JP4524015B2 - (2S) -2-Benzylsuccinic acid monoester organic amine salt and process for producing the same - Google Patents
(2S) -2-Benzylsuccinic acid monoester organic amine salt and process for producing the same Download PDFInfo
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- 0 *CC(*)=Cc1ccccc1 Chemical compound *CC(*)=Cc1ccccc1 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Description
【０００１】
【発明の属する技術分野】
本発明は、一般式
【０００２】
【化５】
（Ｒ1は低級アルキル基であり、Ｒ2はｔｅｒｔ−ブチル基、シクロヘキシル基、２―フェニルエチル基またはベンジル基である）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩に関するものである。
【０００４】
更に詳しく述べれば、本発明は糖尿病治療薬として有用な、式
【０００５】
【化６】
で表される光学活性なベンジルコハク酸モノアミド誘導体またはその薬理学的に許容される塩の出発原料として用いられる光学活性な、一般式
【０００７】
【化７】
（式中のＲ1は低級アルキル基である）で表される（２Ｓ）−２−ベンジルコハク酸モノエステル（特開平４−３５６４５９号公報）の製造中間体として有用な前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩に関するものである。
【０００９】
【従来の技術】
従来、前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの製造方法としては、式
【００１０】
【化８】
で表される（Ｅ）−ベンジリデンコハク酸モノメチルエステルを（２Ｓ，４Ｓ）−ｔｅｒｔ−ブトキシカルボニル−４−ジフェニルホスフィノ−２−ジフェニルホスフィノメチルピロリジン−ロジウム錯体の存在下に５０気圧の水素気流中、５０℃で５０時間反応させて、式
【００１２】
【化９】
で表される（２Ｓ）−２−ベンジルコハク酸モノメチルエステルを製造する方法が知られている（薬学雑誌、１０６巻、５２１〜５３６ページ（１９８６年））。
【００１４】
しかしながら、前記製造方法により得られた前記式（V）で表される（２Ｓ）−２−ベンジルコハク酸モノメチルエステルの光学純度は８１％ｅｅであり、高い光学純度を必要とする医薬品等の製造原料とするには不十分な光学純度である。そのため医薬品等の製造原料として使用するためには、更に精製操作を行う必要があるが、当該化合物は粘性の高い油状物質であるため、精製が困難である。また、前記製造方法は５０気圧という高圧条件下での反応であり、工業的製造方法としては望ましくない。
【００１５】
【発明が解決しようとする課題】
本発明は、緩和な反応条件下で高光学純度の前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルを安定して供給できる方法を提供することである。
【００１６】
【発明の実施の形態】
本発明者らは前記の課題を解決すべく鋭意検討した結果、前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩が極めて良好な結晶性を有し、当該有機アミン塩を用いることにより、簡単な精製操作で容易に光学純度の高い前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルを効率よく製造できることを見出し、本発明をなすに至った。
【００１７】
本発明は糖尿病治療薬として有用な前記式（II）で表される光学活性なベンジルコハク酸モノアミド誘導体またはその薬理学的に許容される塩の製造原料である、前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの製造中間体として有用な、一般式
【００１８】
【化１０】
（式中のＲ1は低級アルキル基であり、Ｒ2はｔｅｒｔ−ブチル基、シクロヘキシル基、２−フェニルエチル基またはベンジル基である）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩およびその製造方法に関するものである。
【００２０】
本発明において、低級アルキル基とはメチル基、エチル基、プロピル基またはイソプロピル基の炭素数１〜３のアルキル基を表す。
【００２１】
本発明において、高光学純度の前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩は以下のようにして製造することができる。
【００２２】
例えば、一般式
【００２３】
【化１１】
（式中のＲ1は前記と同じ意味をもつ）で表される（Ｅ）−ベンジリデンコハク酸モノエステルをメタノール、エタノール、イソプロパノール等のアルコール溶媒中、前記一般式（VI）で表される（Ｅ）−ベンジリデンコハク酸モノエステルに対して１／３０００〜１／５０、好ましくは１／１０００〜１／１００倍モルの（２Ｓ，４Ｓ）−ｔｅｒｔ−ブトキシカルボニル−４−ジフェニルホスフィノ−２−ジフェニルホスフィノメチルピロリジン−ロジウム錯体（以下ＢＰＰＭ−Ｒｈ錯体という）の存在下、トリエチルアミン、ピペリジン等の有機アミンの存在下または非存在下に水素圧１気圧〜１０気圧、好ましくは１気圧〜６気圧で接触還元し、一般式
【００２５】
【化１２】
（式中のＲ1は前記と同じ意味をもつ）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルを製造した後、一般式
【００２７】
【化１３】
（式中のＲ2は前記と同じ意味をもつ）で表される有機アミンと反応させることにより、高光学純度の前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩を製造することができる。反応温度および反応時間は溶媒の種類、触媒の量、水素圧等の反応条件により適宜決定されるが、反応温度は通常０℃〜５０℃、反応時間は通常８〜２０時間程度である。
【００２９】
また、前記一般式（VI）で表される（Ｅ）−ベンジリデンコハク酸モノエステルの代わりに、一般式
【００３０】
【化１４】
（式中のＲ1およびＲ2は前記と同じ意味をもつ）で表される（Ｅ）−ベンジリデンコハク酸モノエステルの有機アミン塩を用いて前記製造方法と同様にして接触還元することにより、直接、前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩を製造することもできる。
【００３２】
本発明の前記製造方法における接触還元により、約９５％ｅｅ以上の光学純度の（２Ｓ）−２−ベンジルコハク酸モノエステルまたはその有機アミン塩を製造することができる。また、本発明の前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩は再結晶操作に適した優れた結晶性を有しており、前記製造方法において、接触還元により得られる前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルと前記一般式（VII）で表される有機アミンとの反応によるか、または接触還元により直接得られる（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩をメタノール、エタノール、イソプロパノール、イソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテル、ヘキサン等の有機溶媒を単独または適宜混合して用いて、常法に従い再結晶することにより、容易に光学純度約９８％ｅｅ以上の前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩を製造することができる。
【００３３】
本発明において使用されるＢＰＰＭ−Ｒｈ錯体は市販の（２Ｓ，４Ｓ）−ｔｅｒｔ−ブトキシカルボニル−４−ジフェニルホスフィノ−２−ジフェニルホスフィノメチルピロリジン（以下ＢＰＰＭという）およびビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウムをアルゴン気流下、十分に酸素を除去したメタノールに加え、溶解するまで室温で撹拌することにより容易に調製することができる。
【００３４】
このようにして製造された前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩は、塩酸、硫酸等の適当な酸を用いて、常法に従い有機アミンを除去することにより、約９８％ｅｅ以上の光学純度の前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルに誘導することができる。
【００３５】
本発明の前記製造方法において出発原料として用いられる前記一般式（VI）で表される（Ｅ）−ベンジリデンコハク酸モノエステルは、ベンズアルデヒドとコハク酸ジエステルからＳｔｏｂｂｅ反応により常法に従い製造することができる。
【００３６】
また、本発明の前記製造方法において出発原料として用いられる前記一般式（VIII）で表される（Ｅ）−ベンジリデンコハク酸モノエステルの有機アミン塩は、前記一般式（VI）で表される（Ｅ）−ベンジリデンコハク酸モノエステルを前記一般式（VII）で表される有機アミンと常法に従い反応させることにより製造することができる。
【００３７】
本発明の前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩は再結晶操作に適した優れた結晶性を有しており、また本発明の前記製造方法は緩和な反応条件下で、高い光学純度の（２Ｓ）−２−ベンジルコハク酸モノエステルを効率よく製造することを可能にするものであり、工業生産にも応用可能な優れた製造方法である。
【００３８】
【実施例】
本発明の内容を以下の参考例および実施例にてさらに詳細に説明するが、本発明はこれらに限定されるものではない。実施例中の反応に使用したメタノールは窒素ガスを２時間バブリングして溶媒中の酸素を十分に除去したものを使用した。なお、実施例中の化合物の光学純度はトリメチルシリルジアゾメタンのヘキサン溶液を用い相当するジエステル誘導体に誘導した後、ＨＰＬＣを用いて、以下の条件にて測定した。
【００３９】
使用カラム ：キラルセルＯＤ（４．６φ×２５０ｍｍ，ダイセル化学工業）
溶出溶媒 ：ｎ−ヘキサン／イソプロパノール＝９８／２（ｖ／ｖ）
流速 ：１．０ｍＬ／分
カラム温度 ：室温
検出波長 ：２２０ｎｍ
【００４０】
参考例１
（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩ベンズアルデヒド５３．１ｇおよびコハク酸ジメチル１４６．２ｇの混合物に４５℃撹拌下にナトリウムメトキシドの２８％メタノール溶液３２８ｇを２５分間かけて加えた後、同温度で３０分間撹拌した。溶媒を減圧下に濃縮した後、濃縮物を濃塩酸１２ｍＬおよび氷２００ｇの混合物に加えた。酢酸エチル２００ｍＬ、水１００ｍＬを加え抽出後、有機層を飽和炭酸水素ナトリウム水溶液１００ｍＬで３回抽出した。水層を合わせて、酢酸エチル１００ｍＬで２回洗浄後、濃塩酸でｐＨ１とし、酢酸エチル１００ｍＬで２回抽出した。有機層を合わせ飽和食塩水１００ｍＬで洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮して、１３３．２ｇの油状物を得た。この油状物を酢酸エチル１５０ｍＬおよびヘキサン２００ｍＬの混合溶媒に溶かし、撹拌下、ｔｅｒｔ−ブチルアミン３６．６ｇのヘキサン２００ｍＬ溶液を加えた。析出した結晶をろ取し、（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩１２８．４ｇを得た。
【００４１】
1H-NMR (CDCl3) δppm:
1.27 (9H, s), 3.43 (2H, s), 3.72 (3H, s), 7.25-7.45 (8H, m), 7.73 (1H, s)
【００４２】
参考例２
（Ｅ）−ベンジリデンコハク酸−１−メチルエステルシクロヘキシルアミン塩
ｔｅｒｔ−ブチルアミンの代わりにシクロヘキシルアミンを用い、参考例１と同様にして、（Ｅ）−ベンジリデンコハク酸−１−メチルエステルシクロヘキシルアミン塩を得た。
【００４３】
1H-NMR (CDCl3) δppm:
1.0-2.0 (10H, m), 2.75-2.85 (1H, m), 3.43 (2H, s), 3.75 (3H, s), 7.25-7.45 (8H, m), 7.71 (1H, s)
【００４４】
実施例１
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルシクロヘキシルアミン塩
水素気流下で（Ｅ）−ベンジリデンコハク酸−１−メチルエステルシクロヘキシルアミン塩１３．６ｇをメタノール８０ｍＬに溶かした後、反応容器内を十分に水素で置換した。この溶液にＢＰＰＭ２６ｍｇおよびビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウム１０．５ｍｇをアルゴン気流下、メタノール５ｍＬに溶かして２０分間撹拌した溶液を加えた。反応容器内を十分に水素で置換した後、室温、水素圧５．２気圧で２０時間撹拌した。溶媒を減圧下に留去し、残留物（光学純度９６．２％ｅｅ）をイソプロパノール−ヘキサンで再結晶し、（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルシクロヘキシルアミン塩１０．５ｇを得た（光学純度９８．３％ｅｅ）。
【００４５】
IR (KBr): 2938, 2214, 1731, 1547, 1406, 1164cm-1
1H-NMR (CDCl3) δppm:
1.05-1.25 (5H, m), 1.55-1.9 (5H, m), 2.23 (1H, dd, J=5.1, 16.0 Hz), 2.49 (1H, dd, J=9.4, 16.0 Hz), 2.7 (1H, dd, J=7.6, 13.0 Hz), 2.75-2.85 (1H, m), 2.92 (1H, dd, J=7.2,13.0 Hz), 2.95-3.05 (1H, m), 3.56 (3H, s), 6.8-7.3 (8H, m)
【００４６】
実施例２
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩
水素気流下で（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩１．４７ｇをメタノール１０ｍＬに溶かした後、反応容器内を十分に水素で置換した。この溶液にＢＰＰＭ１２．２ｍｇとビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウム４．９ｍｇをアルゴン気流下、メタノール２．０ｍＬに溶かして２０分間撹拌した溶液を０．５ｍＬ加えた。反応容器内を十分に水素で置換した後、室温、水素圧５．２気圧で２０時間撹拌した。溶媒を減圧下に留去し、残留物（光学純度９６．２％ｅｅ）をイソプロパノール−ヘキサンで再結晶し、（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩０．９７ｇを得た（光学純度１００％ｅｅ）。
【００４７】
IR (KBr): 2920, 2220, 1732, 1541, 1166cm-1
1H-NMR (CDCl3) δppm:
1.22 (9H, s), 2.24 (1H, dd, J=5.1, 16.3 Hz), 2.50 (1H, dd, J=8.9, 16.3 Hz), 2.75 (1H, dd, J=7.4, 13.2 Hz), 2.91 (1H, dd, J=7.5, 13.2 Hz), 3.0-3.05 (1H, m), 3.53 (3H, s), 7.1-7.3 (8H, m)
【００４８】
実施例３
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩
（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩０．８８ｇをメタノール５ｍＬに溶かした後、反応容器内を十分に水素で置換した。この溶液にＢＰＰＭ１８．２ｍｇとビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウム７．４ｍｇをアルゴン気流下、メタノール１．０ｍＬに溶かして２０分間撹拌した溶液を加えた。反応容器内を十分に水素で置換した後、水素圧５．２気圧で８時間撹拌した。溶媒を減圧下に留去し、残留物（光学純度９６．５%ｅｅ）をイソプロパノール−ヘキサンで再結晶し、（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩０．６１ｇを得た（光学純度９９．８％ｅｅ）。
【００４９】
実施例４
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩
（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩０．８８ｇをメタノール５ｍＬに溶かした後、反応容器内を十分に水素で置換した。この溶液にＢＰＰＭ１８．２ｍｇとビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウム７．４ｍｇをアルゴン気流下、メタノール１．０ｍＬに溶かして２０分間撹拌した溶液を加えた。反応容器内を十分に水素で置換した後、水素圧１気圧で２０時間撹拌した。溶媒を減圧下に留去し、残留物（光学純度９６．７％ｅｅ）をイソプロパノールで再結晶し、（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩０．５９ｇを得た（光学純度１００％ｅｅ）。
【００５０】
実施例５
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩
（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩０．８８ｇをメタノール５ｍＬに溶かした後、５０℃に加熱し、反応容器内を十分に水素で置換した。この溶液にＢＰＰＭ１８．２ｍｇとビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウム７．４ｍｇをアルゴン気流下、メタノール１．０ｍＬに溶かして２０分間撹拌した溶液を加えた。反応容器内を十分に水素で置換した後、５０℃、水素圧５．２気圧で８時間撹拌した。溶媒を減圧下に留去し、残留物（光学純度９５．３％ｅｅ）をイソプロパノール−ヘキサンで再結晶し、（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩 ０．５９ｇを得た（光学純度１００％ｅｅ）。
【００５１】
実施例６
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステル２−フェニルエチルアミン塩
（Ｅ）−ベンジリデンコハク酸−１−メチルエステルｔｅｒｔ−ブチルアミン塩２．９４ｇを２Ｍ塩酸１０ｍＬおよびジエチルエーテル３０ｍＬの混合物に加えて激しく撹拌した後、有機層を分取した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮し、油状の（Ｅ）−ベンジリデンコハク酸−１−メチルエステル２．２５ｇを得た。得られた油状物をメタノール２０ｍＬに溶解した。このメタノール溶液１０ｍＬを反応容器に移し、反応容器内を十分に水素で置換した。この溶液にＢＰＰＭ１２．２ｍｇとビス（１，５−シクロオクタジエン）−μ，μ’−ジクロロジロジウム４．９ｍｇをアルゴン気流下、メタノール２．０ｍＬに溶かして２０分間撹拌した溶液を０．５ｍＬ加えた。反応容器内を十分に水素で置換した後、室温、水素圧５．２気圧で２０時間撹拌した。溶媒を減圧下に留去し、油状の（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルを得た（光学純度９６．７％ｅｅ）。
【００５２】
得られた油状物をイソプロパノールに溶かし２−フェニルエチルアミン０．６２８ｍＬを加えた後、ヘキサンを加えて析出する結晶をろ取し、（２Ｓ）−２−ベンジルコハク酸−１−メチルエステル２−フェニルエチルアミン塩１．０９ｇを得た（光学純度９９．７％ｅｅ）。
【００５３】
IR (KBr): 2948, 2214, 1728, 1523, 1407, 1165cm-1
1H-NMR (CDCl3) δppm:
2.27 (1H, dd, J=4.5, 16.3Hz), 2.51 (1H, dd, J=9.7, 16.3 Hz), 2.71 (1H, dd, J=8.1, 13.2Hz), 2.80-3.05 (6H, m), 3.52 (3H, s), 6.39 (3H, br), 7.10-7.30 (10H, m)
【００５４】
実施例７
（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルベンジルアミン塩
２−フェニルエチルアミンの代わりにベンジルアミンを用い、実施例６と同様にして（２Ｓ）−２−ベンジルコハク酸−１−メチルエステルベンジルアミン塩を得た。
【００５５】
IR (KBr): 2951, 2206, 1732, 1541, 1404, 1163cm-1
1H-NMR (CDCl3) δppm:
2.29 (1H, dd, J=4.6, 16.6 Hz), 2.54 (1H, dd, J=9.5, 16.6 Hz), 2.72 (1H, dd, J=8.0, 13.5 Hz), 2.95-3.05 (2H, m), 3.58 (3H, s), 3.88 (2H, s), 4.6 (3H, br), 7.10-7.35 (10H, m)
【００５６】
【発明の効果】
本発明の前記一般式（I）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルの有機アミン塩を経由する前記製造方法により、医薬品等の製造原料として使用可能な高光学純度の前記一般式（III）で表される（２Ｓ）−２−ベンジルコハク酸モノエステルを効率よく安定して供給することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a general formula
[Chemical formula 5]
(R 1 is a lower alkyl group, R 2 is a tert-butyl group, a cyclohexyl group, a 2-phenylethyl group, or a benzyl group) (2S) -2-benzylsuccinic acid monoester organic amine It is about salt.
[0004]
More specifically, the present invention is useful as a therapeutic agent for diabetes.
[Chemical 6]
An optically active, general formula used as a starting material for an optically active benzylsuccinic acid monoamide derivative represented by the formula:
[Chemical 7]
(Wherein R 1 is a lower alkyl group) represented by the general formula (I) useful as a production intermediate of (2S) -2-benzylsuccinic acid monoester (Japanese Patent Laid-Open No. 4-356659) (2S) -2-benzylsuccinic acid monoester organic amine salt represented by
[0009]
[Prior art]
Conventionally, as a method for producing (2S) -2-benzylsuccinic acid monoester represented by the general formula (III), a compound represented by the formula:
[Chemical 8]
(E) -Benzylidene succinic acid monomethyl ester represented by the formula (2S, 4S) -tert-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine-rhodium complex in the presence of 50 atm hydrogen stream The reaction is carried out at 50 ° C. for 50 hours.
[Chemical 9]
(2S) -2-benzylsuccinic acid monomethyl ester represented by the formula is known (Pharmaceutical Journal, 106, 521-536 (1986)).
[0014]
However, the optical purity of (2S) -2-benzylsuccinic acid monomethyl ester represented by the formula (V) obtained by the above production method is 81% ee, and the production of pharmaceuticals and the like that require high optical purity The optical purity is insufficient to make a raw material. Therefore, in order to use it as a raw material for production of pharmaceuticals and the like, it is necessary to perform further purification operation, but since the compound is a highly viscous oily substance, purification is difficult. The production method is a reaction under a high pressure condition of 50 atm, which is not desirable as an industrial production method.
[0015]
[Problems to be solved by the invention]
The present invention is to provide a method capable of stably supplying (2S) -2-benzylsuccinic acid monoester represented by the general formula (III) having high optical purity under mild reaction conditions.
[0016]
DETAILED DESCRIPTION OF THE INVENTION
As a result of intensive studies to solve the above problems, the present inventors have found that the organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the general formula (I) has extremely good crystallinity. In addition, it was found that by using the organic amine salt, (2S) -2-benzylsuccinic acid monoester represented by the general formula (III) having high optical purity can be easily produced with a simple purification operation. The present invention has been made.
[0017]
The present invention is a raw material for producing an optically active benzylsuccinic acid monoamide derivative represented by the above formula (II) or a pharmacologically acceptable salt thereof useful as a therapeutic agent for diabetes, and represented by the above general formula (III). Useful as an intermediate for the preparation of (2S) -2-benzylsuccinic acid monoester
[Chemical Formula 10]
(Wherein R 1 is a lower alkyl group, and R 2 is a tert-butyl group, a cyclohexyl group, a 2-phenylethyl group or a benzyl group) (2S) -2-benzylsuccinic acid monoester And an organic amine salt thereof.
[0020]
In the present invention, the lower alkyl group represents an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, a propyl group, or an isopropyl group.
[0021]
In the present invention, the organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the general formula (I) having high optical purity can be produced as follows.
[0022]
For example, the general formula [0023]
Embedded image
(Wherein R 1 has the same meaning as described above) (E) -benzylidene succinic acid monoester is represented by the general formula (VI) in an alcohol solvent such as methanol, ethanol, isopropanol or the like ( E) -benzylidene succinic acid monoester is 1/3000 to 1/50, preferably 1/1000 to 1/100 times moles of (2S, 4S) -tert-butoxycarbonyl-4-diphenylphosphino-2- In the presence of diphenylphosphinomethylpyrrolidine-rhodium complex (hereinafter referred to as BPPM-Rh complex), in the presence or absence of organic amines such as triethylamine and piperidine, the hydrogen pressure is 1 to 10 atm, preferably 1 to 6 atm. Reduced by contact with the general formula [0025]
Embedded image
(R 1 in the formula has the same meaning as described above) (2S) -2-benzylsuccinic acid monoester represented by the general formula:
Embedded image
(R 2 in the formula has the same meaning as described above), and reacted with an organic amine represented by the general formula (I) with high optical purity. (2S) -2-benzylsuccinic acid mono Organic amine salts of esters can be prepared. The reaction temperature and reaction time are appropriately determined depending on the reaction conditions such as the type of solvent, the amount of catalyst, and the hydrogen pressure. The reaction temperature is usually 0 ° C. to 50 ° C., and the reaction time is usually about 8 to 20 hours.
[0029]
Further, instead of the (E) -benzylidene succinic acid monoester represented by the general formula (VI), the general formula
Embedded image
(R 1 and R 2 in the formula have the same meaning as described above) (E) -By catalytic reduction using an organic amine salt of benzylidene succinic acid monoester in the same manner as in the above production method, An organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the general formula (I) can also be directly produced.
[0032]
By the catalytic reduction in the production method of the present invention, (2S) -2-benzylsuccinic acid monoester or an organic amine salt thereof having an optical purity of about 95% ee or more can be produced. The organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the general formula (I) of the present invention has excellent crystallinity suitable for recrystallization operation, In (2S) -2-benzylsuccinic acid monoester represented by the general formula (III) obtained by catalytic reduction and an organic amine represented by the general formula (VII), or catalytic reduction (2S) -2-benzylsuccinic acid monoester organic amine salt obtained directly by using an organic solvent such as methanol, ethanol, isopropanol, isopropyl ether, tert-butyl methyl ether, hexane or the like alone or in an appropriate mixture, (2S) -2-benzylsuccinic acid represented by the above general formula (I) having an optical purity of about 98% ee or more easily by recrystallization according to a conventional method. It is possible to manufacture an organic amine salt of the monoester.
[0033]
The BPPM-Rh complex used in the present invention is commercially available (2S, 4S) -tert-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine (hereinafter referred to as BPPM) and bis (1,5-cyclohexane). It can be easily prepared by adding octadiene)-[mu], [mu] '-dichlorodichlorodium to methanol from which oxygen has been sufficiently removed under an argon stream and stirring at room temperature until dissolved.
[0034]
The organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the above general formula (I) produced in this way is organic in accordance with a conventional method using an appropriate acid such as hydrochloric acid or sulfuric acid. By removing the amine, (2S) -2-benzylsuccinic acid monoester represented by the general formula (III) having an optical purity of about 98% ee or more can be derived.
[0035]
The (E) -benzylidene succinic acid monoester represented by the general formula (VI) used as a starting material in the production method of the present invention can be produced from benzaldehyde and succinic acid diester by a Stobbe reaction according to a conventional method. .
[0036]
Further, the organic amine salt of (E) -benzylidene succinic acid monoester represented by the general formula (VIII) used as a starting material in the production method of the present invention is represented by the general formula (VI) ( E) -benzylidene succinic acid monoester can be produced by reacting the organic amine represented by the general formula (VII) with a conventional method.
[0037]
The organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the general formula (I) of the present invention has excellent crystallinity suitable for recrystallization operation. The production method makes it possible to efficiently produce (2S) -2-benzylsuccinic acid monoester with high optical purity under mild reaction conditions, and is an excellent production method applicable to industrial production. It is.
[0038]
【Example】
The contents of the present invention will be described in more detail with reference to the following reference examples and examples, but the present invention is not limited thereto. The methanol used for the reaction in the examples was one in which nitrogen gas was bubbled for 2 hours to sufficiently remove oxygen in the solvent. In addition, the optical purity of the compound in an Example was measured on condition of the following using HPLC, after guide | inducing to the corresponding diester derivative using the hexane solution of trimethylsilyldiazomethane.
[0039]
Column used: Chiral Cell OD (4.6φ × 250mm, Daicel Chemical Industries)
Elution solvent: n-hexane / isopropanol = 98/2 (v / v)
Flow rate: 1.0 mL / min Column temperature: Room temperature Detection wavelength: 220 nm
[0040]
Reference example 1
To a mixture of (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt benzaldehyde 53.1 g and dimethyl succinate 146.2 g, 328 g of a 28% methanol solution of sodium methoxide was added over 25 minutes with stirring at 45 ° C. After that, the mixture was stirred at the same temperature for 30 minutes. After the solvent was concentrated under reduced pressure, the concentrate was added to a mixture of 12 mL of concentrated hydrochloric acid and 200 g of ice. After extraction by adding 200 mL of ethyl acetate and 100 mL of water, the organic layer was extracted three times with 100 mL of saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, washed twice with 100 mL of ethyl acetate, adjusted to pH 1 with concentrated hydrochloric acid, and extracted twice with 100 mL of ethyl acetate. The organic layers were combined, washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 133.2 g of an oil. This oily substance was dissolved in a mixed solvent of 150 mL of ethyl acetate and 200 mL of hexane, and a solution of 36.6 g of tert-butylamine in 200 mL of hexane was added with stirring. The precipitated crystals were collected by filtration to obtain 128.4 g of (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt.
[0041]
1 H-NMR (CDCl 3 ) δppm:
1.27 (9H, s), 3.43 (2H, s), 3.72 (3H, s), 7.25-7.45 (8H, m), 7.73 (1H, s)
[0042]
Reference example 2
(E) -Benzylidene succinic acid-1-methyl ester cyclohexylamine salt In the same manner as in Reference Example 1 except that cyclohexylamine was used instead of tert-butylamine, (E) -benzylidene succinic acid-1-methyl ester cyclohexylamine salt was prepared. Obtained.
[0043]
1 H-NMR (CDCl 3 ) δppm:
1.0-2.0 (10H, m), 2.75-2.85 (1H, m), 3.43 (2H, s), 3.75 (3H, s), 7.25-7.45 (8H, m), 7.71 (1H, s)
[0044]
Example 1
(2S) -2-Benzylsuccinic acid-1-methyl ester cyclohexylamine salt Under a hydrogen stream, 13.6 g of (E) -benzylidene succinic acid-1-methyl ester cyclohexylamine salt was dissolved in 80 mL of methanol, and then in the reaction vessel. Was fully replaced with hydrogen. To this solution, 26 mg of BPPM and 10.5 mg of bis (1,5-cyclooctadiene) -μ, μ′-dichloro dirhodium were dissolved in 5 mL of methanol under an argon stream and a solution stirred for 20 minutes was added. After sufficiently replacing the inside of the reaction vessel with hydrogen, the mixture was stirred at room temperature and a hydrogen pressure of 5.2 atm for 20 hours. The solvent was distilled off under reduced pressure, and the residue (optical purity 96.2% ee) was recrystallized from isopropanol-hexane to give 10.5 g of (2S) -2-benzylsuccinic acid-1-methyl ester cyclohexylamine salt. Obtained (optical purity 98.3% ee).
[0045]
IR (KBr): 2938, 2214, 1731, 1547, 1406, 1164cm -1
1 H-NMR (CDCl 3 ) δppm:
1.05-1.25 (5H, m), 1.55-1.9 (5H, m), 2.23 (1H, dd, J = 5.1, 16.0 Hz), 2.49 (1H, dd, J = 9.4, 16.0 Hz), 2.7 (1H, dd, J = 7.6, 13.0 Hz), 2.75-2.85 (1H, m), 2.92 (1H, dd, J = 7.2,13.0 Hz), 2.95-3.05 (1H, m), 3.56 (3H, s), 6.8 -7.3 (8H, m)
[0046]
Example 2
(2S) -2-Benzylsuccinic acid-1-methyl ester tert-butylamine salt Under a hydrogen stream, 1.47 g of (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt was dissolved in 10 mL of methanol and then reacted. The inside of the container was sufficiently replaced with hydrogen. In this solution, 12.2 mg of BPPM and 4.9 mg of bis (1,5-cyclooctadiene) -μ, μ′-dichlorodichlorodium were dissolved in 2.0 mL of methanol under an argon stream and 0.5 mL of a solution stirred for 20 minutes was added. added. After sufficiently replacing the inside of the reaction vessel with hydrogen, the mixture was stirred at room temperature and a hydrogen pressure of 5.2 atm for 20 hours. The solvent was distilled off under reduced pressure, and the residue (optical purity 96.2% ee) was recrystallized from isopropanol-hexane to give 0.97 g of (2S) -2-benzylsuccinic acid-1-methyl ester tert-butylamine salt. (Optical purity 100% ee) was obtained.
[0047]
IR (KBr): 2920, 2220, 1732, 1541, 1166cm -1
1 H-NMR (CDCl 3 ) δppm:
1.22 (9H, s), 2.24 (1H, dd, J = 5.1, 16.3 Hz), 2.50 (1H, dd, J = 8.9, 16.3 Hz), 2.75 (1H, dd, J = 7.4, 13.2 Hz), 2.91 (1H, dd, J = 7.5, 13.2 Hz), 3.0-3.05 (1H, m), 3.53 (3H, s), 7.1-7.3 (8H, m)
[0048]
Example 3
(2S) -2-Benzylsuccinic acid-1-methyl ester tert-butylamine salt (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt 0.88 g was dissolved in 5 mL of methanol, and the inside of the reaction vessel was sufficiently filled. Was replaced with hydrogen. To this solution, 18.2 mg of BPPM and 7.4 mg of bis (1,5-cyclooctadiene) -μ, μ′-dichlorodirhodium were dissolved in 1.0 mL of methanol under an argon stream and a solution stirred for 20 minutes was added. After sufficiently replacing the inside of the reaction vessel with hydrogen, the mixture was stirred at a hydrogen pressure of 5.2 atm for 8 hours. The solvent was distilled off under reduced pressure, and the residue (optical purity 96.5% ee) was recrystallized from isopropanol-hexane to give 0.62 g of (2S) -2-benzylsuccinic acid-1-methyl ester tert-butylamine salt. (Optical purity 99.8% ee) was obtained.
[0049]
Example 4
(2S) -2-Benzylsuccinic acid-1-methyl ester tert-butylamine salt (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt 0.88 g was dissolved in 5 mL of methanol, and the inside of the reaction vessel was sufficiently filled. Was replaced with hydrogen. To this solution, 18.2 mg of BPPM and 7.4 mg of bis (1,5-cyclooctadiene) -μ, μ′-dichlorodirhodium were dissolved in 1.0 mL of methanol under an argon stream and a solution stirred for 20 minutes was added. After sufficiently replacing the inside of the reaction vessel with hydrogen, the mixture was stirred at a hydrogen pressure of 1 atm for 20 hours. The solvent was distilled off under reduced pressure, and the residue (optical purity 96.7% ee) was recrystallized from isopropanol to obtain 0.59 g of (2S) -2-benzylsuccinic acid-1-methyl ester tert-butylamine salt. (Optical purity 100% ee).
[0050]
Example 5
(2S) -2-Benzylsuccinic acid-1-methyl ester tert-butylamine salt (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt 0.88 g was dissolved in 5 mL of methanol and heated to 50 ° C. The reaction vessel was sufficiently replaced with hydrogen. To this solution, 18.2 mg of BPPM and 7.4 mg of bis (1,5-cyclooctadiene) -μ, μ′-dichlorodirhodium were dissolved in 1.0 mL of methanol under an argon stream and a solution stirred for 20 minutes was added. After sufficiently replacing the inside of the reaction vessel with hydrogen, the mixture was stirred at 50 ° C. and a hydrogen pressure of 5.2 atm for 8 hours. The solvent was distilled off under reduced pressure, and the residue (optical purity 95.3% ee) was recrystallized from isopropanol-hexane to give (2S) -2-benzylsuccinic acid-1-methyl ester tert-butylamine salt 0.59 g (Optical purity 100% ee) was obtained.
[0051]
Example 6
2.94 g of (2S) -2-benzylsuccinic acid-1-methyl ester 2-phenylethylamine salt (E) -benzylidene succinic acid-1-methyl ester tert-butylamine salt is added to a mixture of 10 mL of 2M hydrochloric acid and 30 mL of diethyl ether. After vigorous stirring, the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.25 g of oily (E) -benzylidene succinic acid-1-methyl ester. The obtained oily substance was dissolved in 20 mL of methanol. 10 mL of this methanol solution was transferred to a reaction vessel, and the inside of the reaction vessel was sufficiently replaced with hydrogen. In this solution, 12.2 mg of BPPM and 4.9 mg of bis (1,5-cyclooctadiene) -μ, μ′-dichlorodichlorodium were dissolved in 2.0 mL of methanol under an argon stream and 0.5 mL of a solution stirred for 20 minutes was added. added. After sufficiently replacing the inside of the reaction vessel with hydrogen, the mixture was stirred at room temperature and a hydrogen pressure of 5.2 atm for 20 hours. The solvent was distilled off under reduced pressure to obtain oily (2S) -2-benzylsuccinic acid-1-methyl ester (optical purity 96.7% ee).
[0052]
The obtained oil was dissolved in isopropanol, 0.628 mL of 2-phenylethylamine was added, hexane was added, and the precipitated crystals were collected by filtration, and (2S) -2-benzylsuccinic acid-1-methyl ester 2-phenyl. 1.09 g of an ethylamine salt was obtained (optical purity 99.7% ee).
[0053]
IR (KBr): 2948, 2214, 1728, 1523, 1407, 1165cm -1
1 H-NMR (CDCl 3 ) δppm:
2.27 (1H, dd, J = 4.5, 16.3Hz), 2.51 (1H, dd, J = 9.7, 16.3 Hz), 2.71 (1H, dd, J = 8.1, 13.2Hz), 2.80-3.05 (6H, m) , 3.52 (3H, s), 6.39 (3H, br), 7.10-7.30 (10H, m)
[0054]
Example 7
(2S) -2-Benzylsuccinic acid-1-methyl ester benzylamine salt In the same manner as in Example 6 except that benzylamine was used instead of 2-phenylethylamine, (2S) -2-benzylsuccinic acid-1-methyl ester A benzylamine salt was obtained.
[0055]
IR (KBr): 2951, 2206, 1732, 1541, 1404, 1163cm -1
1 H-NMR (CDCl 3 ) δppm:
2.29 (1H, dd, J = 4.6, 16.6 Hz), 2.54 (1H, dd, J = 9.5, 16.6 Hz), 2.72 (1H, dd, J = 8.0, 13.5 Hz), 2.95-3.05 (2H, m) , 3.58 (3H, s), 3.88 (2H, s), 4.6 (3H, br), 7.10-7.35 (10H, m)
[0056]
【The invention's effect】
According to the production method via the organic amine salt of (2S) -2-benzylsuccinic acid monoester represented by the general formula (I) of the present invention, the high optical purity that can be used as a raw material for production of pharmaceuticals and the like. The (2S) -2-benzylsuccinic acid monoester represented by the general formula (III) can be efficiently and stably supplied.
Claims (3)
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| JP32754499A JP4524015B2 (en) | 1999-11-17 | 1999-11-17 | (2S) -2-Benzylsuccinic acid monoester organic amine salt and process for producing the same |
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| JP32754499A JP4524015B2 (en) | 1999-11-17 | 1999-11-17 | (2S) -2-Benzylsuccinic acid monoester organic amine salt and process for producing the same |
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| JP2001139524A JP2001139524A (en) | 2001-05-22 |
| JP4524015B2 true JP4524015B2 (en) | 2010-08-11 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04356459A (en) * | 1991-04-25 | 1992-12-10 | Kissei Pharmaceut Co Ltd | New benzylsuccinic acid derivative |
| JPH08509988A (en) * | 1993-09-22 | 1996-10-22 | ファイザー・インコーポレーテッド | Hydrogenation |
| WO1999031041A1 (en) * | 1997-12-17 | 1999-06-24 | Chirotech Technology Limited | Asymmetric hydrogenation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1329680C (en) * | 1987-11-23 | 1994-05-17 | Harold Norris Weller, Iii | N-heterocyclic alcohol derivatives |
| US4939288A (en) * | 1989-01-23 | 1990-07-03 | Monsanto Company | Method of preparing (R)-succinic acid derivatives |
| ES2049710T1 (en) * | 1992-03-18 | 1994-05-01 | Monsanto Co | OPTIONALLY ACTIVE HOMO-BETA-AMINO ACIDS PREPARATION PROCEDURE. |
| US5212185A (en) * | 1992-08-14 | 1993-05-18 | G. D. Searle & Co. | Piperidinyl-terminated alkylamino ethynyl alanine amino diol compounds for treatment of hypertension |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04356459A (en) * | 1991-04-25 | 1992-12-10 | Kissei Pharmaceut Co Ltd | New benzylsuccinic acid derivative |
| JPH08509988A (en) * | 1993-09-22 | 1996-10-22 | ファイザー・インコーポレーテッド | Hydrogenation |
| WO1999031041A1 (en) * | 1997-12-17 | 1999-06-24 | Chirotech Technology Limited | Asymmetric hydrogenation |
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