Effect of the Alkyl Group in BPT-Esters on the Polymorphic Crystallization Behavior

Abstract

Effect of the alkyl group of the ester in polymorphic crystallization was investigated by a rapid cooling method in ethanol solutions using BPT methyl ester [Me-est: methyl 2-(3-cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate] and BPT isobutyl ester [i-But-est: 2-methylpropyl 2-(3- cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate]. The crystallization of Me-est resulted in only one crystal form at every initial concentration. On the other hand, in the crystallization of i-But-est at high initial concentrations, metastable A form first appeared, and then the subsequent transformation to the stable B form occurred. At low initial concentrations, the stable form directly crystallized. Such behavior of i-But-est supports Ostwald's step rule, and it is similar to that obtained previously for BPT propyl ester. Crystallographic analysis indicated that the Me-est crystal is constructed by the sheets of a dimer that are formed by the two hydrogen bonds between the molecules. On the other hand, metastable i-But-est crystal is constructed by stacking the zigzag sheets of the molecules, and the stable i-But-est crystal is formed by stacking two types of layers. These results indicate that even a small change in molecular structure gives rise to a large difference in the polymorphic crystallization behavior and crystal structure.