Lipase catalyzed chemo-enzymatic synthesis of propranolol: A newer enzymatic approach

Abstract

The biocatalytic processes are greener and safer alternatives for synthesis of drug and drug intermediates. This study reports one such approach of chemo-enzymatic synthesis of propranolol, a β-adrenergic receptor blocker. A green synthetic route was employed for synthesis of propranolol using enzymatic kinetic resolution. Racemic mixture of secondary alcohol [1-chloro-3-(naphthalen-1-yloxy)propan-2-ol] (RS)-5 was synthesized chemically in two step reaction and further its enzymatic kinetic resolution was carried out by using lipase to synthesize enantiomeric forms (R)-5 and S-(6) of propranolol. The kinetic resolution of (RS)-5 involves the transesterification of secondary racemic alcohol in which vinyl acetate is used as acyl donor. Initially, we screened commercially available lipases for kinetic resolution and of all the screened lipases Addzyme 001 showed the best results. The several reaction parameters such as organic solvent, acyl donor, temperature, reaction time and enzyme concentration were optimized to improve rate of reaction and to achieve maximum enantioselectivity. Addzyme 001 at 40 mg shows the maximum conversion rate of 49% using cyclohexane as the organic solvent, vinyl acetate as the acyl donor and it was found that the reaction yield was higher for (R)-5 along with the (S)-6 (eep = 98%, ees = 97%) at 40 °C in 48 h. Further, the treatment of (R)-5 with isopropyl amine resulted into formation of (S)-propranolol eep = 98%, and overall yield 29% independently. To synthesize (R)-propranolol, S-(6) acetate was produced enzymatically and was further deacylated by chemical hydrolysis for the production of (R)-propranolol. This study reports newer approach for synthesis of (R) and (S) propranolol using chemoenzymatic route.