Early Process Development of a Squaramide-Based CXCR2 Receptor Antagonist

The synthesis of a CXCR2 antagonist is presented, highlighting the process changes made from research synthesis to clinical supply. The target compound is the choline salt of a nonsymmetrical squaramide, and the modifications to the synthetic route which have effect on chemical purity are discussed with reference to the isolated byproducts. Although drug substance quality was shown to increase following optimization of the linear sequence, an alternative one-pot, convergent sequence was introduced, which makes dual use of choline hydroxide as both base and salt-forming agent. The overall benefits of the strategic change is discussed in terms of overall yield and economy.