Factors screening to statistical experimental design of racemic atenolol kinetic resolution via transesterification reaction in organic solvent using free Pseudomonas fluorescens lipase

Abstract

As the (R)‐enantiomer of racemic atenolol has no β‐blocking activity and no lack of side effects, switching from the racemate to the (S)‐atenolol is more favorable. Transesterification of racemic atenolol using free enzymes investigated as a resource to resolve the racemate via this method is limited. Screenings of enzyme, medium, and acetyl donor were conducted first to give Pseudomonas fluorescens lipase, tetrahydrofuran, and vinyl acetate. A statistical design of the experiment was then developed using Central Composite Design on some operational factors, which resulted in the conversions of 11.70–61.91% and substrate enantiomeric excess (ee) of 7.31–100%. The quadratic models are acceptable with R2 of 95.13% (conversion) and 89.63% (ee). The predicted values match the observed values reasonably well. Temperature, agitation speed, and substrate molar ratio factor have low effects on conversion and ee, but enzyme loading affects the responses highly. The interaction of temperature–agitation speed and temperature–substrate molar ratio show significant effects on conversion, while temperature–agitation speed, temperature–substrate molar ratio, and agitation speed–substrate molar ratio affect ee highly. Optimum conditions for the use of Pseudomonas fluorescens lipase, tetrahydrofuran, and vinyl acetate were found at 45°C, 175 rpm, 2000 U, and 1:3.6 substrate molar ratio.

Simulation and optimization of Novozym 40086 kinetic resolution of α‐cyclopentylphenylacetic acid enantiomers

“…Over the past decades, a series of low‐cost and green resolution methods have been developed for obtaining single enantiomers . Enzymatic kinetic resolution of racemates is a promising technique to produce enantiomerically pure compounds, which relies on the difference in reaction rates of enantiomers in the presence of a chiral reagent . So far, lipase has been found to be one of the most popular biocatalysts compared to other enzymes due to its characteristics of high enantioselectivity, mild reaction conditions and few side reactions .…”

Lipase‐catalyzed hydrolysis of (R,S)‐2,3‐diphenylpropionic methyl ester enhanced by hydroxypropyl‐β‐cyclodextrin

“…In spite of the advances in asymmetric synthesis of pure enantiomer, the dominant chiral preparation process in industrial applications is still the racemic resolution method. The resolution methods for racemic drugs, such as crystallization, 6,7 capillary electrophoresis, 8,9 chromatography, 10,11 membrane separation, [12][13][14][15] enantioselective liquid-liquid extraction, [16][17][18] and enzymatic kinetic resolution [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] have been developed. Enzymatic kinetic resolution reaction can be used in esterification, 20,21 transesterification, [22][23][24][25] hydrolysis, [26][27][28][29][30][31][32][33] and so forth.…”

Fast liquid chromatography for racemic atenolol acetate separation—The analytical protocol

“…Assymetric syntheses of the ( S )‐atenolol were conducted using chiral or achiral raw materials, which required the chiral catalysts or addendums such as ( R , R )‐Co‐(salen) complexes, ( R )‐ or ( S )‐epichlorohydrin being present during the syntheses . Enzymatic resolutions of the racemic compound by immobilized lipases were developed via enantioselective esterification or and hydrolysis . Kinetic resolutions of the ( R , S )‐atenolol to give the ( S )‐atenolol could be done microbially using Rhizopus arrhizus or Geothricum candidum ; however, the ( R , S )‐atenolol acetate was used as well to give the single enantiomeric atenolol .…”

“…[4][5][6][7][8][9][10] Enzymatic resolutions of the racemic compound by immobilized lipases were developed via enantioselective esterification or and hydrolysis. [11][12][13][14][15] Kinetic resolutions of the (R,S)-atenolol to give the (S)-atenolol could be done microbially using Rhizopus arrhizus or Geothricum candidum; however, the (R,S)-atenolol acetate was used as well to give the single enantiomeric atenolol. 11 Since the racemic atenolol acetate could develop the single enantiomeric compound, it is important to estimate both enantiomers' concentration during the resolution processes.…”