A cooperative water effect in proazaphosphatranecatalysed heterocycle synthesis

The synthesis of oxazolines and imidazolines was achieved by activation of isocyanides with water. Mechanistic studies show that the organosuperbase proazaphosphatrane is tolerant of water within the reaction medium, with a beneficial and cooperative effect being observed

Three-component, one-pot tandem Sonogashira/Suzuki–Miyaura coupling reactions and derivatization for the synthesis of a library of ceramide-transport protein inhibitors that were designed in silico

We have developed a one-pot, tandem Sonogashira/Suzuki–Miyaura coupling reaction, which is unknown synthetically, and applied it for the synthesis of a library of potential natural ligand nonmimetic inhibitors of the lipid-transfer protein, ceramide-transport protein (CERT). The characteristic feature of this reaction is that the two-step coupling reaction proceeds smoothly with only 5 mol% of palladium catalyst. Furthermore, the location of the formed carbon–carbon bond would be strictly defined because of the difference in reactivity. Therefore, many derivatives could be synthesized in high yields without the formation of regioisomeric byproducts by the same procedure. We also performed a semi-gram scale synthesis of several derivatives to provide the bioactive assey. After synthesizing as many as 113 derivatives, we identified a nonnatural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)-HPA-12

Multistep Continuous Flow Synthesis of (R)- and (S)-Rolipram Using Heterogeneous Catalysts

Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility1, 2, 3, 4. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems5, 6. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram7, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives8. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.化学品の製造は、バッチ法か連続フロー法のいずれかを用いて行われる。フロー法には、特に生産性、熱効率、混合効率、安全性、再現性の点で、バッチ法に勝る長所がある。しかし、連続フロー法では医薬品などの複雑な構造を有する分子の合成が困難であったため、医薬品製造には50年以上にわたってバッチ法が用いられてきた。今回我々は、不均一系触媒を充填したカラムのみを用いる医薬品の連続フロー合成について報告する。アキラル不均一系触媒またはキラル不均一系触媒を充填した合計4本のカラムに、市販の出発物質を順次通過させ、抗炎症薬でγ-アミノ酪酸（GABA）誘導体ファミリーの1つである、( R )-ロリプラムを合成した。さらに我々は、キラル不均一触媒を充填したカラムを、逆のエナンチオマーを充填した別のカラムに置き換えるだけで、対掌体の( S )-ロリプラムを得ることができた。同様に、GABAファミリーに属する別の医薬品、( R )-フェニバットの合成も行った。これらのフロー法は簡便かつ安定であり、金属触媒の漏出も見られない。今回の結果は、不均一触媒のみを用いたフロー条件の下で、医薬品合成を目的とした多段階（今回の場合は8段階）化学変換が、中間体の単離や、触媒、共生成物、副生成物、過剰試薬の分離を行わなくても円滑に進行することを実証したものである。我々は、本フロー合成法が医薬品製造に役立つことを期待している。UTokyo Research掲載「医薬品、ファインケミカルの新しい製造法」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/new-synthetic-technology-for-medicines-and-fine-chemicals.htmlUTokyo Research "New synthetic technology for medicines and fine chemicals" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/new-synthetic-technology-for-medicines-and-fine-chemicals.htm

Multistep Continuous Flow Synthesis of (R)- and (S)-Rolipram Using Heterogeneous Catalysts

Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility1, 2, 3, 4. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems5, 6. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram7, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives8. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.化学品の製造は、バッチ法か連続フロー法のいずれかを用いて行われる。フロー法には、特に生産性、熱効率、混合効率、安全性、再現性の点で、バッチ法に勝る長所がある。しかし、連続フロー法では医薬品などの複雑な構造を有する分子の合成が困難であったため、医薬品製造には50年以上にわたってバッチ法が用いられてきた。今回我々は、不均一系触媒を充填したカラムのみを用いる医薬品の連続フロー合成について報告する。アキラル不均一系触媒またはキラル不均一系触媒を充填した合計4本のカラムに、市販の出発物質を順次通過させ、抗炎症薬でγ-アミノ酪酸（GABA）誘導体ファミリーの1つである、( R )-ロリプラムを合成した。さらに我々は、キラル不均一触媒を充填したカラムを、逆のエナンチオマーを充填した別のカラムに置き換えるだけで、対掌体の( S )-ロリプラムを得ることができた。同様に、GABAファミリーに属する別の医薬品、( R )-フェニバットの合成も行った。これらのフロー法は簡便かつ安定であり、金属触媒の漏出も見られない。今回の結果は、不均一触媒のみを用いたフロー条件の下で、医薬品合成を目的とした多段階（今回の場合は8段階）化学変換が、中間体の単離や、触媒、共生成物、副生成物、過剰試薬の分離を行わなくても円滑に進行することを実証したものである。我々は、本フロー合成法が医薬品製造に役立つことを期待している。UTokyo Research掲載「医薬品、ファインケミカルの新しい製造法」 URI: http://www.u-tokyo.ac.jp/ja/utokyo-research/research-news/new-synthetic-technology-for-medicines-and-fine-chemicals.htmlUTokyo Research "New synthetic technology for medicines and fine chemicals" URI: http://www.u-tokyo.ac.jp/en/utokyo-research/research-news/new-synthetic-technology-for-medicines-and-fine-chemicals.htm

Sulfonylimidates as Nucleophiles in Catalytic Addition Reactions

International audienc