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Temperature Selective Diastereo-Recognition (TSD): Enantiomeric Ibuprofen via Environmentally Benign Selective Crystallization

“…Classical resolution of ( R , S )-ibuprofen via conventional techniques utilizing equimolar quantities of ( R , S )-ibuprofen and ( S )-lysine (as the resolving agent) in aqueous ethanol afforded the diastereomeric ( S )-(+)-ibuprofen/( S )-lysinate salt in >99% optical purity after two crystallizations. Conceptually, we envisaged the possibility of selective crystallization of ( S )-(+)-ibuprofen/( S )-lysinate utilizing only 0.5 mol of ( S )-lysine per 1 mol of ( R , S )-ibuprofen in the crystallization medium, provided a significant differential rate of crystal growth exists between the two diastereomeric salts,7b thereby promoting the crystallization of only one diastereomer with the mother liquor being enriched in the other enantiomer as shown in Scheme . Crystallization studies were conducted by adding an aqueous solution of ( S )-lysine to an ethanolic solution of ( R , S )-ibuprofen, followed by seeding.…”

“…The ability to produce either diastereomer utilizing the same chiral auxiliary (( S )-lysine) is previously unreported 7c…”

“…The process obviates the shortcomings associated with both classical resolution (involving expensive synthetic resolving agents) and enzyme technology. The process also produces the enantiomeric ibuprofen directly as the preferred lysinate salt, which is desirable for human consumption thereby avoiding the obligatory separation of ibuprofen from a chiral auxiliary (atom economy) 7e. Diastereomeric enrichment of ( S )-(+)-ibuprofen lysinate to a 99% level via a single recrystallization also demonstrates the superiority of lysine as a resolving agent for ibuprofen.…”

“…Although already demonstrated, the existing methods for resolving ( R , S )-ibuprofen via fractional crystallization of diastereomeric salts with chiral amines (e.g., α-methybenzylamine, ( S )-lysine) suffers from the following disadvantages: (a) Classical resolution is always accompanied by the production of at least 1 mol of salt (waste) with a maximum theoretical yield of only 50% (based on the chiral auxiliary). (b) Although synthetic resolving agents (e.g., α-methybenzylamine) are available in both enantiomeric forms, naturally occurring agents (e.g., ( S )-lysine) are often only available in one enantiomeric form, thereby limiting the scope of such diastereomeric separations. 2a, (c) And, the success of resolution methods depends on an efficient racemization and recycling of the unwanted ( R )-isomer. Existing technologies to racemize ibuprofen are often nontrivial and waste producing.…”

“…In addition, we also report a convenient, waste-free, thermal racemization of ( S )-(+)-ibuprofen that does not require any external reagent, catalyst, and/or solvent, thus rendering alternate racemization technologies less attractive. This racemization method, when utilized in conjunction with the selective crystallization technology, provides an efficient and environmentally benign technology to prepare ( S )-(+)-ibuprofen lysinate in an overall yield which is nearly quantitative 7e…”