Aryl boronic acids and esters are important building blocks in API synthesis. The palladium-catalyzed Suzuki-Miyaura borylation is the most common method for their preparation. This paper describes an improvement of the current reaction conditions. By using lipophilic bases such as potassium 2-ethyl hexanoate, the borylation reaction could be achieved at 35 °C in less than 2 h with very low palladium loading (0.5 mol %). A preliminary mechanistic study shows a hitherto unrecognized inhibitory effect by the carboxylate anion on the catalytic cycle, whereas 2-ethyl hexanoate minimizes this inhibitory effect. This improved methodology enables borylation of a wide range of substrates under mild conditions.
Odalasvir
is a selective inhibitor of hepatitis C virus NS5A protein,
a key target for combination therapies. This paper describes the chemical
process development for the synthesis of this active pharmaceutical
ingredient and the improvements that were achieved over the medicinal
chemistry route. Optimization of all of the reaction conditions and
crystallizations resulted in higher throughput and a highly improved
process mass intensity. The process is robust and has been scaled
up to ∼100 kg batches without issues.
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