１．００，メタノール，２３℃）
光学純度：１００％（Ｃ法による）（ただしラセミ体の保持時間は２４．８分および２８．４分）
【００３４】
参考例５
（−）−α−（２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸の調製
特願平７−２６２３３７記載の方法で製造した（±）−α−（２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸を、参考例３と同様の方法で光学分割した。
融点：１０７−１１０℃
［α］_D＝−１０９．０°（ｃ＝１．００，メタノール，２３℃）
光学純度：１００％（Ｃ法による）（ただしラセミ体の保持時間は２０．４分および２２．７分）
元素分析：Ｃ１７Ｈ１７ＮＯ５
計算値：Ｃ；６４．７５， Ｈ；５．４３， Ｎ；４．４４
実測値：Ｃ；６４．７０， Ｈ；５．４４， Ｎ；４．７２
【００３５】
実施例１
（−）−Ｎ−（４−イソプロピルベンゼンスルホニル）−α−メトキシフェニルアセトアミドの調製
参考例１で得た（−）−α−メトキシフェニル酢酸５０ｍｇ（０．３３１mmol）を塩化メチレン２ｍｌにとかし、ジメチルホルムアミドを一滴加えた後０℃に冷却した。塩化オキザリル０．０２８ｍｌ（０．３１６mmol）を滴下し、同温度で１時間攪拌後、減圧下溶媒を留去し、無色油状の酸塩化物を得た。この化合物はこれ以上の精製を行わずに次の反応に用いた。４−イソプロピルベンゼンスルホンアミド６６ｍｇ（０．３０１mmol）、粉末状の水酸化カリウム４４ｍｇ（８５％、０．６６２mmol）を塩化メチレン中（１ｍｌ）室温で１時間攪拌した。この反応溶液に、上記の方法で得た酸塩化物の塩化メチレン溶液（１ｍｌ）を滴下し、室温で１時間攪拌した。氷水、１規定塩酸水溶液０．１８ｍｌを加え、酢酸エチルで３回抽出した。合わせた有機層を水、飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝９：１）で精製した。
光学純度：１００％（Ａ法による）（ただしラセミ体の保持時間は２８．９分および３１．９分）
分析用サンプルを得るために、アセトン−イソプロピルエーテルで１回再結晶し、無色結晶５９ｍｇ（５６％）を得た。
融点：８９−９１℃
［α］_D＝−１６．４°（ｃ＝１．００，メタノール，２５℃）
ＮＭＲ（ＣＤＣｌ３）：１．２５（６Ｈ，ｍ），２．９６（１Ｈ，ｍ），３．３３（３Ｈ，ｓ），４．５９（１Ｈ，ｓ），７．２２−７．３５（７Ｈ，ｍ），７．９４（２Ｈ，ｄ，Ｊ＝７．８），９．１２（１Ｈ，ｂｒ）
元素分析：Ｃ₁₈Ｈ₂₁ＮＳＯ₄．０．１Ｈ₂Ｏ
計算値：Ｃ；６１．９１，Ｈ；６．１２，Ｎ；４．０１，Ｓ；９．１８
実測値：Ｃ；６１．９２，Ｈ；６．０８，Ｎ；４．２６，Ｓ；８．９４
【００３６】
実施例２
（＋）−Ｎ−（４−イソプロピルベンゼンスルホニル）−α−（４−メチルフェノキシ）フェニルアセトアミドの調製
参考例２で得た（＋）−α−（４−メチルフェノキシ）フェニル酢酸１００ｍｇ（０．４１３mmol）を塩化メチレン２ｍｌにとかし、ジメチルホルムアミドを１滴加え氷冷した。塩化オキザリル０．０３８ｍｌ（０．４３３mmol）を滴下し、同温でさらに１時間攪拌した。揮発物を減圧留去し無色油状の酸塩化物をえた。このものはこれ以上の精製を行うことなく以下の反応に用いた。４−イソプロピルベンゼンスルホンアミド９１ｍｇ（０．４５４mmol）、粉末状の水酸化カリウム６０ｍｇ（８５％、０．９０９mmol）を塩化メチレン中（２ｍｌ）室温で１時間攪拌した。この反応溶液に、上記の方法で得た酸塩化物の塩化メチレン溶液（２ｍｌ）を滴下し、室温で１時間攪拌した。氷水、１規定塩酸水溶液０．５ｍｌを加え、酢酸エチルで３回抽出した。合わせた有機層を水、飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥した。減圧下、溶媒を留去し残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝９：１）で精製した。
光学純度：１００％（Ａ法による）（ただしラセミ体の保持時間は３６．１分および４０．０分）
分析用サンプルを得るために、酢酸エチル−ｎ-ヘキサンで１回再結晶し、無色結晶１０５ｍｇ（６０％）を得た。
融点：１３７−１３８．５℃
［α］_D＝＋１４．５°（ｃ＝１．００，メタノール，２５℃）
ＮＭＲ（ＣＤＣｌ３）：１．２５−１．２８（６Ｈ，ｍ），２．２６（３Ｈ，ｓ），２．９７（１Ｈ，ｍ），５．４２（１Ｈ，ｓ），６．７３（２Ｈ，ｄ，Ｊ＝８．６）、７．０１（２Ｈ，ｄ，Ｊ＝８．６），７．３０−７．３６（７Ｈ，ｍ），７．８８（２Ｈ，ｄ，Ｊ＝８．６）
元素分析：Ｃ２４Ｈ２５ＮＯ４Ｓ
計算値：Ｃ；６８．０６，Ｈ；５．９５，Ｎ；３．３１，Ｓ；７．５７
実測値：Ｃ；６７．９２，Ｈ；５．９４，Ｎ；３．３１，Ｓ；７．５０
【００３７】
実施例３
（−）−Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
参考例３で得た（−）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸（５１９ｍｇ，１．５８mmol）を１，２−ジクロロエタン（８ｍｌ）に懸濁し、室温で攪拌しながら塩化オキザリル（０．１４ｍｌ、１．５８mmol）をゆっくり滴下した。１５分攪拌後揮発物をすべて減圧留去し、酸塩化物を得た。このものはこれ以上の精製は行わず以下の反応に用いた。１，２−ジクロロエタン（５ｍｌ）にイソプロピルベンゼンスルホンアミド（３２５ｍｇ，１．５６mmol）と粉末状の水酸化カリウム（純度８６％、３２５ｍｇ、１．６３mmol）を懸濁し、氷冷下約１時間攪拌した。ここに酸塩化物を１，２−ジクロロエタン（８ｍｌ）にとかして約１５分で滴下した。その後さらに１時間攪拌を続けた後、水、１規定塩酸水を順次加えしばらく攪拌した。反応混合物を酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後溶媒を減圧留去し、無色油状の粗製物（８４０ｍｇ）を得た。
光学純度：９８％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
さらに、この粗製物を９５％エタノールに溶解し、過剰の４規定塩酸酢酸エチル溶液を加え塩酸塩とした。
融点：１８５℃（分解）
［α］_D＝−７７．６°（ｃ＝１．０１，メタノール，２２．５℃）
元素分析：Ｃ２７Ｈ３１Ｎ２Ｏ６ＳＣｌ
計算値：Ｃ；５９．２８，Ｈ；５．７１，Ｎ；５．１２，Ｓ；５．８６，Ｃｌ；６．４８
実測値：Ｃ；５９．５８，Ｈ；５．７７，Ｎ；５．２０，Ｓ；５．９２，Ｃｌ；６．４４
光学純度：＞９９％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
【００３８】
実施例４
（−）−α−Ｎ−（４−イソプロピルフェニルスルホニル）−α−（２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
参考例５で得た（−）−α−（２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸（６．６０ｇ，０．０２０９ｍｏｌ）を実施例３と全く同様に対応する酸塩化物とした。引き続き実施例３と同様の方法により粗製の（−）−α−Ｎ−（４−イソプロピルフェニルスルホニル）−α−（２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミド（９．０ｇ，８６％）を得た。
光学純度：９６％（Ｂ法による）（ただしラセミ体の保持時間は１８．０分および２０．８分）
分析用サンプルは、エタノールから再結晶した。
融点：１７０−１７２℃
元素分析：Ｃ２６Ｈ２８Ｎ２Ｏ６Ｓ
計算値：Ｃ；６２．８９，Ｈ；５．６８，Ｎ；５．６４，Ｓ；６．４６
実測値：Ｃ；６２．９４，Ｈ；５．７０，Ｎ；５．７３，Ｓ；６．４６
［α］_D＝−７９．３°（ｃ＝１．００６，メタノール，２２℃）
上記で得た化合物（５．３ｇ）をさらに９５％エタノール中、過剰の４規定塩酸酢酸エチル溶液を加えて、塩酸塩（４．７ｇ，７１％）とした。
融点：１８５℃（分解）
元素分析：Ｃ２６Ｈ２９Ｎ２Ｏ６ＳＣｌ
計算値：Ｃ；５８．５９，Ｈ；５．４８，Ｎ；５．２６，Ｓ；６．０２，Ｃｌ；６．６５
実測値：Ｃ；５８．４３，Ｈ；５．４９，Ｎ；５．３４，Ｓ；６．１０，Ｃｌ；６．５８
［α］_D＝−８１．９°（ｃ＝１．００２，メタノール，２２．５℃）
光学純度：＞９９％（Ｂ法による）（ただしラセミ体の保持時間は１８．０分および２０．８分）
【００３９】
実施例５
（＋）−α−Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
参考例４で得た（＋）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−酢酸（６．５８ｇ，０．０２０９ｍｏｌ）を実施例３と同様の方法で塩化メチレン中、酸塩化物（８．５６ｇ）とした。引き続き実施例３と同様の方法によりイソプロピルベンゼンスルホニルアミド（４．３８ｇ，０．０２２mmol）、粉末水酸化ナトリウム（３．３７ｇ，６０mmol）とともに塩化メチレン中反応させ、粗製の（＋）−α−Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミド（９．２３ｇ，９０％）を得た。
光学純度：９８％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
粗生物を９５％エタノール中、過剰の４規定塩酸酢酸エチル溶液を加えて、塩酸塩として精製した。
融点：１８５−１９２℃（分解）
元素分析：Ｃ２７Ｈ３１Ｎ２Ｏ６ＳＣｌ
計算値：Ｃ；５９．２８，Ｈ；５．７１，Ｎ；５．１２，Ｓ；５．８６，Ｃｌ；６．４８
実測値：Ｃ；５９．２３，Ｈ；５．９６，Ｎ；４．９１，Ｓ；５．６７，Ｃｌ；６．２１
［α］_D＝＋７５．６°（ｃ＝１．００７，メタノール，２３℃）
光学純度：＞９９％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
【００４０】
実施例６
（−）−α− Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
実施例３と同様の方法で合成した酸塩化物をイソプロピルベンゼンスルホンアミド（１３３ｍｇ，０．６６８mmol）、リン酸三カリウム・ｘ水和物（５６８ｍｇ）をジメトキシエタン（２ｍｌ）中室温で攪拌しながら、酸塩化物のジメトキシエタン溶液（３ｍｌ）を滴下した。４５分後水を加え、攪拌しながら１規定塩酸でｐＨ４とし酢酸エチルで抽出した。有機層は無水硫酸ナトリウムで乾燥後、溶媒を留去し、目的化合物（２９８ｍｇ）を得た。
光学純度：；９５％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
【００４１】
実施例７
（−）−α−Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
４−イソプロピルベンゼンスルホンアミド（１３３ｍｇ，０．６６８ｍｍｏｌ）と水素化ナトリウム（８０ｍｇ，２．００ｍｍｏｌ）をテトラヒドロフラン中室温で１時間攪拌した。実施例３と同様の方法で、カルボン酸（２００ｍｇ，０．６０７ｍｍｏｌ）から酸塩化物を合成し、テトラヒドロフラン（２ｍｌ）に溶解して上記懸濁液中に滴下し２時間攪拌した。その後、氷水と１規定塩酸（０．７９ｍｌ）を順次加え酢酸エチルで抽出した。有機層は水洗し、無水硫酸ナトリウムで乾燥後溶媒を減圧留去し、無色油状物（３２４ｍｇ）を得た。
光学純度：９５％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
【００４２】
以下に従来法におけるアシルスルホンアミド化法による比較例を示す。
比較例１（Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，１９８８、２９、１６５３−１６５６記載の方法）
Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
カルボン酸（５０ｍｇ，０．１５２mmol）およびカルボニルジイミダゾール（２５ｍｇ，０．１５２mmol）を無水テトラヒドロフラン（１ｍｌ）中、窒素気流下室温で３０分攪拌し、引き続き３０分環流した。放冷後、イソプロピルベンゼンスルホニルアミド（３０ｍｇ，０．１５２mmol）と１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（２３ｍｇ，０．１５２mmol）を加え１時間攪拌した。その後氷水を加えておき、クロロホルム抽出した。有機層を水洗後、無水硫酸マグネシウムで乾燥し溶媒を減圧留去し無色油状物質８０ｍｇを得た。
光学純度：２％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
【００４３】
比較例２（向山試薬を用いた方法）
Ｎ−（４−イソプロピルフェニルスルホニル）−α−（６−メチル−２−プロピル−３−ピリジルオキシ）−１，３−ベンゾジオキソール−５−アセトアミドの調製
窒素気流下２−クロルピリジン・よう化メチル塩（４７ｍｇ，０．１８２mmol）とカルボン酸（５０ｍｇ，０．１５２mmol）を塩化メチレン（２ｍｌ）に懸濁し攪拌した。そこにイソプロピルベンゼンスルホニルアミド（３０ｍｇ，０．１５２mmol）とトリエチルアミン（３７ｍｇ，０．３６５ｍｍｏｌ）の塩化メチレン（１ml）溶液を滴下した。固形物は徐々に溶解し１時間で均一溶液にかわった。反応混合物に氷水を加え、クロロホルムで抽出した。有機層は水で洗浄後無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、無色油状物１２ｍｇを得た。
光学純度：４％（Ｂ法による）（ただしラセミ体の保持時間は１８．９分および２１．９分）
【００４４】
【発明の効果】
本発明を用いれば、α位オキシ基置換された不斉炭素を有する光学活性カルボン酸を出発原料とし、不斉を保持したまま、医薬品として繁用されるアシルスルホンアミド類へと変換することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing optically active acylsulfonamides having an α-position oxy group-substituted asymmetric carbon.
[0002]
The acylsulfonamide group is a weakly acidic functional group that is almost the same as the corresponding carboxylic acid, but its physical properties such as molecular size and distribution ratio differ greatly compared to the corresponding carboxylic acid, so the biochemical equivalent of the carboxylic acid It is particularly useful as a body as an effective side chain of pharmaceuticals (Schaaf, J. Med. Chem., 1979, 22, 1340).
[0003]
[Prior art]
There are many compounds with asymmetric carbon atoms in the molecule, such as pharmaceuticals, that have significant biological and pharmacological activity, and there is a close relationship between the arrangement of the asymmetric center and the pharmacological action. Are known. For example, when stereoisomers are in enantiomeric relationship with each other, both may show a significant difference in medicinal efficacy and toxicity. Therefore, the Ministry of Health and Welfare Pharmaceutical Manufacturing Guidelines (1985 version) also states that “when the drug is a racemate, it is desirable to examine the absorption, distribution, metabolism, and excretion dynamics of each isomer”. A method for producing a high-purity optically active substance in which one unnecessary enantiomer is excluded as much as possible is indispensable for the production of pharmaceuticals.
[0004]
Examples of a method for producing such a specific optically active substance include a method in which an optically active substance is obtained at the stage of a starting material or an appropriate intermediate in the manufacturing process, and the final product is derived while maintaining asymmetry, or the final There is a method of optical resolution at the product stage. If the optical purity of the final product is sufficiently high, it is possible to further increase the optical purity by using an appropriate purification means such as a recrystallization method, and finally obtain an optically pure pharmaceutical product. .
[0005]
In the case of a compound having an asymmetric center at the α-position of the carbonyl group, the asymmetric center may be epimerized very easily by an acid, base, heat or the like to give a mixture of stereoisomers. Since the production of acylsulfonamides may involve the same epimerization, when producing an optically active substance as a starting material, the epimerization at the α-position in the production process must be minimized.
[0006]
In general, acylsulfonamides are produced on the basis of a method by Hohenlohe-Ohringen et al. In which a carboxylic acid or derivative thereof and a sulfonamide are condensed.
Carboxylic acids are one of the most easily and frequently used functional groups for optically resolving racemates as optically active sources like amines, whereas acylsulfonamides are comparable to carboxylic acids. In spite of its acidity, there are few examples of optical resolution.
In view of the above, if a racemic carboxylic acid can be optically resolved and then converted to acylsulfonamides with minimal epimerization, it can be derived into optically active acylsulfonamides with minimal steps. It is extremely useful as a general production method.
The methods of Hohenlohe-Oehringen et al. Are classified into three groups below.
[0007]
1) A method in which a carboxylic acid is condensed with sulfonyl isocyanates at a high temperature (K. Hohenlohe-Oehringen, Monatsh, Chem, 1972, 103, 1534-1541).
2) A method in which a carboxylic acid is condensed with a sulfonamide in the presence of a condensing agent and a base. In this case, carbodiimides are generally used as condensing agents, and metal bases of sulfonamides themselves or organic bases such as dimethylaminopyridine are used as bases (K. Hohenlohe-Oehringen, Monatsh, Chem, 1968, 99, 1289-1300).
3) A method in which a carboxylic acid is first converted into an active ester, an acid chloride, an acid anhydride, etc. and activated, and then a sulfonamide is condensed as a nucleophile in the presence of a base (K. Hohenlohee-Oehringen, Monatsh). Chem., 1972, 103, 1534-1541; K. Hohenlohe-Oehringen, Monatsh, Chem, 1968, 99, 1301-1131;
[0008]
These methods are general methods for producing racemic acylsulfonamides. However, if the starting material is an optically active carboxylic acid having an asymmetric carbon at the α-position, it is generally a reaction in a high temperature condition or a reaction condition using a strong base. It is difficult to do.
[0009]
As an improved method of the Hohenlohe-Ohringen method, 1 '), 2'), and 3 ') corresponding to 1), 2), and 3) of the above classification are shown below.
1 ′) A method in which a carboxylic acid is condensed with a sulfonyl isocyanate in the presence of a base catalyst at room temperature in order to make the reaction under milder conditions (G. Graf, Angew. Chem. Int. Ed., 1968). , 7, 172-182, MW Winkley, US-4438031).
2 ′) A method of condensing a carboxylic acid and a sulfonamide in the presence of a base using water-soluble carbodiimide as a condensing agent in order to prevent the formation of a hardly soluble by-product and facilitate purification (F. Thomas). , WO9526360; RT Jacobs, J. Med. Chem, 1994, 37, 1282-1297).
3 ') a method using Mukoyama's quaternary pyridine salt reagent as an activator (DP Astles, EP411706) and potassium hydride or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). (J. L. Belletier, Tetrahedron Lett., 1986, 27, 131-134, JT Drummond, Tetrahedron Lett., 1988, 29, 1653-1656) .
[0010]
Compared with the Hohenlohe-Oehringen method, these improved methods are milder and easier to purify, but require not only expensive condensing agents, but also increase production costs. The manufacturing process becomes complicated, for example, requiring anhydrous conditions. Further, when the starting material is an optically active carboxylic acid having an asymmetric carbon at the α-position, it is difficult to maintain the steric form of the starting material for the same reason as described above. It cannot be an efficient and general synthesis method.
[0011]
As a specific example in which racemization is clearly caused by the above production method, for example, an example described in WO95 / 26360 shown in 2 ′) can be given. Here, when deriving from carboxylic acid to acylsulfonamides, it is written as (L) -tryptophan in the starting material, but it is clearly shown as (D, L) -tryptophan in the product. It is speculated that racemization occurred.
In addition, the examples described in US Pat. No. 4,438,031 shown in 1 ′) also describe the production of two stereoisomers from a starting material having a single configuration, and the asymmetric center in the condensation process is described. Inversion is suggested.
In addition to the above, in the production examples by the conventional method, there are examples in which there is no description example of the optical rotation that proves that it is an optically active substance, and there is an example that suggests that racemization is clearly occurring even if not explicitly stated. There are many.
[0012]
On the other hand, as a method different from the above, a method using a Wittig reaction using a ketone or an aldehyde derivative as a raw material (HJ Bestman, Chem. Ber, 1980, 113, 912-918), or having a double bond A method using an electrophilic addition reaction with a sulfonyl isocyanate, starting from a compound (JK Rasmussen, Chem. Rev., 1976, 76, 389-408; D. Mostwickz, Carbohydra.res., 1991, 212, 283-288) or the like may be used.
However, these methods are often limited in starting materials, and are not general methods for producing acylsulfonamides.
[0013]
In addition, acylsulfonamides can be synthesized in principle by reacting acid amides with sulfonic acid chlorides.
However, even in this method, since O-sulfonylation is preferentially advanced in many cases, it is not suitable for use as a general method (CR Stephens, J. Amer. Chem. Soc., 1955, 77, 1701-1702).
[0014]
As described above, it is difficult to obtain optically active acylsulfonamides having asymmetry at the α-position by the conventional techniques, and the process for producing the acylsulfonamides that can be applied simply, efficiently, and generally can be used. Development was desired.
[0015]
[Problems to be solved by the invention]
In view of the above, the present inventors have studied to establish a general method for producing optically active acylsulfonamides having asymmetry at the α-position.
[0016]
[Means for Solving the Problems]
As a result of diligent research, the present inventors have used a low-cost reagent alone and, in a simple production process, an optically active carboxylic acid having an α-position oxy group-substituted asymmetric carbon as a corresponding acid chloride as an intermediate. The present inventors have found a production method that can be converted to optically active acylsulfonamides while maintaining the above. The present invention will be described in detail below.
[0017]
That is, the present invention has a general formula (III) having an α-position oxy group substituted asymmetric carbon
[Chemical formula 5]

(In the formula, * indicates the position of the asymmetric carbon atom, R¹Represents phenyl optionally having substituent (s), R²Is an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heteroaryl)
1 to 2 equivalents of a chlorinating agent is reacted in an inert solvent at −30 ° C. to room temperature in the absence of a base, and the general formula (II):
[Chemical 6]

(Wherein R¹And R²Is as defined above)
After the acid chloride represented by general formula (IV):
[Chemical 7]

(Wherein R^ThreeRepresents optionally substituted aryl, R^FourRepresents a hydrogen atom or lower alkyl)
1 to 2 equivalents of a compound represented by the formula (IV) is reacted at −30 ° C. to room temperature in the presence of 2 to 8 equivalents of an inorganic base in an inert solvent, or a metal salt 1 of a compound represented by the general formula (IV) ~ 2 equivalents are reacted in an inert solvent in the absence of a base, general formula (I):
[Chemical 8]

(In the formula, *, R¹, R², R^ThreeAnd R^FourIs as defined above)
And an acylsulfonamide having an optical purity of 95% or more represented by
[0018]
In the present specification, “lower alkyl” means linear or branched C₁~ C₆Alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
In the present specification, “lower alkenyl” refers to C₂~ C₆By linear or branched alkenyl is meant eg vinyl, allyl, propenyl, and butenyl.
In the present specification, “aryl” means a monocyclic or condensed cyclic aromatic hydrocarbon such as phenyl, naphthyl, and indenyl.
In the present specification, “heteroaryl” is a 5- to 7-membered heteroaromatic ring containing one or more N, O, or S atoms in the ring and optionally condensed with a carbocyclic ring or other heterocyclic ring. Means, for example, pyridyl, quinolyl, thienyl, furyl, indolyl, or benzofuryl.
As used herein, “alkyloxy” refers to alkyloxy in which the alkyl moiety is lower alkyl, such as methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, and tert -Means butyloxy.
As used herein, “alkyloxycarbonyl” means alkyloxycarbonyl in which the alkyl moiety is lower alkyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl.
In the present specification, “aralkyl” refers to a lower alkyl substituted with aryl, for example, benzyl, phenethyl, phenylpropyl, and naphthylmethyl.
[0019]
In the present specification, “optionally substituted phenyl” means a lower alkyl group, a lower alkenyl group, an alkyloxy group, a nitro group, a hydroxyl group, an alkyloxycarbonyl group, an aralkyl group, a carboxyl group, an amide group. Alternatively, it means phenyl optionally substituted at one or more positions with halogen. Examples include 1,3-dibenzooxolyl, methoxyphenyl, fluorophenyl, and carboxyphenyl.
[0020]
In the present specification, the substituent in the “optionally substituted lower alkyl” includes an alkyloxy group, an aryloxy group in which the aryl moiety may be substituted with a nitro group or a halogen, an aralkyl group, a nitro group and a halogen. Is mentioned.
[0021]
In the present specification, “optionally substituted aryl” refers to a lower alkyl group, a lower alkenyl group, an alkyloxy group, a carboxyl group, an alkoxycarbonyl group, an aralkyl group, and an alkyl moiety that is a lower alkyl group or a lower alkenyl group. It means aryl optionally substituted by one or more acyloxy group, nitro group or halogen. Examples include tolyl, cumenyl, mesityl, isopropylphenyl, tert-butylphenyl, biphenyl, dansyl, cyclohexylphenyl, carboxyphenyl, indanyl, and tetrahydronaphthyl.
[0022]
In the present specification, “optionally substituted heteroaryl” is substituted with one or more positions by a lower alkyl group, a lower alkenyl group, an alkyloxy group, a carboxyl group, an alkoxycarbonyl group, an aralkyl group, a nitro group or a halogen. Means heteroaryl which may optionally be present. Examples include 2-methyl-4-propyl-3-pyridyl and 4-propyl-3-pyridyl.
[0023]
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises two steps.
In the first step, 1 equivalent of the optically active carboxylic acid (III) that is the starting material of the method of the present invention is added to methylene chloride, 1,2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, benzene, Or dissolved in a solvent such as toluene, preferably methylene chloride or acetonitrile, and 1-2 equivalents, preferably 1.05-1.20 equivalents of a chlorinating agent, preferably oxalyl chloride or thionyl chloride, at -30 ° C to room temperature. Under conditions, preferably under ice-cooling, and stirred for 5 minutes to 5 hours, preferably 15 minutes, all volatiles are distilled off under reduced pressure to give the desired acid chloride. A small amount of dimethylformamide may be appropriately added as a catalyst.
[0024]
The second step is a step of condensing the acid chloride and sulfonamide in the presence of an inorganic base, and includes two types of methods in which the order of adding the reagents shown below is different and a method using a metal salt of sulfonamide. There is no difference in the results regardless of which method is used.
[0025]
In the first method, sulfonamide (IV) 1 to 2 equivalents, preferably 1.05 equivalents, and an inorganic base such as sodium hydroxide, potassium hydroxide, trisodium phosphate, or tripotassium phosphate in powder form, Alternatively, 2 to 8 equivalents, preferably 2.2 to 3.3 equivalents as a 40 to 50% aqueous solution are added to a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, preferably methylene chloride or tetrahydrofuran. In addition, a solution containing 1 equivalent of the chloride dissolved in the organic solvent is added dropwise at −30 ° C. to room temperature, preferably under ice cooling to room temperature, and then at the same temperature for 15 minutes to 5 hours. Preferably, stirring is performed for 1 hour. Thereafter, water and 1N hydrochloric acid are sequentially added, and after extraction with an organic solvent, the organic layer is dried with a drying agent such as anhydrous magnesium sulfate. An optically active acylsulfonamide can be obtained by distilling off the solvent under reduced pressure.
[0026]
In the second method, 1 equivalent of the chloride is dissolved in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, or 1,4-dioxane, preferably methylene chloride or tetrahydrofuran, and this is preferably performed at −30 ° C. to room temperature. 2 to 8 equivalents, preferably 2 to 8 equivalents, in the form of a powder or a 40-50% aqueous solution of an inorganic base such as sodium hydroxide, potassium hydroxide, trisodium phosphate, or tripotassium phosphate under ice cooling to room temperature. Add 2 to 3.3 equivalents, and further slowly drop 1 to 2 equivalents, preferably 1.05 equivalents, of a sulfonamide dissolved in the above solvent, and stir for 15 minutes to 5 hours, preferably 1 hour. Thereafter, water and 1N hydrochloric acid are sequentially added, and after extraction with an organic solvent, the organic layer is dried with a drying agent such as anhydrous magnesium sulfate. An optically active acylsulfonamide can be obtained by distilling off the solvent under reduced pressure.
[0027]
In the third method, sulfonamide (IV) 1-2 equivalents, preferably 1.10 equivalents, 2-5 equivalents, preferably 2-3.5 equivalents of sodium hydride, tetrahydrofuran, 1,4-dioxane, etc. A solution containing 1 equivalent of an acid chloride dissolved in the above organic solvent was added dropwise under a temperature of −30 ° C. to room temperature, preferably under ice cooling, followed by 15 minutes at the same temperature. Stir for ~ 5 hours, preferably 1 hour. Thereafter, water and 1N hydrochloric acid are sequentially added and stirred, and then extracted with an organic solvent. The organic layer is dried with a drying agent such as anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain an optically active acylsulfonamide.
However, when there is a substituent that hinders the reaction, the substituent is protected with an appropriate protecting group, and deprotection is performed at an appropriate stage.
The optically active crude acylsulfonamides obtained as described above can be further improved in optical purity by direct recrystallization or by recrystallization and purification after forming an appropriate salt.
[0028]
As a method of accurately quantifying whether the reaction has progressed without racemization or how much it has been racemized in the course of the reaction, the respective enantiomeric ratios of the starting material and the reaction product are separately quantified, There is a way to compare. In this specification, the enantiomeric ratio is expressed as optical purity, but the optical purity can be determined from the abundance ratio of both enantiomers according to the following formula.
[Formula 1]
Optical purity (%) = 100 × (A−B) / (A + B) (1)
(In the formula, A and B indicate the abundance ratio of the respective enantiomers)
The abundance ratio of both enantiomers can be determined by a high performance liquid chromatography (HPLC) method using a column having an optically active substance as a carrier.
In order to determine optical purity with the HPLC method, the retention times of both enantiomers can be accurately determined and the peaks must be separated on the baseline. Therefore, first, the same reaction must be carried out using the racemate of the compound as a starting material to obtain a reaction product as a racemate, and then the optimum analysis conditions for each compound must be determined.
The retention time obtained by this analysis method may vary depending on environmental changes during analysis. Therefore, it is desirable to analyze the racemic specimen in advance immediately before analyzing the specimen and calibrate the holding time. The holding times given in the following examples are merely average holding times, and the holding times are not always accurately reproduced.
Further, the three analysis conditions shown in the examples are not universally applied to all compounds.
[0029]
【Example】
EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
First, three types of HPLC analysis conditions for determining the optical purity of each compound listed in this example are shown below.
A) Column: Sumichiral OA4900 (4.6 × 250 mm) manufactured by Sumitomo Chemical; moving bed: methanol containing 20 mM ammonium acetate; flow rate: 1.0 ml / min; detection: UV (240 nm)
B) Column: Sumichiral OA4900 (4.6 x 250 mm) manufactured by Sumitomo Chemical; moving bed: methanol containing 20 mM ammonium acetate; flow rate: 1.0 ml / min; detection: UV (286 nm)
C) Column: CHIRALPAC OD (4.6 x 250 mm) manufactured by Daicel Chemical; moving bed: hexane: ethanol: trifluoroacetic acid (850: 150: 1); flow rate: 0.5 ml / min; detection: UV (286 nm)
About the measurement result on the above analysis conditions, abundance ratio was calculated | required from the area ratio of the peak originating in both enantiomers, and optical purity was determined by Formula (1).
[0030]
Reference example 1
Preparation of (−)-α-methoxyphenylacetic acid
Commercially available (racemic) -α-methoxyphenylacetic acid was prepared according to J. Am. Chem. Soc. , 1962, 1519 and synthesized by optical resolution with ephedrine.
Melting point: 187-189 ° C
[Α]_D= −74.6 ° (c = 1.16, methanol, 23 ° C.)
Optical purity: 100% (according to method A) (however, racemate retention times are 16.8 minutes and 18.0 minutes)
[0031]
Reference example 2
Preparation of (+)-α- (4-methylphenoxy) phenylacetic acid
A dimethylformamide solution (20 ml) of 1.51 g (13.95 mmol) of p-cresol was added at room temperature to a suspension (10 ml) of 1.17 g (29.3 mmol) of 60% sodium hydride. After stirring for 30 minutes, a dimethylformamide solution (30 ml) of 3.0 g (13.95 mmol) of α-bromophenylacetic acid was added dropwise at the same temperature. After 1 hour, 0.15 g (1.40 mmol) of p-cresol and 0.12 g (2.93 mmol) of 60% sodium hydride were added, and the mixture was further stirred at room temperature for 16 hours. Ice water was added to the reaction solution, and the mixture was adjusted to pH 3 with 1N hydrochloric acid aqueous solution and extracted three times with ether. The ether layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid residue was recrystallized from ethyl acetate-n-hexane to obtain 1.99 g (59%) of racemic acid as colorless crystals.
Melting point: 111-112 ° C
1.50 g (6.19 mmol) of (±) -α- (4-methylphenoxy) phenylacetic acid obtained above, (1S, 2S)-(+)-2-amino-1-phenyl-1,3- Propanediol 1.04 g (6.19 mmol) was dissolved in 95% ethanol 9 ml and allowed to stand at room temperature for 3 hours, and then the precipitated crystals were collected by filtration. This operation was repeated twice to obtain 717 mg of white crystals. Water was added to 547 mg (1.34 mmol) of the obtained crystals, and the mixture was adjusted to pH 3 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane to obtain 296 mg of (+)-form of colorless crystals.
Melting point: 109.5-110.5 ° C
[Α]_D= + 126.2 ° (c = 1.00, methanol, 25 ° C.)
NMR (CDCl3): 2.27 (3H, s), 5.60 (1H, s), 6.84 (2H, d), 7.06 (2H, d, J = 8.6), 7.36 -7.44 (3H, m), 7.54-7.59 (2H, m)
Elemental analysis: C15H14O3
Calculated value: C; 74.36, H; 5.82
Found: C; 74.52, H; 5.84
Optical purity: 100% (according to method A) (however, racemate retention times are 17.7 and 19.3 minutes)
[0032]
Reference example 3
Preparation of (−)-α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid
(±) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid 1000 g produced by the method described in Japanese Patent Application No. 7-262337, (1S, 2R)-(+)-norephedrine 459 g was dissolved in acetonitrile (10 L) -isopropanol (1 L). After standing at room temperature, the precipitated crystals were collected by filtration and washed with 2.5 L of acetonitrile to obtain 1036 g (71.0%) of crude crystals. The crude crystals were dissolved in a mixed solution of acetonitrile: isopropanol = 1: 1, recrystallized by adding 8 L of acetonitrile, filtered, washed twice with 2 L of acetonitrile, and dried to give 923 g (63.3%) organic salt. Got.
Melting point: 180-182 ° C
[Α]_D= -50.2 ° (c = 1.00, methanol, 25 ° C)
922 g of the obtained organic salt was suspended in 3.7 L of water, 959 ml of 2N aqueous hydrochloric acid solution was added, and the mixture was cooled with ice, and the resulting crystals were collected by filtration and washed with 2 L of cold water. Further, the crystals were dissolved in 2.46 L of methanol, 2.46 L of ethyl acetate was added and concentrated under reduced pressure to obtain 572 g (90.6%) of (−)-acid.
Melting point: 156-158 ° C
[Α]_D= -112.0 ° (c = 1.00, methanol, 23 ° C)
Optical purity: 100% (according to method C) (racemic retention times of 24.8 minutes and 28.4 minutes)
Elemental analysis: C18H19NO5
Calculated value: C; 65.64, H; 5.82, N; 4.25
Found: C; 65.55, H; 5.82, N; 4.46
[0033]
Reference example 4
Preparation of (+)-α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid
The recrystallized mother liquor obtained in Reference Example 3 was concentrated, adjusted to pH 4 with 1N aqueous hydrochloric acid under ice cooling, and extracted with chloroform: methanol = 9: 1. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from 95% ethanol to obtain colorless crystals of (+)-acid.
Melting point: 155-157 ° C
[Α]_D= + 111.2 ° (c = 1.00, methanol, 23 ° C.)
Optical purity: 100% (according to method C) (racemic retention times of 24.8 minutes and 28.4 minutes)
[0034]
Reference Example 5
Preparation of (−)-α- (2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid
(±) -α- (2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid produced by the method described in Japanese Patent Application No. 7-262337 was prepared in the same manner as in Reference Example 3. Was optically split.
Melting point: 107-110 ° C
[Α]_D= −109.0 ° (c = 1.00, methanol, 23 ° C.)
Optical purity: 100% (according to method C) (however, racemate retention times are 20.4 minutes and 22.7 minutes)
Elemental analysis: C17H17NO5
Calculated values: C; 64.75, H; 5.43, N; 4.44
Found: C; 64.70, H; 5.44, N; 4.72
[0035]
Example 1
Preparation of (−)-N- (4-isopropylbenzenesulfonyl) -α-methoxyphenylacetamide
50 mg (0.331 mmol) of (−)-α-methoxyphenylacetic acid obtained in Reference Example 1 was dissolved in 2 ml of methylene chloride, one drop of dimethylformamide was added, and the mixture was cooled to 0 ° C. 0.028 ml (0.316 mmol) of oxalyl chloride was added dropwise and stirred at the same temperature for 1 hour, and then the solvent was distilled off under reduced pressure to obtain a colorless oily acid chloride. This compound was used in the next reaction without further purification. 4-Isopropylbenzenesulfonamide 66 mg (0.301 mmol) and powdered potassium hydroxide 44 mg (85%, 0.662 mmol) were stirred in methylene chloride (1 ml) at room temperature for 1 hour. To this reaction solution, a methylene chloride solution (1 ml) of the acid chloride obtained by the above method was added dropwise and stirred at room temperature for 1 hour. Ice water and 0.18 ml aqueous 1N hydrochloric acid solution were added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 9: 1).
Optical purity: 100% (according to method A) (however, racemate retention times are 28.9 minutes and 31.9 minutes)
In order to obtain an analytical sample, it was recrystallized once with acetone-isopropyl ether to obtain 59 mg (56%) of colorless crystals.
Melting point: 89-91 ° C
[Α]_D= -16.4 ° (c = 1.00, methanol, 25 ° C)
NMR (CDCl3): 1.25 (6H, m), 2.96 (1H, m), 3.33 (3H, s), 4.59 (1H, s), 7.22-7.35 (7H) M), 7.94 (2H, d, J = 7.8), 9.12 (1H, br)
Elemental analysis: C₁₈H_{twenty one}NSO_Four. 0.1H₂O
Calculated values: C; 61.91, H; 6.12, N; 4.01, S; 9.18
Found: C; 61.92, H; 6.08, N; 4.26, S; 8.94
[0036]
Example 2
Preparation of (+)-N- (4-isopropylbenzenesulfonyl) -α- (4-methylphenoxy) phenylacetamide
100 mg (0.413 mmol) of (+)-α- (4-methylphenoxy) phenylacetic acid obtained in Reference Example 2 was dissolved in 2 ml of methylene chloride, and 1 drop of dimethylformamide was added and ice-cooled. 0.038 ml (0.433 mmol) of oxalyl chloride was added dropwise, and the mixture was further stirred at the same temperature for 1 hour. Volatiles were removed under reduced pressure to give a colorless oily acid chloride. This was used in the following reaction without further purification. 91 mg (0.454 mmol) of 4-isopropylbenzenesulfonamide and 60 mg (85%, 0.909 mmol) of powdered potassium hydroxide were stirred in methylene chloride (2 ml) at room temperature for 1 hour. To this reaction solution, a methylene chloride solution (2 ml) of the acid chloride obtained by the above method was added dropwise and stirred at room temperature for 1 hour. Ice water and 0.5 ml of 1N hydrochloric acid aqueous solution were added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 9: 1).
Optical purity: 100% (according to method A) (however, racemate retention times are 36.1 minutes and 40.0 minutes)
In order to obtain an analytical sample, it was recrystallized once with ethyl acetate-n-hexane to obtain 105 mg (60%) of colorless crystals.
Melting point: 137-138.5 ° C
[Α]_D= + 14.5 ° (c = 1.00, methanol, 25 ° C.)
NMR (CDCl3): 1.25-1.28 (6H, m), 2.26 (3H, s), 2.97 (1H, m), 5.42 (1H, s), 6.73 (2H) , D, J = 8.6), 7.01 (2H, d, J = 8.6), 7.30-7.36 (7H, m), 7.88 (2H, d, J = 8. 6)
Elemental analysis: C24H25NO4S
Calculated value: C; 68.06, H; 5.95, N; 3.31, S; 7.57
Found: C; 67.92, H; 5.94, N; 3.31, S; 7.50
[0037]
Example 3
Preparation of (−)-N- (4-isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
The (−)-α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid (519 mg, 1.58 mmol) obtained in Reference Example 3 was replaced with 1,2 -Suspended in dichloroethane (8 ml) and oxalyl chloride (0.14 ml, 1.58 mmol) was slowly added dropwise with stirring at room temperature. After stirring for 15 minutes, all volatiles were distilled off under reduced pressure to obtain acid chloride. This was used in the following reaction without further purification. Isopropylbenzenesulfonamide (325 mg, 1.56 mmol) and powdered potassium hydroxide (purity 86%, 325 mg, 1.63 mmol) were suspended in 1,2-dichloroethane (5 ml) and stirred for about 1 hour under ice cooling. . The acid chloride was dissolved in 1,2-dichloroethane (8 ml) and added dropwise in about 15 minutes. Thereafter, the mixture was further stirred for 1 hour, and water and 1N hydrochloric acid were sequentially added thereto, followed by stirring for a while. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a colorless oily crude product (840 mg).
Optical purity: 98% (according to method B) (however, racemate retention times are 18.9 minutes and 21.9 minutes)
Further, this crude product was dissolved in 95% ethanol, and an excess of 4N hydrochloric acid ethyl acetate solution was added to obtain a hydrochloride.
Melting point: 185 ° C (decomposition)
[Α]_D= -77.6 ° (c = 1.01, methanol, 22.5 ° C.)
Elemental analysis: C27H31N2O6SCl
Calculated values: C; 59.28, H; 5.71, N; 5.12, S; 5.86, Cl; 6.48
Found: C; 59.58, H; 5.77, N; 5.20, S; 5.92, Cl; 6.44
Optical purity:> 99% (according to method B) (racemic retention times of 18.9 and 21.9 minutes)
[0038]
Example 4
Preparation of (−)-α-N- (4-Isopropylphenylsulfonyl) -α- (2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
The (−)-α- (2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid (6.60 g, 0.0209 mol) obtained in Reference Example 5 was completely the same as Example 3. Similarly, the corresponding acid chloride was obtained. Subsequently, crude (−)-α-N- (4-isopropylphenylsulfonyl) -α- (2-propyl-3-pyridyloxy) -1,3-benzodioxole-5 was prepared in the same manner as in Example 3. -Acetamide (9.0 g, 86%) was obtained.
Optical purity: 96% (according to method B) (however, racemate retention times are 18.0 minutes and 20.8 minutes)
The analytical sample was recrystallized from ethanol.
Melting point: 170-172 ° C
Elemental analysis: C26H28N2O6S
Calculated values: C; 62.89, H; 5.68, N; 5.64, S; 6.46
Found: C; 62.94, H; 5.70, N; 5.73, S; 6.46
[Α]_D= -79.3 ° (c = 1.006, methanol, 22 ° C.)
The compound obtained above (5.3 g) was further added with an excess of 4 N hydrochloric acid ethyl acetate solution in 95% ethanol to obtain hydrochloride (4.7 g, 71%).
Melting point: 185 ° C (decomposition)
Elemental analysis: C26H29N2O6SCl
Calculated values: C; 58.59, H; 5.48, N; 5.26, S; 6.02, Cl; 6.65
Found: C; 58.43, H; 5.49, N; 5.34, S; 6.10, Cl; 6.58
[Α]_D= −81.9 ° (c = 1.002, methanol, 22.5 ° C.)
Optical purity:> 99% (according to method B) (however, racemate retention times are 18.0 minutes and 20.8 minutes)
[0039]
Example 5
Preparation of (+)-α-N- (4-isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
(+)-Α- (6-Methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetic acid (6.58 g, 0.0209 mol) obtained in Reference Example 4 was carried out. In the same manner as in Example 3, acid chloride (8.56 g) was obtained in methylene chloride. Subsequently, the reaction was carried out in the same manner as in Example 3 with isopropylbenzenesulfonylamide (4.38 g, 0.022 mmol) and powdered sodium hydroxide (3.37 g, 60 mmol) in methylene chloride to obtain crude (+)-α-N. -(4-Isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide (9.23 g, 90%) was obtained.
Optical purity: 98% (according to method B) (however, racemate retention times are 18.9 minutes and 21.9 minutes)
The crude product was purified as a hydrochloride salt by adding an excess of 4N hydrochloric acid ethyl acetate solution in 95% ethanol.
Melting point: 185-192 ° C (decomposition)
Elemental analysis: C27H31N2O6SCl
Calculated values: C; 59.28, H; 5.71, N; 5.12, S; 5.86, Cl; 6.48
Found: C; 59.23, H; 5.96, N; 4.91, S; 5.67, Cl; 6.21
[Α]_D= + 75.6 ° (c = 1.007, methanol, 23 ° C.)
Optical purity:> 99% (according to method B) (racemic retention times of 18.9 and 21.9 minutes)
[0040]
Example 6
Preparation of (−)-α-N- (4-isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
The acid chloride synthesized in the same manner as in Example 3 was stirred in isopropylbenzenesulfonamide (133 mg, 0.668 mmol) and tripotassium phosphate x hydrate (568 mg) in dimethoxyethane (2 ml) at room temperature. A solution of acid chloride in dimethoxyethane (3 ml) was added dropwise. After 45 minutes, water was added, and the mixture was adjusted to pH 4 with 1N hydrochloric acid while stirring and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain the target compound (298 mg).
Optical purity: 95% (according to method B) (racemic retention times of 18.9 and 21.9 minutes)
[0041]
Example 7
Preparation of (−)-α-N- (4-Isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
4-Isopropylbenzenesulfonamide (133 mg, 0.668 mmol) and sodium hydride (80 mg, 2.00 mmol) were stirred in tetrahydrofuran at room temperature for 1 hour. In the same manner as in Example 3, an acid chloride was synthesized from carboxylic acid (200 mg, 0.607 mmol), dissolved in tetrahydrofuran (2 ml), dropped into the suspension and stirred for 2 hours. Thereafter, ice water and 1N hydrochloric acid (0.79 ml) were sequentially added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a colorless oil (324 mg).
Optical purity: 95% (according to method B) (however, racemate retention times are 18.9 minutes and 21.9 minutes)
[0042]
The comparative example by the acyl sulfonamidation method in the conventional method is shown below.
Comparative Example 1 (Method described in Tetrahedron Lett., 1988, 29, 1653-1656)
Preparation of N- (4-isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
Carboxylic acid (50 mg, 0.152 mmol) and carbonyldiimidazole (25 mg, 0.152 mmol) were stirred in anhydrous tetrahydrofuran (1 ml) at room temperature for 30 minutes under a nitrogen stream, and then refluxed for 30 minutes. After allowing to cool, isopropylbenzenesulfonylamide (30 mg, 0.152 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (23 mg, 0.152 mmol) were added and stirred for 1 hour. Thereafter, ice water was added, followed by extraction with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 80 mg of a colorless oily substance.
Optical purity: 2% (according to Method B) (however, racemate retention times are 18.9 and 21.9 minutes)
[0043]
Comparative Example 2 (method using Mukaiyama reagent)
Preparation of N- (4-isopropylphenylsulfonyl) -α- (6-methyl-2-propyl-3-pyridyloxy) -1,3-benzodioxole-5-acetamide
Under a nitrogen stream, 2-chloropyridine / methyl iodide (47 mg, 0.182 mmol) and carboxylic acid (50 mg, 0.152 mmol) were suspended in methylene chloride (2 ml) and stirred. Thereto was added dropwise a solution of isopropylbenzenesulfonylamide (30 mg, 0.152 mmol) and triethylamine (37 mg, 0.365 mmol) in methylene chloride (1 ml). The solid was gradually dissolved and changed to a homogeneous solution in 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 12 mg of a colorless oil.
Optical purity: 4% (according to method B) (however, racemate retention times are 18.9 and 21.9 minutes)
[0044]
【The invention's effect】
According to the present invention, an optically active carboxylic acid having an asymmetric carbon substituted with an α-position oxy group can be used as a starting material and converted to acylsulfonamides frequently used as pharmaceuticals while maintaining asymmetry. it can.

Claims (6)

Formula (III) having an α-position oxy group-substituted asymmetric carbon:

(In the formula, * represents the position of the asymmetric carbon atom, R ¹ represents phenyl optionally having substituent (s), R ² represents optionally substituted lower alkyl, optionally substituted) Represents aryl or optionally substituted heteroaryl)
1 to 2 equivalents of a chlorinating agent is reacted in an inert solvent at −30 ° C. to room temperature, and the general formula (II):

(Wherein R ¹ and R ² are as defined above)
After the acid chloride represented by general formula (IV):

(Wherein R ³ represents an optionally substituted aryl, and R ⁴ represents a hydrogen atom or lower alkyl)
1 to 2 equivalents of a compound represented by the formula (IV) is reacted at −30 ° C. to room temperature in the presence of 2 to 8 equivalents of an inorganic base in an inert solvent, or a metal salt 1 of a compound represented by the general formula (IV) ~ 2 equivalents are reacted in an inert solvent in the absence of a base, general formula (I):

(Wherein, *, R ¹ , R ² , R ³ and R ⁴ are as defined above)
A process for producing acylsulfonamides having an optical purity of 95% or more represented by: The process according to claim 1, wherein R ² in the general formula (I) is pyridyl which may be substituted. The process according to claim 1, wherein, in general formula (I), R ² is optionally substituted phenyl. The manufacturing method of Claims 1-3 whose R < ⁴ > is a hydrogen atom in general formula (IV). The production method according to any one of claims 1 to 4, wherein the chlorinating agent is oxalyl chloride or thionyl chloride. The manufacturing method in any one of Claims 1-5 whose inorganic base is trisodium phosphate, tripotassium phosphate, sodium hydroxide, or potassium hydroxide.