JP2005047803A - Method for producing (3r,5s)-7-substituted-3,5-dihydroxyhept-6-enoic acid - Google Patents
Method for producing (3r,5s)-7-substituted-3,5-dihydroxyhept-6-enoic acid Download PDFInfo
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、コレステロール低下剤（ＨＭＧ−ＣｏＡ還元酵素阻害薬）の合成中間体として有用な、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸の製法に関し、特に、（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸の製法に関する。
【０００２】
【従来の技術】
従来、７−置換−３，５−ジヒドロキシヘプト−６−エン酸の光学異性体混合物から、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸を選択的に製造する方法としては、キラルなアミン（例えば、（Ｒ）−（＋）−α−メチルベンジルアミン）を使用する方法が知られている（Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．，９，２９７７（１９９９））。しかしながら、この方法では、高価なキラルなアミンを化学量論量用いなければならず、又、目的とする（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸の収率が３０％程度と低い等、工業的に好適な方法ではなかった。
【０００３】
【発明が解決しようとする課題】
本発明の課題は、上記の問題点を解決し、工業的に好適な（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸の製法を提供するものである。
【０００４】
【課題を解決するための手段】
本発明の課題は、
（Ａ）式（１）
【０００５】
【化７】
で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）に、一般式（２）
【０００７】
【化８】
（式中、Ｒ１、Ｒ２及びＲ３は、水素原子又は炭化水素基を示す。）
で示されるアキラルなアミンを反応させて、一般式（３）
【０００９】
【化９】
（式中、Ｒ１、Ｒ２及びＲ３は、前記と同義である。）
で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を生成させる第一工程、
（Ｂ）次いで、７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を溶媒中で晶析させて、一般式（４）
【００１１】
【化１０】
（式中、Ｒ１、Ｒ２及びＲ３は、前記と同義である。）
で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を選択的に得る第二工程、
（Ｃ）更に、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を酸性化して、式（５）
【００１３】
【化１１】
で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸を得る第三工程、を含んでなることを特徴とする、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸の製法によって解決される。
【００１５】
【発明の実施の形態】
本発明は、
（Ａ）式（１）で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）に、一般式（２）で示されるアキラルなアミンを反応させて、一般式（３）で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を生成させる第一工程、
（Ｂ）次いで、７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を溶媒中で晶析させて、一般式（４）で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミンを選択的に得る第二工程、
（Ｃ）更に、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を酸性化して、式（５）で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸を得る第三工程、
を含んでなる三工程によって、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸を製造するものである。
【００１６】
引き続き、前記の三つの工程を順次説明する。
（Ａ）第一工程
本発明の第一工程は、式（１）で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）に、一般式（２）で示されるアキラルなアミンを反応させて、一般式（３）で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を生成させる工程である。
【００１７】
本発明の第一工程で使用される７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）は、前記の式（１）で示されるが、具体的には、式（６）
【００１８】
【化１２】
で示される４種の光学異性体の混合物であり、特に、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸を主成分として含む光学異性体の混合物を示す。
【００２０】
前記の７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）は、例えば、特開平８−９２２１７号公報に記載の方法によって合成される７−置換−３，５−ジヒドロキシヘプト−６−エン酸エステル（光学異性体混合物）を加水分解することによって容易に得ることが出来る（参考例１〜３に記載）。
【００２１】
本発明の第一工程で使用されるアキラルなアミンとは、具体的には、不斉炭素原子を有しないアミンのことを示す。アキラルなアミンは、前記の一般式（２）で示されるが、その一般式（２）において、Ｒ１、Ｒ２及びＲ３は、水素原子又は炭化水素基であり、例えば、水素原子；メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等の炭素数１〜１０のアルキル基；シクロプロピル基、シクロブチル基、シクロペンチル基、シクロへキシル基、シクロヘプチル基、シクロオクチル基、シクロノニル基、シクロデシル基等の炭素数３〜１０のシクロアルキル基；ベンジル基、フェニルエチル基、フェニルプロピル基等の炭素数７〜１２のアラルキル基が挙げられる。なお、前記のＲ１、Ｒ２及びＲ３の好ましい態様としては、Ｒ１及びＲ２が水素原子でＲ３がアラルキル基、Ｒ１が水素原子でＲ２及びＲ３がシクロアルキル基である。
【００２２】
前記アキラルなアミンの使用量は、７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）１ｍｏｌに対して、好ましくは０．５〜２．０ｍｏｌ、更に好ましくは０．８〜１．２ｍｏｌである。
【００２３】
本発明の第一工程は、溶媒の存在下で行うのが好ましく、使用される溶媒としては、反応を阻害しないものならば特に限定されないが、例えば、水；メタノール、エタノール、イソプロピルアルコール、ｔ−ブチルアルコール等のアルコール類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン等のエーテル類；酢酸メチル、酢酸エチル等のカルボン酸エステル類；塩化メチレン、クロロホルム、ジクロロエタン等のハロゲン化脂肪族炭化水素類が挙げられるが、好ましくはカルボン酸エステル類、更に好ましくは酢酸エチルが使用される。これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００２４】
前記溶媒の使用量は、反応液の均一性や攪拌性によって適宜調節するが、７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）１ｇに対して、好ましくは５〜１００ｇ、更に好ましくは１０〜５０ｇである。
【００２５】
本発明の第一工程は、例えば、７−置換−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）、アキラルなアミン及び溶媒を混合して、攪拌する等の方法によって行われる。その際の反応温度は、好ましくは−２０〜１００℃、更に好ましくは０〜５０℃であり、反応圧力は特に制限されない。
【００２６】
本発明の第一工程によって得られる７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）は、例えば、反応終了後、反応液を冷却することで結晶として取得することが出来る。
【００２７】
（Ｂ）第二工程
本発明の第二工程は、第一工程において得られた、一般式（３）で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を溶媒中で晶析させて、一般式（４）で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を選択的に得る工程である。
【００２８】
本発明の第二工程において使用される溶媒としては、例えば、水；メタノール、エタノール、イソプロピルアルコール、ｔ−ブチルアルコール等のアルコール類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン等のエーテル類；塩化メチレン、クロロホルム等のハロゲン化炭化水素類；ベンゼン、トルエン、キシレン等の芳香族炭化水素類；酢酸メチル、酢酸エチル等のカルボン酸エステル類；アセトニトリル、プロピオニトリル等のニトリル類；アセトン、メチルイソブチルケトン等のケトン類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド等のアミド類が挙げられるが、好ましくはエーテル類、ケトン類、アミド類、更に好ましくはエーテル類、ケトン類、特に好ましくはテトラヒドロフラン、メチルイソブチルケトンが使用される。これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００２９】
前記溶媒の使用量は、７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）１ｇに対して、好ましくは１〜１００ｇ、更に好ましくは５〜５０ｇ、特に好ましくは１０〜３０ｇである。
【００３０】
本発明の第二工程は、例えば、第一工程において得られた７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を溶媒に溶解して均一溶液とした後（必要ならば、加熱して溶解させても良い）、冷却して結晶を析出させる（晶析させる）等の方法によって行われる。その際の冷却温度は、好ましくは−５０〜８０℃、更に好ましくは−２０〜４０℃、特に好ましくは−１０〜２０℃である。なお、必要ならば、この操作を繰り返し行っても良い。
【００３１】
本発明の第二工程によって選択的に得られる（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩は、例えば、晶析終了後、濾過することで遊離の結晶として取得することが出来る。
【００３２】
（Ｃ）第三工程
本発明の第三工程は、第二工程において得られた、一般式（４）で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を酸性化して、式（５）で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸を得る工程である。
【００３３】
本発明の第三工程における酸性化とは、カルボン酸塩を酸性化して遊離のカルボン酸を得る一般的な方法ならば特に限定されないが、酸の存在下、溶媒中で行われるのが望ましい。
【００３４】
本発明の第三工程において使用する酸としては、例えば、塩酸、硫酸、硝酸、リン酸等の鉱酸類；メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸等のスルホン酸類が挙げられるが、好ましくは鉱酸、更に好ましくは塩酸、硫酸が使用される。これらの酸は、単独又は二種以上を混合して使用しても良い。
【００３５】
前記酸の使用量は、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を酸性化して、遊離のカルボン酸（（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸）とし得る量ならば特に制限はされないが、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩１ｍｏｌに対して、好ましくは１．０〜１．１ｍｏｌである。
【００３６】
本発明の第三工程において使用する溶媒としては、反応を阻害しないものならば特に限定されないが、例えば、水；メタノール、エタノール、イソプロピルアルコール、ｔ−ブチルアルコール等のアルコール類；アセトニトリル、プロピオニトリル等のニトリル類が挙げられるが、好ましくはアルコール類、更に好ましくはメタノール、エタノールが使用される。これらの溶媒は、単独又は二種以上を混合して使用しても良い。
【００３７】
前記溶媒の使用量は、反応液の均一性や攪拌性によって適宜調節するが、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩１ｇに対して、好ましくは１〜５０ｇ、更に好ましくは１０〜３０ｇである。
【００３８】
本発明の第三工程は、例えば、第二工程において得られた（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩、酸及び溶媒を混合して攪拌する等の方法によって行われる。その際の温度は、好ましくは−２０〜１００℃、更に好ましくは０〜５０℃であり、圧力は特に制限されない。
【００３９】
本発明の第三工程によって得られる（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸は、例えば、加水分解終了後、抽出、濃縮、再結晶等による一般的な方法によって分離・精製される。
【００４０】
【実施例】
次に、実施例を挙げて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
なお、実施例における光学純度（エナンチオマー過剰率（％ｅｅ）及びジアステレオマー過剰率（％ｄｅ））は、以下の分析条件により高速液体クロマトグラフィーを用いて行った。なお、（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロヘプト−６−エン酸の光学純度は、該化合物を芳香族炭化水素溶媒中で加熱して、対応するラクトン（（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オン）に誘導した後に測定した（後の参考例４及び５に記載）。
【００４１】
高速液体クロマトグラフィーの分析条件：
（エナンチオマー過剰率）
（ジアステレオマー過剰率）
参考例１（７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝５−ヒドロキシヘプト−６−エン酸イソプロピル（光学異性体混合物）の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積１００ｍｌのフラスコに、チタンテトライソプロポキシド６．５８ｇ（２２．０ｍｍｏｌ）、（Ｓ）−２−｛Ｎ−（３，５−ジ−ｔｅｒｔ−ブチルサリチリデン）アミノ｝−３−メチル−１−ブタノール６．７０ｇ（２１．０ｍｍｏｌ）及び塩化メチレン４０ｍｌを加え、室温で１時間攪拌させた。次いで、反応液を−３０℃まで冷却し、３−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝プロプ−２−エナール６．３６ｇ（２０．０ｍｍｏｌ）を塩化メチレン６ｍｌに溶解したものを加えて３０分間攪拌させた。更に、ジケテン２．５２ｇ（３０．０ｍｍｏｌ）を加えて−２０℃まで昇温しながら６時間反応させた。
反応終了後、得られた反応液を取り出し、５．０質量％シュウ酸水溶液１０５．２９ｇ（４２．０ｍｍｏｌ）及び１，２−ジクロロエタン５０ｍｌの混合液に加え、室温で１時間激しく攪拌させた。その後、有機層を取り出し、５．０質量％シュウ酸水溶液５０ｍｌ、水５０ｍｌ、飽和炭酸水素ナトリウム水溶液３０ｍｌの順で洗浄し、無水硫酸マグネシウムで乾燥させた。セライトで濾過後、濾液を減圧下で濃縮し、濃縮物にｎ−ヘキサン５０ｍｌを加えて、１時間激しく攪拌させたところ固体が析出した。これを濾過して乾燥させ、黄色粉末として７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−５−ヒドロキシ−３−オキソヘプト−６−エン酸イソプロピル（光学異性体混合物）７．８４ｇを得た（単離収率：８５．０％）。
【００４４】
参考例２（７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸イソプロピル（光学異性体混合物）の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積３００ｍｌのフラスコに、参考例１で合成した７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−５−ヒドロキシ−３−オキソヘプト−６−エン酸イソプロピル（光学異性体混合物）６．９１ｇ（１５．０ｍｍｏｌ）、テトラヒドロフラン１２０ｍｌ及びメタノール３０ｍｌを加えて−７５℃に冷却し、１ｍｏｌ／ｌジエチルメトキシホウ素テトラヒドロフラン溶液１６．５ｍｌを加えて３０分間攪拌した。次いで、水素化ホウ素ナトリウム６８４ｍｇ（１８．０ｍｍｏｌ）を加え、同温度で５時間反応させた。反応終了後、酢酸１１ｍｌ及び酢酸エチル１００ｍｌを加え、室温で２０分間攪拌させた。得られた反応液を飽和炭酸水素ナトリウムで１００ｍｌで２回、飽和食塩水５０ｍｌで１回の順で洗浄し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮した。得られた濃縮物に、メタノール１００ｍｌを加え、常圧加熱下で濃縮した。この操作を３回繰り返し、黄色油状物として７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸イソプロピル（光学異性体混合物）６．６０ｇを得た（単離収率：９５．３％）。
なお、本化合物を高速液体クロマトグラフィーにより分析したところ、（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸イソプロピルの光学純度は７３％ｅｅ及び９７％ｄｅであった。
【００４５】
参考例３（７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）の合成）
攪拌装置、温度計及び滴下漏斗を備えた内容積５０ｍｌのフラスコに、参考例２で合成した７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸イソプロピル（光学異性体混合物）４．６３ｇ（１０．０ｍｍｏｌ）、メタノール１０ｍｌ及び１ｍｏｌ／ｌ水酸化ナトリウム水溶液１２ｍｌ（１２．０ｍｍｏｌ）を加え、室温で１時間反応させた。反応終了後、１ｍｏｌ／ｌ塩酸を加えて反応液のｐＨを３．５に調整した。次いで、酢酸エチル１０ｍｌで２回抽出した後、有機層を分液し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、淡黄色油状物として７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）４．２１ｇを得た（単離収率：１００％）。
【００４６】
実施例１（第一工程：７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩（光学異性体混合物）の合成）
攪拌装置及び温度計を備えた内容積５０ｍｌのフラスコに、参考例３で得られた７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）４．２１ｇ（１０．０ｍｍｏｌ）、ベンジルアミン１．０７ｇ（１０．ｏｍｍｏｌ）及び酢酸エチル３０ｍｌを加え、攪拌しながら０℃まで冷却すると結晶が析出して来た。結晶を濾過し、０℃に冷却した酢酸エチル１５ｍｌで洗浄した後に減圧下で乾燥させ、無色結晶として７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩（光学異性体混合物）５．０１ｇを得た（単離収率：９４．９％）。
【００４７】
実施例２（第二工程：（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩の合成）
攪拌装置及び温度計を備えた内容積１００ｍｌのフラスコに、実施例１で得られた７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩（光学異性体混合物）４．２２ｇ（８．００ｍｍｏｌ）及びテトラヒドロフラン８４ｍｌを加え、攪拌しながら５０℃まで昇温して均一溶液とした。次いで、反応液を０℃まで冷却すると結晶が析出して来たので、結晶を濾過し、０℃に冷却したテトラヒドロフラン４２ｍｌで洗浄した。この晶析操作を２回繰り返した。得られた結晶を減圧下で乾燥させ、無色結晶として（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩２．５２ｇを得た（単離収率：６０．０％）。
なお、（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩は、以下の物性値で示される新規な化合物である。
【００４８】
融点；１１８〜１２０℃
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，δ（ｐｐｍ））；１．０４〜１．０７（２Ｈ，ｍ）、１．２５〜１．２８（２Ｈ，ｍ）、１．２８〜１．３３（１Ｈ，ｍ）、１．５１〜１．５６（１Ｈ，ｍ）、２．２３〜２．２９（２Ｈ，ｍ）、２．５１〜２．５５（１Ｈ，ｍ）、３．７６〜３．８０（１Ｈ，ｍ）、４．２５〜４．２９（１Ｈ，ｍ）、５．６６（１Ｈ，ｄｄ，Ｊ＝６．３，１５．９Ｈｚ）、６．６２（１Ｈ，ｄｄ，Ｊ＝１．２，１５．９Ｈｚ）、７．２４〜７．４０（４Ｈ，ｍ）、７．４０〜７．４４（２Ｈ，ｍ）、７．４４〜７．４９（５Ｈ，ｍ）、７．５８〜７．６１（１Ｈ，ｍ）、７．９１（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ）
【００４９】
実施例３（第三工程：（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸の合成）
攪拌装置を備えた内容積５０ｍｌのフラスコに、実施例２で得られた（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩２．１１ｇ（４．００ｍｍｏｌ）及びメタノール１０ｍｌを加えた。その後、１ｍｏｌ／ｌ塩酸を加えて反応液のｐＨを３．５に調整した。次いで、酢酸エチル１０ｍｌで２回抽出した後、有機層を分液し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、無色油状物として（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸１．６６ｇを得た（単離収率：９９．０％）。
【００５０】
参考例４（（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オンの合成）
攪拌装置、温度計、還流冷却器及びＤｅａｎ−Ｓｔａｒｋ装置を備えた内容積２０ｍｌのフラスコに、実施例３で得られた（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸１．２６ｇ（３．００ｍｍｏｌ）及びトルエン５ｍｌを加え、生成する水を除去しながら、９０〜１１０℃で２時間反応させた。反応終了後、室温まで冷却し、減圧下で濃縮して得られた固体を乾燥させ、無色結晶として（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オン１．２１ｇを得た（単離収率：１００％）。
なお、本化合物を高速液体クロマトグラフィーにより分析したところ、（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オンの光学純度は９９％ｅｅ以上及び９９％ｄｅ以上であった。
【００５１】
実施例４（第一工程：７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ジシクロヘキシルアミン塩（光学異性体混合物）の合成）
攪拌装置及び温度計を備えた内容積５０ｍｌのフラスコに、参考例３と同様の方法で得られた７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸（光学異性体混合物）４．２１ｇ（１０．０ｍｍｏｌ）、ジシクロヘキシルアミン１．８１ｇ（１０．０ｍｍｏｌ）及び酢酸エチル３０ｍｌを加え、攪拌しながら０℃まで冷却すると結晶が析出して来た。結晶を濾過し、０℃に冷却した酢酸エチル１５ｍｌで洗浄した後に減圧下で乾燥させ、無色結晶として７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ジシクロヘキシルアミン塩（光学異性体混合物）５．６６ｇを得た（単離収率：９４．０％）。
【００５２】
実施例５（第二工程：（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ジシクロヘキシルアミン塩の合成）
攪拌装置及び温度計を備えた内容積１００ｍｌのフラスコに、実施例４で得られた７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ジシクロヘキシルアミン塩（光学異性体混合物）４．８１ｇ（８．００ｍｍｏｌ）及びテトラヒドロフラン７２ｍｌを加え、攪拌しながら５０℃まで昇温して均一溶液とした。次いで、反応液を０℃まで冷却すると結晶が析出して来たので、結晶を濾過し、０℃に冷却したテトラヒドロフラン３６ｍｌで洗浄した。この晶析操作を３回繰り返した。得られた結晶を減圧下で乾燥させ、無色結晶として（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ジシクロヘキシルアミン塩２．５０ｇを得た（単離収率：５１．９％）。
なお、（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ジシクロヘキシルアミン塩は、以下の物性値で示される新規な化合物である。
【００５３】
融点；１５４〜１５６℃
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ，δ（ｐｐｍ））；１．０４〜１．０７（２Ｈ，ｍ）、１．０７〜１．４８（６Ｈ，ｍ）、１．５１〜１．６１（２Ｈ，ｍ）、１．６１〜１．７５（２Ｈ，ｍ）、１．７５〜１．９３（４Ｈ，ｍ）、１．９３〜２．２０（４Ｈ，ｍ）、２．２０〜２．３０（２Ｈ，ｍ）、２．４９〜２．５２（１Ｈ，ｍ）、３．１２〜３．２０（２Ｈ，ｍ）、３．６８〜３．８２（１Ｈ，ｍ）、４．２０〜４．３１（１Ｈ，ｍ）、５．６６（１Ｈ，ｄｄ，Ｊ＝６．３，１５．６Ｈｚ）、６．６２（１Ｈ，ｄｄ，Ｊ＝１．２，１５．６Ｈｚ）、７．３０〜７．３４（４Ｈ，ｍ）、７．３４〜７．３９（２Ｈ，ｍ）、７．５５〜７．６８（１Ｈ，ｍ）、７．９１（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ）
【００５４】
実施例６（第三工程：（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸の合成）
攪拌装置を備えた内容積５０ｍｌのフラスコに、実施例５で得られた（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸ベンジルアミン塩２．４１ｇ（４．００ｍｍｏｌ）及びメタノール１０ｍｌを加えた。その後、１ｍｏｌ／ｌ塩酸を加えて反応液のｐＨを３．５に調整した。次いで、酢酸エチル１０ｍｌで２回抽出した後、有機層を分液し、無水硫酸マグネシウムで乾燥させた。濾過後、濾液を減圧下で濃縮し、無色油状物として（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸１．６４ｇを得た（単離収率：９７．５％）。
【００５５】
参考例５（（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オンの合成）
攪拌装置、温度計、還流冷却器及びＤｅａｎ−Ｓｔａｒｋ装置を備えた内容積２０ｍｌのフラスコに、実施例６で得られた（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸１．２６ｇ（３．００ｍｍｏｌ）及びトルエン５ｍｌを加え、生成する水を除去しながら、９０〜１１０℃で２時間反応させた。反応終了後、室温まで冷却し、減圧下で濃縮して得られた固体を乾燥させ、無色結晶として（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オン１．２０ｇを得た（単離収率：９９．３％）。
なお、本化合物を高速液体クロマトグラフィーにより分析したところ、（４Ｒ，６Ｓ）−６−［２−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝エテニル］−４−ヒドロキシテトラヒドロピラン−２−オンの光学純度は９９％ｅｅ以上及び９９％ｄｅ以上であった。
【００５６】
【発明の効果】
本発明により、工業的に好適な（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸、特に、（３Ｒ，５Ｓ）−７−｛２−シクロプロピル−４−（４−フルオロフェニル）キノリン−３−イル｝−３，５−ジヒドロキシヘプト−６−エン酸の製法を提供することが出来る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid, which is useful as a synthesis intermediate of a cholesterol-lowering agent (HMG-CoA reductase inhibitor). In particular, it relates to a process for producing (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid.
[0002]
[Prior art]
Conventionally, (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is selectively selected from a mixture of optical isomers of 7-substituted-3,5-dihydroxyhept-6-enoic acid. As a method for producing the compound, a method using a chiral amine (for example, (R)-(+)-α-methylbenzylamine) is known (Bioorg. Med. Chem. Lett., 9 , 2977 (1999)). However, this method requires the use of a stoichiometric amount of an expensive chiral amine, and the desired (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid. It was not an industrially suitable method because the yield was as low as about 30%.
[0003]
[Problems to be solved by the invention]
The object of the present invention is to solve the above problems and provide an industrially suitable process for producing (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid.
[0004]
[Means for Solving the Problems]
The subject of the present invention is
(A) Formula (1)
[0005]
[Chemical 7]
7-substituted-3,5-dihydroxyhept-6-enoic acid (a mixture of optical isomers) represented by the general formula (2)
[0007]
[Chemical 8]
(Wherein R 1 , R 2 And R 3 Represents a hydrogen atom or a hydrocarbon group. )
Is reacted with an achiral amine represented by the general formula (3)
[0009]
[Chemical 9]
(Wherein R 1 , R 2 And R 3 Is as defined above. )
A first step of producing an achiral amine salt (a mixture of optical isomers) of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
(B) Then, an achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid is crystallized in a solvent to obtain a compound represented by the general formula (4)
[0011]
Embedded image
(Wherein R 1 , R 2 And R 3 Is as defined above. )
A second step of selectively obtaining an achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
(C) Further, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is acidified to give a compound of formula (5)
[0013]
Embedded image
And (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the third step It is solved by the process of -3,5-dihydroxyhept-6-enoic acid.
[0015]
DETAILED DESCRIPTION OF THE INVENTION
The present invention
(A) A 7-substituted-3,5-dihydroxyhept-6-enoic acid (mixture of optical isomers) represented by the formula (1) is reacted with an achiral amine represented by the general formula (2), A first step of generating an achiral amine salt (a mixture of optical isomers) of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (3);
(B) Then, an achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid was crystallized in a solvent and represented by the general formula (4) ( A second step for selectively obtaining an achiral amine of 3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid;
(C) Furthermore, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is acidified to give (3R, 5S)-represented by formula (5) A third step to obtain 7-substituted-3,5-dihydroxyhept-6-enoic acid;
(3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is produced by three steps comprising:
[0016]
Subsequently, the above three steps will be described sequentially.
(A) First step
In the first step of the present invention, a 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture) represented by the formula (1) is converted to an achiral amine represented by the general formula (2). Is a step of producing an achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (3).
[0017]
The 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture) used in the first step of the present invention is represented by the above formula (1). Specifically, Formula (6)
[0018]
Embedded image
In particular, a mixture of optical isomers comprising (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid as a main component. .
[0020]
The 7-substituted-3,5-dihydroxyhept-6-enoic acid (a mixture of optical isomers) is synthesized by, for example, a method described in JP-A-8-92217. -Dihydroxyhept-6-enoic acid ester (optical isomer mixture) can be easily obtained by hydrolysis (described in Reference Examples 1 to 3).
[0021]
The achiral amine used in the first step of the present invention specifically indicates an amine having no asymmetric carbon atom. The achiral amine is represented by the general formula (2), and in the general formula (2), R 1 , R 2 And R 3 Is a hydrogen atom or a hydrocarbon group, for example, hydrogen atom; carbon number 1 such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, etc. A cycloalkyl group having 3 to 10 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group; a benzyl group and a phenyl group Examples thereof include aralkyl groups having 7 to 12 carbon atoms such as ethyl group and phenylpropyl group. The above R 1 , R 2 And R 3 In a preferred embodiment of R, R 1 And R 2 Is a hydrogen atom and R 3 Is an aralkyl group, R 1 Is a hydrogen atom and R 2 And R 3 Is a cycloalkyl group.
[0022]
The amount of the achiral amine to be used is preferably 0.5 to 2.0 mol, more preferably 0, per 1 mol of 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture). .8 to 1.2 mol.
[0023]
The first step of the present invention is preferably performed in the presence of a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, t- Alcohols such as butyl alcohol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran; carboxylic acid esters such as methyl acetate and ethyl acetate; methylene chloride, chloroform and dichloroethane And halogenated aliphatic hydrocarbons such as carboxylic acid esters, more preferably ethyl acetate. These solvents may be used alone or in combination of two or more.
[0024]
The amount of the solvent used is appropriately adjusted depending on the homogeneity and stirrability of the reaction solution, but is preferably 1 g of 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture). 5 to 100 g, more preferably 10 to 50 g.
[0025]
The first step of the present invention is performed, for example, by a method such as mixing 7-substituted-3,5-dihydroxyhept-6-enoic acid (optical isomer mixture), achiral amine and solvent and stirring. Is called. The reaction temperature at that time is preferably -20 to 100 ° C, more preferably 0 to 50 ° C, and the reaction pressure is not particularly limited.
[0026]
The achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid obtained by the first step of the present invention can be cooled, for example, after completion of the reaction. Can be obtained as crystals.
[0027]
(B) Second step
The second step of the present invention is an achiral amine salt of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (3) obtained in the first step (mixture of optical isomers). ) In a solvent to selectively obtain an achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (4). It is a process.
[0028]
Examples of the solvent used in the second step of the present invention include water; alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran; methylene chloride and chloroform. Halogenated hydrocarbons such as benzene, toluene, xylene, etc .; Carboxylic acid esters such as methyl acetate and ethyl acetate; Nitriles such as acetonitrile and propionitrile; Acetone, methyl isobutyl ketone, etc. Ketones; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and the like, preferably ethers, ketones, amides, more preferably ethers, ketones, particularly preferably tetrahydrofuran, Me Louis Soviet-butyl ketone is used. These solvents may be used alone or in combination of two or more.
[0029]
The amount of the solvent to be used is preferably 1 to 100 g, more preferably 5 to 1 g of achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid. 50 g, particularly preferably 10 to 30 g.
[0030]
In the second step of the present invention, for example, the achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid obtained in the first step is dissolved in a solvent. After making it into a uniform solution (if necessary, it may be dissolved by heating), followed by cooling to precipitate crystals (crystallization). The cooling temperature in that case becomes like this. Preferably it is -50-80 degreeC, More preferably, it is -20-40 degreeC, Most preferably, it is -10-20 degreeC. If necessary, this operation may be repeated.
[0031]
The achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid obtained selectively by the second step of the present invention is filtered, for example, after crystallization is completed. Can be obtained as free crystals.
[0032]
(C) Third step
The third step of the present invention is an achiral amine of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by the general formula (4) obtained in the second step. In this step, the salt is acidified to obtain (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by formula (5).
[0033]
The acidification in the third step of the present invention is not particularly limited as long as it is a general method for acidifying a carboxylate to obtain a free carboxylic acid, but it is preferably performed in a solvent in the presence of an acid.
[0034]
Examples of the acid used in the third step of the present invention include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Preferably, a mineral acid, more preferably hydrochloric acid or sulfuric acid is used. These acids may be used alone or in combination of two or more.
[0035]
The amount of the acid used is determined by acidifying the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid to form a free carboxylic acid ((3R, 5S)- 7-substituted-3,5-dihydroxyhept-6-enoic acid) is not particularly limited, but (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid The amount is preferably 1.0 to 1.1 mol with respect to 1 mol of the achiral amine salt.
[0036]
The solvent used in the third step of the present invention is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol; acetonitrile, propionitrile And nitriles such as alcohol, preferably alcohols, more preferably methanol and ethanol. These solvents may be used alone or in combination of two or more.
[0037]
The amount of the solvent used is appropriately adjusted depending on the homogeneity and stirrability of the reaction solution. On the other hand, it is preferably 1 to 50 g, more preferably 10 to 30 g.
[0038]
In the third step of the present invention, for example, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid obtained in the second step, an acid and a solvent are mixed. And stirring. The temperature at that time is preferably -20 to 100 ° C, more preferably 0 to 50 ° C, and the pressure is not particularly limited.
[0039]
(3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid obtained by the third step of the present invention is generally obtained by, for example, extraction, concentration, recrystallization and the like after completion of hydrolysis. Separated and purified by various methods.
[0040]
【Example】
Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
In addition, the optical purity (enantiomeric excess (% ee) and diastereomeric excess (% de)) in the examples was performed using high performance liquid chromatography under the following analysis conditions. The optical purity of (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydrohept-6-enoic acid is determined by By heating in a group hydrocarbon solvent to give the corresponding lactone ((4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4- It was measured after derivatization to hydroxytetrahydropyran-2-one (described in Reference Examples 4 and 5 later).
[0041]
Analysis conditions for high performance liquid chromatography:
(Enantiomeric excess)
(Diastereomer excess)
Reference Example 1 (Synthesis of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} 5-hydroxyhept-6-enoic acid isopropyl (optical isomer mixture))
Into a 100-ml flask equipped with a stirrer, thermometer and dropping funnel, titanium tetraisopropoxide 6.58 g (22.0 mmol), (S) -2- {N- (3,5-di-tert- 6.70 g (21.0 mmol) of butylsalicylidene) amino} -3-methyl-1-butanol and 40 ml of methylene chloride were added and stirred at room temperature for 1 hour. Subsequently, the reaction solution was cooled to −30 ° C., and 6.36 g (20.0 mmol) of 3- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} prop-2-enal was added to methylene chloride. What was dissolved in 6 ml was added and stirred for 30 minutes. Furthermore, 2.52 g (30.0 mmol) of diketene was added and reacted for 6 hours while raising the temperature to −20 ° C.
After completion of the reaction, the obtained reaction solution was taken out, added to a mixed solution of 105.29 g (42.0 mmol) of 5.0 mass% oxalic acid aqueous solution and 50 ml of 1,2-dichloroethane, and vigorously stirred at room temperature for 1 hour. Thereafter, the organic layer was taken out, washed in the order of 50 ml of a 5.0% by mass oxalic acid aqueous solution, 50 ml of water and 30 ml of a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. After filtration through celite, the filtrate was concentrated under reduced pressure, 50 ml of n-hexane was added to the concentrate, and the mixture was vigorously stirred for 1 hour to precipitate a solid. This was filtered and dried and isopropyl 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -5-hydroxy-3-oxohept-6-enoate (optical isomerism) as a yellow powder. Body mixture) 7.84 g was obtained (isolation yield: 85.0%).
[0044]
Reference Example 2 (Synthesis of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid isopropyl (optical isomer mixture))
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -5-hydroxy synthesized in Reference Example 1 was added to a 300-ml flask equipped with a stirrer, a thermometer and a dropping funnel. Add 6.91 g (15.0 mmol) of isopropyl-3-oxohept-6-enoate (optical isomer mixture), 120 ml of tetrahydrofuran and 30 ml of methanol, cool to −75 ° C., and 1 mol / l diethylmethoxyboron tetrahydrofuran solution 16. 5 ml was added and stirred for 30 minutes. Next, 684 mg (18.0 mmol) of sodium borohydride was added and reacted at the same temperature for 5 hours. After completion of the reaction, 11 ml of acetic acid and 100 ml of ethyl acetate were added and stirred at room temperature for 20 minutes. The obtained reaction solution was washed with 100 ml of saturated sodium hydrogen carbonate twice and once with 50 ml of saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the obtained concentrate, 100 ml of methanol was added and concentrated under normal pressure heating. This operation was repeated 3 times, and isopropyl 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoate (optical isomerism) was obtained as a yellow oily substance. Body mixture) 6.60 g was obtained (isolation yield: 95.3%).
In addition, when this compound was analyzed by high performance liquid chromatography, (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept The optical purity of isopropyl-6-enoate was 73% ee and 97% de.
[0045]
Reference Example 3 (Synthesis of 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid (mixture of optical isomers))
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5 synthesized in Reference Example 2 was added to a 50 ml internal flask equipped with a stirrer, a thermometer and a dropping funnel. -Addition of 4.63 g (10.0 mmol) of isopropyl dihydroxyhept-6-enoate (optical isomer mixture), 10 ml of methanol and 12 ml (12.0 mmol) of 1 mol / l aqueous sodium hydroxide solution, and reaction at room temperature for 1 hour It was. After completion of the reaction, 1 mol / l hydrochloric acid was added to adjust the pH of the reaction solution to 3.5. Subsequently, after extracting twice with 10 ml of ethyl acetate, the organic layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-ene as a pale yellow oil. 4.21 g of acid (optical isomer mixture) was obtained (isolation yield: 100%).
[0046]
Example 1 (first step: 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid benzylamine salt (optical isomer) Synthesis of mixture)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxy obtained in Reference Example 3 was added to a 50-ml flask equipped with a stirrer and a thermometer. When 4.21 g (10.0 mmol) of hept-6-enoic acid (a mixture of optical isomers), 1.07 g (10.ommol) of benzylamine and 30 ml of ethyl acetate are added and cooled to 0 ° C. with stirring, crystals are precipitated. I came. The crystals were filtered, washed with 15 ml of ethyl acetate cooled to 0 ° C. and then dried under reduced pressure to give 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3 as colorless crystals. , 5-dihydroxyhept-6-enoic acid benzylamine salt (optical isomer mixture) 5.01 g was obtained (isolation yield: 94.9%).
[0047]
Example 2 (second step: benzyl (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoate Synthesis of amine salt)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxy obtained in Example 1 was placed in a 100-ml flask equipped with a stirrer and a thermometer. 4.22 g (8.00 mmol) of hept-6-enoic acid benzylamine salt (optical isomer mixture) and 84 ml of tetrahydrofuran were added, and the mixture was heated to 50 ° C. with stirring to obtain a homogeneous solution. Next, when the reaction solution was cooled to 0 ° C., crystals were precipitated, and the crystals were filtered and washed with 42 ml of tetrahydrofuran cooled to 0 ° C. This crystallization operation was repeated twice. The obtained crystals were dried under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept as colorless crystals. 2.52 g of -6-enoic acid benzylamine salt was obtained (isolation yield: 60.0%).
In addition, (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid benzylamine salt is It is a novel compound represented by physical property values.
[0048]
Melting point: 118-120 ° C
1 H-NMR (CD 3 OD, δ (ppm)); 1.04 to 1.07 (2H, m), 1.25 to 1.28 (2H, m), 1.28 to 1.33 (1H, m), 1.51 ˜1.56 (1H, m), 2.23 to 2.29 (2H, m), 2.51 to 2.55 (1H, m), 3.76 to 3.80 (1H, m), 4 .25 to 4.29 (1H, m), 5.66 (1H, dd, J = 6.3, 15.9 Hz), 6.62 (1H, dd, J = 1.2, 15.9 Hz), 7.24-7.40 (4H, m), 7.40-7.44 (2H, m), 7.44-7.49 (5H, m), 7.58-7.61 (1H, m) ), 7.91 (1H, d, J = 8.1 Hz)
[0049]
Example 3 (third step: (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid Synthesis)
(3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3, obtained in Example 2, was added to a flask with an internal volume of 50 ml equipped with a stirrer. 2.11 g (4.00 mmol) of 5-dihydroxyhept-6-enoic acid benzylamine salt and 10 ml of methanol were added. Thereafter, 1 mol / l hydrochloric acid was added to adjust the pH of the reaction solution to 3.5. Subsequently, after extracting twice with 10 ml of ethyl acetate, the organic layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhe as a colorless oil. 1.66 g of pt-6-enoic acid was obtained (isolation yield: 99.0%).
[0050]
Reference Example 4 (Synthesis of (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one)
(3R, 5S) -7- {2-cyclopropyl-4- (4-) obtained in Example 3 was placed in a 20-ml flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus. Fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid (1.26 g, 3.00 mmol) and toluene (5 ml) were added, and the water formed was removed at 90 to 110 ° C. while removing 2 Reacted for hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to dry the solid, and (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) was obtained as colorless crystals. ) Quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one was obtained (isolated yield: 100%).
In addition, when this compound was analyzed by high performance liquid chromatography, (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4- The optical purity of hydroxytetrahydropyran-2-one was 99% ee or more and 99% de or more.
[0051]
Example 4 (first step: 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid dicyclohexylamine salt (optical isomer) Synthesis of mixture)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3 obtained in the same manner as in Reference Example 3 in a 50-ml flask equipped with a stirrer and a thermometer , 5-dihydroxyhept-6-enoic acid (optical isomer mixture) 4.21 g (10.0 mmol), dicyclohexylamine 1.81 g (10.0 mmol) and ethyl acetate 30 ml were added, and the mixture was cooled to 0 ° C. with stirring. Then crystals began to precipitate. The crystals were filtered, washed with 15 ml of ethyl acetate cooled to 0 ° C. and then dried under reduced pressure to give 7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3 as colorless crystals. , 5-dihydroxyhept-6-enoic acid dicyclohexylamine salt (optical isomer mixture) 5.66 g was obtained (isolation yield: 94.0%).
[0052]
Example 5 (second step: (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid dicyclohexyl Synthesis of amine salt)
7- {2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxy obtained in Example 4 was placed in a 100-ml flask equipped with a stirrer and a thermometer. 4.81 g (8.00 mmol) of hept-6-enoic acid dicyclohexylamine salt (optical isomer mixture) and 72 ml of tetrahydrofuran were added, and the mixture was heated to 50 ° C. with stirring to obtain a homogeneous solution. Next, when the reaction solution was cooled to 0 ° C., crystals began to precipitate, and the crystals were filtered and washed with 36 ml of tetrahydrofuran cooled to 0 ° C. This crystallization operation was repeated three times. The obtained crystals were dried under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept as colorless crystals. 2.50 g of 6-enoic acid dicyclohexylamine salt was obtained (isolation yield: 51.9%).
In addition, (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid dicyclohexylamine salt is: It is a novel compound represented by physical property values.
[0053]
Melting point: 154-156 ° C
1 H-NMR (CD 3 OD, δ (ppm)); 1.04 to 1.07 (2H, m), 1.07 to 1.48 (6H, m), 1.51 to 1.61 (2H, m), 1.61 ˜1.75 (2H, m), 1.75 to 1.93 (4H, m), 1.93 to 2.20 (4H, m), 2.20 to 2.30 (2H, m), 2 .49 to 2.52 (1H, m), 3.12 to 3.20 (2H, m), 3.68 to 3.82 (1H, m), 4.20 to 4.31 (1H, m) 5.66 (1H, dd, J = 6.3, 15.6 Hz), 6.62 (1H, dd, J = 1.2, 15.6 Hz), 7.30-7.34 (4H, m ), 7.34 to 7.39 (2H, m), 7.55 to 7.68 (1H, m), 7.91 (1H, d, J = 8.4 Hz)
[0054]
Example 6 (third step: (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid Synthesis)
(3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3, obtained in Example 5, was added to a 50-ml flask equipped with a stirrer. 2.41 g (4.00 mmol) of 5-dihydroxyhept-6-enoic acid benzylamine salt and 10 ml of methanol were added. Thereafter, 1 mol / l hydrochloric acid was added to adjust the pH of the reaction solution to 3.5. Subsequently, after extracting twice with 10 ml of ethyl acetate, the organic layer was separated and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (3R, 5S) -7- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhe as a colorless oil. 1.64 g of pt-6-enoic acid was obtained (isolation yield: 97.5%).
[0055]
Reference Example 5 (Synthesis of (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one)
(3R, 5S) -7- {2-cyclopropyl-4- (4-) obtained in Example 6 was placed in a 20-ml flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus. Fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid (1.26 g, 3.00 mmol) and toluene (5 ml) were added, and the water formed was removed at 90 to 110 ° C. while removing 2 Reacted for hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to dry the solid, and (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) was obtained as colorless crystals. ) Quinolin-3-yl} ethenyl] -4-hydroxytetrahydropyran-2-one 1.20 g (isolation yield: 99.3%).
In addition, when this compound was analyzed by high performance liquid chromatography, (4R, 6S) -6- [2- {2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl} ethenyl] -4- The optical purity of hydroxytetrahydropyran-2-one was 99% ee or more and 99% de or more.
[0056]
【The invention's effect】
According to the present invention, industrially suitable (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid, in particular (3R, 5S) -7- {2-cyclopropyl-4- A method for producing (4-fluorophenyl) quinolin-3-yl} -3,5-dihydroxyhept-6-enoic acid can be provided.
Claims (2)
で示されるアキラルなアミンを反応させて、一般式（３）
で示される７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を生成させる第一工程、
（Ｂ）次いで、７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩（光学異性体混合物）を溶媒中で晶析させて、一般式（４）
で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を選択的に得る第二工程、
（Ｃ）更に、（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩を酸性化して、式（５）
Is reacted with an achiral amine represented by the general formula (3)
A first step of producing an achiral amine salt (a mixture of optical isomers) of 7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
(B) Then, an achiral amine salt (optical isomer mixture) of 7-substituted-3,5-dihydroxyhept-6-enoic acid is crystallized in a solvent to obtain a compound represented by the general formula (4)
A second step of selectively obtaining an achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
(C) Further, the achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid is acidified to give a compound of formula (5)
で示される（３Ｒ，５Ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸のアキラルなアミン塩。General formula (4)
An achiral amine salt of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid represented by
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| PCT/JP2002/004710 WO2002092570A1 (en) | 2001-05-15 | 2002-05-15 | Process for producing (3r,5s)-7-substituted-3,5-dihydroxyhept-6-enoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007132482A2 (en) * | 2006-05-17 | 2007-11-22 | Manne Satyanarayana Reddy | Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts |
| JP5533654B2 (en) * | 2008-09-05 | 2014-06-25 | 日産化学工業株式会社 | Method for producing 3,5-dihydroxy-6-heptenoic acid amine salt |
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| US8455640B2 (en) | 2006-05-03 | 2013-06-04 | Msn Laboratories Limited | Process for statins and its pharmaceutically acceptable salts thereof |
| EP2086945B1 (en) | 2006-10-09 | 2016-01-06 | MSN Laboratories Private Limited | Novel process for the preparation of statins and their pharmaceutically acceptable salts thereof |
| WO2010089770A2 (en) * | 2009-01-19 | 2010-08-12 | Msn Laboratories Limited | Improved process for the preparation of highly pure (3r,5s)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3,5-dihydroxy-6(e)-heptenoic acid and pharmaceutically acceptable salts thereof |
| WO2011086584A2 (en) | 2010-01-18 | 2011-07-21 | Msn Laboratories Limited | Improved process for the preparation of amide intermediates and their use thereof |
| CN102477032B (en) * | 2010-11-26 | 2015-04-01 | 上海医药工业研究院 | 2-cyclopropyl-4-substituted-phenoxy-quinoline derivatives, and its preparation method, intermediate and application |
| CN102816114B (en) * | 2011-06-09 | 2014-01-29 | 上海京新生物医药有限公司 | Preparation method of HMG-CoA reductase inhibitor |
Citations (3)
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| JPS593470B2 (en) * | 1975-11-08 | 1984-01-24 | ノヒラ ヒロユキ | N-benzoyl-cis-2-aminocyclohexanecarbonanno |
| JPH01175956A (en) * | 1988-01-04 | 1989-07-12 | Muraki Buhin Kk | Purification of optically pure 3-hydroxy acids |
| JPH05148237A (en) * | 1991-06-24 | 1993-06-15 | Nissan Chem Ind Ltd | Diastereomer salt of optically active quinoline mevalonic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS593470B2 (en) * | 1975-11-08 | 1984-01-24 | ノヒラ ヒロユキ | N-benzoyl-cis-2-aminocyclohexanecarbonanno |
| JPH01175956A (en) * | 1988-01-04 | 1989-07-12 | Muraki Buhin Kk | Purification of optically pure 3-hydroxy acids |
| JPH05148237A (en) * | 1991-06-24 | 1993-06-15 | Nissan Chem Ind Ltd | Diastereomer salt of optically active quinoline mevalonic acid |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007132482A2 (en) * | 2006-05-17 | 2007-11-22 | Manne Satyanarayana Reddy | Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts |
| WO2007132482A3 (en) * | 2006-05-17 | 2008-04-10 | Reddy Manne Satyanarayana | Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts |
| JP5533654B2 (en) * | 2008-09-05 | 2014-06-25 | 日産化学工業株式会社 | Method for producing 3,5-dihydroxy-6-heptenoic acid amine salt |
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