Mass Transfer and Phase Diagram Study for Crystallization-Extraction Coupling Enantioseparation of ( <i>RS</i> )-1-(1-Naphthyl)ethylamine and Mother Liquor Reuse

Diastereomeric crystallization is a prevalent method for enantioseparation; however, it is hindered by the significant generation of waste mother liquor. Therefore, our previous research introduced a pairwise crystallization-circulating extraction coupling (PC-CE) method for mother liquor regeneration and reuse. Despite its potential, the circulating extraction requires several hours (4–20 h), highlighting the need for enhanced mass transfer rates to expedite the process. This study examines the mass transfer intensification in three sets of PC-CE equipment (designated as Equipment Nos. 1–3) by enhancing phase separation capabilities. Specifically, the crystallization-extraction coupling devices of Equipment Nos. 1–3 were developed through structural modifications of a “gas-washing bottle”, a “Soxhlet extractor”, and a “volatile oil extractor”, respectively. The diastereomeric crystallization of (RS)-1-(1-naphthyl)ethylamine was investigated, with enantiomeric excess (ee) values and the mixing degree (h) of the mother liquors measured at various flow rates. As a result, Equipment Nos. 2 and 3 exhibit a lower mixing degree (<4.03%) and significantly reduced circulating extraction time (20 to 60 min) compared to Equipment No. 1. Furthermore, the crystallization process was studied from the perspective of phase equilibrium. Initially, the impact of various factors was investigated, which was followed by the deduction of phase diagrams to provide a theoretical explanation for PC-CE and to predict the total solute dosage range (lines f2_q0 and f′2_q′0). Ultimately, Equipment No. 3 with a flow rate of 14.7 × 10–4 m/s and a circulating extraction time of 45 min was selected for mother liquor reuse. The ee values of the two (R)-/(S)-1-(1-naphthyl)ethylamine salt crystals obtained through 15 cycles of crystallization reuse ranged from 94.34% to 99.02% and from 93.66% to 97.02%, respectively. This research represents a significant reduction in regeneration time from the previous 4–6 h to just 45 min, thereby enhancing the practicality of the PC-CE method.