Development of Scalable Conditions for the Ugi Reaction—Application to the Synthesis of (R)-Lacosamide

The Ugi reaction is applied for the preparation of ( R )-lacosamide, an important drug for the treatment of epilepsy. To this end, key issues associated with the Ugi reaction, such as a practical preparation of the foul-smelling isocyanide as well as the efficient introduction of chirality via a cheap and easily removable chiral directing group, were solved. Enantiomerically pure (>99.9% ee) drug substance meeting all required purity specifications is prepared in operationally simple four steps in 40% overall yield from the commodity chemical benzylamine.