Solvent effect on polymorphism in crystallization of BPT propyl ester

BPT propyl ester (propyl 2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylate) was synthesized, and the solvent effect in the polymorphic crystallization of the BPT propyl ester was investigated. The rapid-cooling crystallization was carried out from ethanol (EtOH), acetonitrile (MeCN), and cyclohexane (c-Hxn) solutions. From EtOH and c-Hxn solutions at high initial concentrations, a metastable form first appeared, and after that, a subsequent transformation to a stable form occurred. On the other hand, at low concentrations the stable form crystallized directly. Crystallization from MeCN solutions resulted in only a stable form under all the conditions. X-ray analysis indicates that both the stable and metastable forms are constructed by stacking of the sheet structures of the molecules (the phenyl and thiazole rings and ester group are on the same plane). In the metastable form, a nitrile group and a methyl group on the thiazole ring are located in cis positions. On the other hand, in the stable form, these groups are in trans positions. The structure of the stable form is stabilized by hydrogen bonding through the nitrile and carbonyl groups. The two-step nucleation mechanism of the metastable and stable forms in EtOH and c-Hxn solutions and the nucleation mechanism of only the stable form in MeCN solution are described.