Sunitinib malate

In this chapter, the evolution of the active pharmaceutical ingredient (API) manufacturing process for sunitinib malate will be described. The different routes evaluated to prepare the API, the factors that influenced the choice of the commercial process, salt selection, scale-up experience, and regulatory issues will be discussed in detail. The benefits and challenges of developing a one-pot process will also be highlighted. It is hoped that this chapter will provide a sense of the spectrum of issues to be considered while designing a commercial process. 

The free-base form of sunitinib malate (2) contains a highly substituted pyrrole core bearing an amide side chain at the 3-position and an indolinone substituent at the 5-position. Two routes were originally evaluated for the synthesis of free base 2. These were the early and late amidation routes. In the early amidation route, the pyrrole core is assembled after the amide side chain is installed, and the late amidation route involves amidation after the pyrrole core is assembled. These two approaches are depicted in Figure 4.2. 

Now, this series of chemical transformations had to be translated into a good process for the manufacture of sunitinib malate, 1. The first factor to be considered was the solvents to be used in each of the transformations. The CDI activation and amidation reactions (Steps lA and IB) were found to run satisfactorily in a variety of solvents, and THF was ultimately chosen as the solvent for these steps due to its relatively low boiling point. 

Addition of L-malic acid to the reaction mixture containing free base 2 followed by concentration by vacuum distillation led to precipitation of sunitinib malate (1), which was isolated by filtration. The filtration of the L-malate salt took only about 30 min on a 50-kg scale (compared to 8 h for 13 kg of the free base), thereby vindicating the choice of the L-malate salt as the API. 

It was also determined that 26 was formed by reaction of 9 with CDI and not imidazole. Thus, the maximum amount of 26 that could be formed in the sequence to synthesize sunitinib malate cannot be greater than the excess amount of CDI used (assuming imidazolide formation is faster... 

Weise AM, Liu CY, Shields AF. Fatal liver failure in a patient on acetaminophen treated with sunitinib malate and levothyroxine. Ann Pharmacother 2009 43(4) 761-6. 

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