Identification, Synthesis and Characterization of Novel Palbociclib Impurities

Palbociclib is used for breast cancer treatment along with letrozole. Five major impurities were observed during the synthesis as well as in forced degradation studies, out of which, three impurities were identified during the penultimate step of palbociclib API synthesis. These three impurities were confirmed as palbociclib desacetyl impurity (PDA impurity), palbociclib desacetyl hydroxy impurity (PDH impurity) and palbociclib desacetyl hydroxyl methyl impurity (PDHM impurity). These impurities were formed due to the usage of palladium catalyst during the pre-final reaction between 1 and 2. The other two impurities were identified as N-oxides, which were formed due to the forced oxidative degradation studies of palbociclib. These two impurities were confirmed as palbociclib pyridine N-oxide and palbociclib piperazine N-oxide. All the five major impurities were identified, synthesized, characterized and confirmed by spectral analyses (1H NMR, 13C NMR and mass spectra). These impurities were potentially important as reference standards for the R&D scientists working in process development and formulation development of palbociclib.