Approaches for multi-gram scale isolation of enantiomers for drug discovery

ABSTRACT

Introduction: Over the last 30 years, the scientific community has directed its efforts towards the identification of enantioselective approaches to obtain the desired active enantiomer. Accordingly, efficient production of single enantiomers from small to large scale, throughout Drug Discovery (DD) programs, has become of great interest and a fundamental challenge.

Areas covered: This review focuses on two fundamental strategies for preparing enantiomers in high yields and with an excellent enantiomeric excess (ee). Separation of racemates, enantioselective synthesis procedures, and integrated approaches have been extensively reviewed, to offer a guide that enables the selection of the suitable methodology for producing pure enantiomers in scales from small to large.

Expert opinion: Over the past two decades, drug regulatory agencies have set strict rules on the use of racemates and pure enantiomers, leading to the transformation of the drug market. Indeed, the number of drugs approved as a single enantiomer has exponentially increased, outclassing the racemic compounds. As a consequence, the academia and pharmaceutical companies are eager to develop efficient procedures for obtaining enantiopure compounds on the desired scale.

KEYWORDS:

• Enantiomers
• separation of racemates
• enantioselective synthesis
• multi grams-scale

Article highlights

• The demand for enantiopure drugs has led, during the last decades, to the widespread need of enantiopure compounds, deeply affecting the drug discovery (DD) process in all its phases.

• Different techniques can be exploited to obtain enantiopure compounds, and an accurate evaluation of advantages and limitations of each procedure is essential.

• Two main approaches are usually adopted: either separation of enantiomers (which involves different techniques such as enantioselective chromatography over chiral stationary phases and crystallization) or enantioselective synthesis (which includes chiral pool synthesis, enantioselective catalysis and biocatalysis).

• Depending on DD stage (from hit identification to early development), enantiomeric purity required, synthetic feasibility, environmental impact and economic budget, the best amongst the reported approaches should be identified.

• Sometimes, using only one technique could result in unsatisfactory results in terms of purity, productivity or scalability. In these cases, integrated approaches are crucial: combining two or more of the described techniques could significantly improve the overall efficiency

This box summarizes key points contained in the article.

Acknowledgment

The Authors are grateful to Professor Richard Kellogg of Syncom, the Netherlands for his scientific support.

Declaration of interest

M Juza is an employee of Corden Pharma Switzerland LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.