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

Continuous flow hydrogenation using polysilane-supported palladium/alumina hybrid catalysts

Continuous flow systems for hydrogenation using polysilane-supported palladium/alumina (Pd/(PSi–Al2O3)) hybrid catalysts were developed. Our original Pd/(PSi–Al2O3) catalysts were used successfully in these systems and the hydrogenation of unsaturated C–C bonds and a nitro group, deprotection of a carbobenzyloxy (Cbz) group, and a dehalogenation reaction proceeded smoothly. The catalyst retained high activity for at least 8 h under neat conditions

RANTES Production from Mononuclear Cells in Response to the Specific Allergen in Asthma Patients

Background: Eosinophils are considered to be the major inflammatory cells in asthma. Since regulated on activation, normal T expressed and secreted (RANTES) is a potent chemoattractant for various important inflammatory cells such as eosinophils as well as memory T cells potentially recruiting these cells to an inflamed focus, RANTES has been considered to play a key role in various allergic disorders such as asthma. Methods: To extend our understanding of the participation of eosinophils and T cells in relation to the production of RANTES in response to the specific allergen in asthma, we examined the production of RANTES from peripheral blood mononuclear cells cultured with specific allergen in atopic asthma patients by a sandwich enzyme-linked immunosorbent assay. Results: It was revealed that mononuclear cells produced RANTES but not eotaxin in response to the specific allergen in asthma. RANTES production from mononuclear cells of asthma patients with eosinophilia was greater than that of asthma patients without eosinophilia. Moreover, in this study, no differences in RANTES production between CD4 negative cells and CD8 negative cells were observed. Conclusions: Taken together, these findings may suggest that mononuclear cells play a crucial role in the pathogenesis, particular in eosinophil and T lymphocyte recruitment into the inflamed focus of asthma through RANTES production in response to the specific allergen