2012 Volume 70 Issue 9 Pages 896-907
In the last decade, rapidly evolving microreaction technology based on tiny microchannels has attracted broad attention in organic synthesis. The new technology has also a great potential even for pharmaceutical production because time-saving optimization of flow reaction conditions can be accomplished using an automated microreactor system and the optimal condition can readily be applied to large scale production. A microreaction system also guarantees the quality of products, the operational safety, and the low energy cost. Herein, we report the synthesis of a key intermediate of myriceric acid A, an endothelin receptor antagonist (S-0139) and a matrix metalloproteinase inhibitor (S-3304) using a flow microreactor as model cases. The intermediate of S-0139 was synthesized by Barton reaction using a photo-microreactor and a compact light source, such as a black light or a UV-LED, with high energy efficiency. Using an automated microreactor system, MiChS System X-1, quick optimization of the reaction conditions and the 100 g scale synthesis of the S-3304 by Sonogashira coupling reaction was achieved. We also demonstrate that the flow reaction system using ionic liquid as catalyst support allowed facile separation of products from the catalyst. Large scale synthesis of a key intermediate of S-3304 was also achieved in combination with a micro-extraction/catalyst recycling system, in which the ionic liquid containing the Pd catalyst was continuously recycled. Moreover, parallel synthesis of triazoles by azidation using MiChS System X-1 followed by Huisgen reaction using a batch reactor was successfully carried out.
