Attrition Induced Deracemisation of 2-Fluorophenylglycine

Abstract

By search of a library of closely related structures, two conglomerate imines of the amide of 2-fluorophenylglycine have been discovered and unambiguously characterized. One conglomerate is formed on reaction with benzaldehyde and the other on reaction with 4-Br-benzaldehyde. The crystal structures of both have been determined. Both deracemise on grinding of the crystals under conditions whereby racemisation in solution can occur. Deracemisation of the former compound is hampered both by hydrate formation and formation of a polymorph. In contrast the latter deracemises efficiently. Hydrolysis of the enantiomerically pure (R)-imine to enantiomerically pure (R)-2-fluorophenylglycine proceeds smoothly. Either the (R)- or the (S)-enantiomer of the imine can be produced at will by seeding.

Particle Breakage Kinetics and Mechanisms in Attrition-Enhanced Deracemization

“…A few years later, Noorduin et al 2 successfully developed the equivalent process for intrinsically chiral molecules that undergo racemization and form conglomerate crystals, establishing the attrition-enhanced deracemization or Viedma ripening process as a feasible means to obtain enantiopure pharmaceutical precursors in quantitative yields [3][4][5] . Since the seminal studies of Viedma and Noorduin, several achiral [6][7][8] and chiral [9][10][11][12][13][14][15][16] compounds have been successfully deracemized and many intriguing variations of the process have appeared, such as temperature cycling-enhanced deracemization [17][18][19] , combination of Viedma ripening with reactions 20,21 or crystal transformations [22][23][24] or the concomitant use of Viedma ripening with chiral additives 25,26 .…”

Coupling Viedma Ripening with Racemic Crystal Transformations: Mechanism of Deracemization

“…Viedma ripening was first demonstrated for sodium chlorate, an intrinsically achiral compound that crystallizes as conglomerate crystals, but has since then been modified to work also for intrinsically chiral compounds e.g. amino acids [4][5][6][7] and pharmaceuticals [8][9][10] that crystallize as conglomerate crystals by incorporating a fast racemization reaction. The outcome of the deracemization process depends on the initial conditions 11,12 : mass or crystal size distribution (CSD) imbalance between the enantiomers 1,[13][14][15] , presence of chiral impurities 16 or additives [17][18][19] or circularly polarized light 20 .…”

Deracemization Controlled by Reaction-Induced Nucleation: Viedma Ripening as a Safety Catch for Total Spontaneous Resolution

“…6,14,15 Because in these cases the ee was determined in the end, it is unclear to what extent secondary nucleation and Viedma ripening were involved.…”