Identification and Synthesis of Process-Related Impurities in Lisdexamfetamine Dimesylate

During the process optimization of Lisdexamfetamine dimesylate, two process impurities were observed. Methods: These impurities remained a concern for commercialization and were isolated, on characterization, were found to be H-Lys-ε-Lys-d-amphetamine and other being its regio- isomer H-Lys-α-Lysd- amphetamine. The main target of this study was to synthesize reference compounds for HPLC analysis of these impurities produced in Lisdexamfetamine. Result: To the best of our knowledge, these impurities are not commercially available and no synthetic methods have been reported. Both of these potential impurities were synthesized, and their structures were established by various spectral techniques. Conclusion: Furthermore, herein we also report the synthesis of two process impurities Boc- Lys(Boc)-ε-Lys(α-Boc)-O-Nitrophenol and Boc-Lys(Boc)-α-Lys(ε-Boc)-O-Nitrophenol and their fate for the formation of impurities H-Lys-ε-Lys-d-amphetamine and H-Lys-α-Lys-d-amphetamine.