On Solute Recovery and Productivity in Chiral Resolution through Solid-State Deracemization by Temperature Cycling

Abstract

Temperature cycling represents an effective means for the deracemization of chiral compounds that crystallize as conglomerates and racemize in solution. In such a process, a suspension enriched in the desired enantiomer is converted into an enantiopure one through periodic cycles of crystal dissolution and crystal growth. We show that performing temperature cycling at higher temperatures leads to faster deracemization and, consequently, higher productivity. However, this comes at the cost of lower recovery, as the solution contains potentially relevant amounts of solute due to the higher solubility at an elevated temperature. In this work, we introduce and compare two process variants that mitigate this issue. The first involves temperature cycling, followed by linear cooling, whereas the second is based on merging the temperature cycles and cooling crystallization. Experiments carried out with the chiral compound N-(2-methylbenzylidene)-phenylglycine amide show that the former variant is faster than the latter, and it is easier to design and implement. In this process, the choice of an appropriate cooling rate is essential to avoid nucleation of the undesired enantiomer.

Improved Experimental Yield of Temperature Cycle Induced Deracemization (TCID) with Cooling and Crystal Washing: Application of TCID for the Industrial Scale.

“…However, neither work presented promising yields to demonstrate the potential of this method. The compound specific effects are also clear, as 1 crystallizes differently to the other molecules studied, and do not undergo thermal decomposition, as seen for glutamic acid in the work by Pálovics et al, and the cooling rates that induced nucleation in the work of Hosseinalipour et al, was not observed for 1 [15,16].…”

“…by favoring the crystal growth of the major enantiomer. This simple cooling technique has been demonstrated by Palovics et al and Hosseinalipour et al however, neither team demonstrated favorable experimental mass yields [15,16].…”