No abstract

Developing a robust crystallization process for an active pharmaceutical ingredient (API) molecule with a complex polymorphic profile can present a significant challenge. The presented case illustrates an unusual crystallization development problem where a polymorphically complex API has the additional obstacles of poor solubility in standard crystallization solvents as well as a propensity for forming solvates. After early polymorph screening of this candidate highlighted the potential for a complex solid form profile, a variety of experimental approaches was utilized to determine the low-energy polymorph and characterize the various solvates formed. Characterization of the API crystallization process identified a critical solvent composition range for the transformation from a metastable solvate form to the desired polymorph. During subsequent crystallization process development studies, a new lower-energy polymorph was discovered. Examination of the crystal structures led to a rationale for the formation of solvates and the existence of a new lower-energy form.

A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has been found to catalyze the amidation of acyl imidazoles. The rate acceleration is especially evident with traditionally unreactive, electron-deficient anilines. DBU is readily available and offers safety and cost advantages over more commonly employed catalysts such as 1-hydroxybenzotriazole.