Preparative resolution of etodolac enantiomers by preferential crystallization method

Abstract

Pure enantiomers are of large interest for several industries. This study was aimed to establish a method for separation of etodolac enantiomers by preferential crystallization after a conglomerate formation of its derivatives. S-(+)-etodolac and R-(-)-etodolac enantiomers were both prepared by classical resolution via crystallization of diastereoisomeric salt with (-)-brucine and (-)-cinchonidine. Enantiomeric purity of etodolac was determined by HPLC method using Chiralcel OD-H column. The pure diastereomeric salt collected from repeated recrystallization was further fractionated by liquid-liquid extraction to pure enantiomers. Etodolac enantiomers were recovered with overall yield more than 20% and the purities were over 99.9%.

Advances and applications of chiral resolution in pharmaceutical field

“…The preferential crystallization process is simple, low cost and high efficiency, which makes it an ideal mass separation method. As a consequence, preferential crystallization is widely used in industrial production of chiral drugs, for example, milnacipran for the treatment of major depressive disorders, 86 N-Methylephedrine (potential central nervous stimulant drugs), 87 Etodolac enantiomers, 88 and Albuterol (β2-adrenoceptor agonist prescribed for the treatment of bronchial asthma). 89 F I G U R E 3 Techniques of preferential crystallization [77][78][79][80][81]…”

Synthesis of Single‐enantiomer Bioactive Molecules: A Brief Overview

“…7). 75 The CSPs liquid chromatographic methods have been extensively used in the separation of drugs, organic building blocks and biologically active molecules. The α-amino acid esters as benzophenone Schiff derivatives on coated CSPs (Chiralcel OD-H, Chiralcel OD, Chiralpak AD-H, Chiralpak AD and Chiralpak AS) or covalently immobilized CSPs (Chiralpak IA, Chiralpak IB and Chiralpak IC) derived from polysaccharide derivatives has been conveniently described by Huang et al 76 The benzophenone imine derivatives of α-amino acid esters were prepared by stirring benzophenone imine and the hydrochloride salts of α-amino acid esters in 2-propanol.…”

Principles, Concepts and Strategies of Stereoselective Synthesis

“…96 Using this method, etodolac enantiomers were recovered with an overall yield of more than 20% and the purities were greater than 99.9%. Methods for the separation of enantiomers during crystallization are discussed in chapter 56 in more detail.…”