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-solidliquid 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 liquidgas 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 dm 3 scale.

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