TCID is a method used for obtaining enantiopure solids from racemic mixtures in the crystalline phase, while fast racemization occurs in solution, with solubility affected by temperature swings. Although TCID theoretically doubles the yield compared to chiral separation methods due to the conversion of the counter enantiomer, the experimental yield remains unproven. One setback is the extraction of the dissolved solute while maintaining chiral purity. Furthermore, due to the slow induction time and the stochasticity of deracemization, an initial suspension with 20% c.e.e. (crystal enantiomeric excess) is commonly imposed to bias the deracemization, but this investment may be undesirable for industrial applications.

Herein, we applied TCID to (1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl) pentan-3-one), employing a cooling step at the end of the process to overcome the issue of yield, and a washing step to further improve the c.e.e. This adjustment produced a mass yield of 92% with 99.9% c.e.e. within 24 hours on an 8.6 g scale. The final cooling step removes the majority of dissolved solute, enhancing the yield without significantly prolonging the process, and the washing step improves the enantiopurity.

Additionally, we investigate the stochasticity of deracemization during the initial stages, focusing on the development of c.e.e. from low initial values (1-5% c.e.e.) at a 2.5-gram scale. By assessing the kinetics, we determine that an initial c.e.e. of 2% for this system is adequate without significant risk of chiral flipping and to avoid the induction time. Our findings show the suitability of TCID to be performed on the industrial scale, with reduced initial c.e.e. to direct and overcome the induction time and a simple method to optimize the final yield and purity.