A Scalable Synthesis of l-Leucine-N-carboxyanhydride

Due to its relevance in the synthesis of well-defined oligopeptides, the l-leucine-N-carboxyanhydride (leucine-NCA) synthesis was selected for fine chemical scale-up with a scope on application on larger scales. The heterogeneous gas−solid−liquid nature of the leucine-NCA synthesis implied a mass transfer limited reaction rate towards phosgenation and was investigated on bench scale. Upon scale increase, the liquid−gas mass transport of HCl is drastically reduced, retarding the reaction and consequently rendering the process unsuitable for scale-up. Addition of an HCl scavenger such as (+)-limonene prevented side reactions thus allowing a cost reduction, a considerably faster reaction, and minimization of the amount of phosgene source used. The modified leucine-NCA synthesis has successfully been made scalable, maintaining high product purity on a 1.0 dm3 scale.