Improved Synthesis and Impurity Identification of (R)-Lacosamide

An improved synthesis of Lacosamide 1 with high purity has been developed. Critical parameters of each step were identified as well as the impurities generated. Moreover, a creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-N-benzyl-3-methoxy­propionamide 10 by forming salt with an achiral acid (phosphoric acid) was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further developed for the deprotection of the Boc group.