Biocatalytic Approach for the Synthesis of Enantiopure Acebutolol as a β 1 ‐Selective Blocker

• Published in: Chirality
• Main Authors: Banoth, Linga, Thakur, Neeraj Singh, Bhaumik, Jayeeta, Banerjee, Uttam Chand
• Other Authors: Department of Biotechnology , Ministry of Science and Technology
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2015
• Subjects: Organic Chemistry; Spectroscopy; Drug Discovery; Pharmacology; Catalysis; Analytical Chemistry; Antarc*; Antarctica
• Online Access: http://dx.doi.org/10.1002/chir.22444; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fchir.22444; https://onlinelibrary.wiley.com/doi/pdf/10.1002/chir.22444

Abstract A new chemoenzymatic route is reported to synthesize acebutolol, a selective β 1 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. Chirality 27:382–391, 2015. © 2015 Wiley Periodicals, Inc.