Green and efficient enantioseparation of amlodipine using a novel pairwise crystallization-circulating extraction coupling method aimed at in situ reuse of mother liquor

• A new pairwise crystallization-circulating extraction coupling method was designed. • PC-CE is a green enantioseparation method for the in situ reuse of mother liquor. • Ternary phase diagram analysis and experiments proved the feasibility of PC-CE. • After reuse of mother liquor for 15 times, the ee of crystal was remained at >98%. • The overall yields can be considered close to 100% except for the operating loss. Diastereomeric crystallization is a widely used enantioseparation method, but its yield is low due to mother liquor waste. To realize in situ regeneration and reuse of mother liquor, a novel green pairwise crystallization-circulating extraction coupling (PC-CE) method was developed. By using two resolving agents ( D -/ L -tartaric acid), the two enantiomers ( S -/ R -amlodipine) of racemate were separately crystallized as S-D and R-L salts in two crystallizers. Moreover, by circulating extraction between the crystallizers, the accumulated R- enantiomer in the S-D salt crystallizer was transferred into the R-L salt crystallizer, and the accumulated S- enantiomer in the R-L salt crystallizer was transferred into the S-D salt crystallizer. Therefore, the enantiomeric excess ( ee ) of two mother liquors decreased to nearly 0%, and they returned to a racemic state and can be reused by supplementing raw materials. In contrast, conventional direct in situ reuse of mother liquor is infeasible due to the accumulation of non-target enantiomer. Theoretical analysis using ternary phase diagrams and experiments confirmed the above description. During the conventional direct in situ reuse of mother liquor process, the crystal ee values changed greatly. PC-CE can be used to form a stable and efficient cyclic operation for the mother liquors in situ reuse and the efficient crystallization enantioseparation. The influences of different conditions on the batch PC-CE process were studied. After reuse of mother liquor for 15 times, the two crystals with ee values of 98% ∼ 99% were consecutively obtained, and the overall yields were close to 100% except for the operating loss. Due to the in situ reuse of mother liquor, PC-CE is a green enantioseparation method and has practical application potential in many chiral resolution fields.