title: Biocatalytic Approach for the Synthesis of Enantiopure Acebutolol as a β₁-Selective Blocker.
abstract: A new chemoenzymatic route is reported to synthesize acebutolol, a selective β1 adrenergic receptor blocking agent in enantiopure (R and S) forms. The enzymatic kinetic resolution strategy was used to synthesize enantiopure intermediates (R)- and (S)-N-(3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl)butyramide from the corresponding racemic alcohols. The results showed that out of eleven commercially available lipase preparations, two enzyme preparations (Lipase A, Candida antarctica, CLEA [CAL CLEA] and Candida rugosa lipase, 62316 [CRL 62316]) act in enantioselective manner. Under optimized conditions the enantiomeric excess of both (R)- and (S)-N-(3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl)butyramide were 99.9 and 96.8%, respectively. N-alkylation of both the (R) and (S) intermediates with isopropylamine gave enantiomerically pure (R and S)- acebutolol with a yield 68 and 72%, respectively. This study suggests a high yielding, easy and environmentally green approach to synthesize enantiopure acebutolol.
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
authors.forename: Linga
authors.initials: L
authors.lastname: Banoth
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
authors.forename: Neeraj Singh
authors.initials: NS
authors.lastname: Thakur
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Bhaumik
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
authors.forename: Uttam Chand
authors.initials: UC
authors.lastname: Banerjee
mesh_terms: D000070:Acebutolol / Q000138:chemical synthesis*; D058671:Adrenergic beta-1 Receptor Antagonists / Q000138:chemical synthesis*; D055162:Biocatalysis; D008954:Models, Biological; D015394:Molecular Structure; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000070:Acebutolol
keywords: enantiopure drug; enantioselectivity; lipase; transesterification; β-blockers