Resolution of (±)-Imeglimin-2,4-dichlorophenylacetate Methanol Solvate by Preferential Crystallization

Abstract

The resolution of this derivative was optimized at 2-L scale in methanol by using two preferential crystallization modes (auto-seeded polythermic programmed preferential crystallization, hereafter AS3PC, and seeded isothermal preferential crystallization, hereafter SIPC) and by tuning the starting temperature. The results evidenced that the AS3PC mode is more efficient than the SIPC mode, and the higher the starting temperature, the higher the productivity. Despite a careful tuning of the operating conditions and a stable conglomerate offering a full chiral discrimination in the solid state, the enantiomeric excess of the crude solid obtained by preferential crystallization remained lower than 90%. However, this can be improved up to 99% by a single recrystallization of the methanol solvate of the imeglimin-2,4-dichlorophenylacetate since it crystallizes as a stable conglomerate without any detectable partial solid solution.

A review of phenformin, metformin, and imeglimin

“…The biguanide pharmacophore is a common structural motif of many small molecules for various medicinal uses (Kathuria, Bankar, & Bharatam, ). Metformin and phenformin are biguanide congeners containing acyclic nitrogen's, while imeglimin is a constrained cyclic “dihydro‐1,3,5‐triazine” derivative (Figure ; Wacharine‐Antar, Levilain, Dupray, & Coquerel, ). Bioisosterism is an important approach in rational drug discovery (Patani & LaVoie, ).…”

“…Imeglimin has a chiral center and exhibits stereoselectivity. The R ‐isomer has better anti‐diabetic profile than the S ‐isomer (Figure ; Moinet, Cravo, Doare, Kergoat, & Mesangeau, ; Wacharine‐Antar et al, ).…”

Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization**

“…[14] The main limitation of this latter is the requirement for the target compound to crystallize as a conglomerate-a physical mixture of mirror-image crystalline phases exhibiting symmetrical enantiomeric excesses. [14a] The statistics for a specific compound to crystallize as a conglomerate is observed to be < 10 % [15] and crystal engineering tools are used to transform racemic compound systems into conglomerate ones, typically through salt, [16] solvate, [17] or more recently cocrystal formation with the use of achiral agents (acid, base, solvent or coformer). [18,19] Going beyond the use of achiral compounds, racemic carboxylic acids and racemic amines were successfully combined to form conglomerate salts.…”

Solubility of chiral species as function of the enantiomeric excess

“…Figure a shows an important case where a stable racemic compound forming system can be transformed into a stable conglomerate forming system because of the crystallization of a stable solvate. All the benefits of a conglomerate can be obtained here, even if it is an efflorescent compound [29]. In view to seek for a conglomerate, it is important to emphasize that a twofold screening has to be conducted: For each counter‐ion or co‐crystal former a secondary screen of different solvents should be implemented.…”