Synthesis of Enantiopure (S)-Atenolol by Utilization of Lipase-Catalyzed Kinetic Resolution of a Key Intermediate

Abstract

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% enantiomeric excess (ee) with the use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. A catalytic amount of base was used in deprotonation of the phenol building block. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination to yield the final drug. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles. The overall yield of (S)-atenolol was 9.9%, which will be further optimized.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents

“…Most of these methods rely on the use of toxic or expensive unusual catalysts [ 9 , 10 , 11 , 12 , 13 ], Volatile Organic Compound (VOC)-based harmful solvents [ 9 , 10 , 11 , 12 ], as well as high reaction temperatures [ 14 ], harsh reaction conditions, long reaction times [ 15 ], and solubility issues [ 16 ], which can hamper the efficiency and scalability of the synthesis. Various strategies have been proposed for the enzymatic kinetic resolution of racemic atenolol, as well as for the enantioselective synthesis of the ( S )-enantiomer to which the maximum 1-blocking activity is attributed [ 17 , 18 , 19 , 20 , 21 ]. Although the efficient methods that lead to the formation of enantiomerically pure ( S )-atenolol can be of interest to the pharmaceutical industry and academia, the proposed routes use multistep procedures with a low overall yield, thus not aligning with the current environmental challenges [ 17 , 18 , 19 ].…”

“…Various strategies have been proposed for the enzymatic kinetic resolution of racemic atenolol, as well as for the enantioselective synthesis of the ( S )-enantiomer to which the maximum 1-blocking activity is attributed [ 17 , 18 , 19 , 20 , 21 ]. Although the efficient methods that lead to the formation of enantiomerically pure ( S )-atenolol can be of interest to the pharmaceutical industry and academia, the proposed routes use multistep procedures with a low overall yield, thus not aligning with the current environmental challenges [ 17 , 18 , 19 ]. A recent approach suggests the use of glycerol as an eco-friendly reaction medium for the last step in atenolol synthesis [ 22 , 23 ].…”