Systematic study of lipase-catalyzed resolution of propanolol precursors

Propranolol [(R,S)-1-isopropylamino-3-(1-naphthoxy)-2-propanol], is a well-known beta-adrenergic blocking agent used for treatment of arterial hypertension and other cardiovascular disorders [Prichard et al. BMJ-British Medical Journal. 1964, 2, 725-727], which is commercially available as a racemic mixture. However, it is also well proven that only the (S)-enantiomer has the desired therapeutic effect [Howe et al. J. Med. Chem. 1968, 11, 1118-1121]; therefore, many stereoselective synthetic protocols for the preparation of the (S)-eutomer can be found in literature, in most cases the introduction of chirality being mediated by an enzymatic resolution of the chemically-prepared racemate [Bevinakatti et al. J. Org. Chem. 1991, 56, 5372-5375; Pamies et al. J. Org. Chem. 2002, 67, 9006-9010]. Generally speaking, the resolution should preferentially be carried out in the first steps of the synthetic scheme, on a precursor of the desired target drug such as the racemic aryloxyhalohydrines, easily prepared by opening epychlorhydrine with an aromatic alcohol.

In this communication we will present the kinetic resolution of aryloxyhalohydrines (precursors of propranolol and other beta-adrenergic blockers) by lipase-catalysed stereoselective transterification with enol esters. A factorial design of experiments was undertaken to assess best reaction conditions (temperature, solvent, acyl donor, …) for the efficient separation of enantiomers, both of them useful for therapeutic purposes; in fact, besides the previously antihypertensive activity of (S)-propranolol, the correspondent (R)-antipode displays a stronger antiarrhythmic and membrane-stabilizing effect [Wang et al. Circ.-Arrhythmia Electrophysiol. 2008, 1, 370-378], and it is also useful as a vaginal contraceptive [Borumand et al. J. Drug Deliv. Sci. Technol. 2014, 24, 637-644]. Through this stereoselective enzymatic acylation, the corresponding halohydrine ester and remnant alcohol can be easily separated and efficiently transformed into both enantiomers of propranolol.