Single-enantiomer drugs

Gattuso M. J., McCulloch B., House D. W., Baumann W. M., Gottschall K. (1996) Simulated Moving Bed Technology - The Preparation of Single Enantiomer Drugs, Pharm. Tech. Europe 8 20-25. 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

TABLE 2 Sales (U.S., Millions) of Enantiomeric Intermediates and Single Enantiomer Drugs... 

Valsartan (Diovan, 13.35), a medication for high blood pressure, is a single enantiomer drug. The stereocenter in valsartan is derived from L-valine (13.33) and incorporated early in the synthesis by a simple SN2 alkylation (Scheme 13.5).15... 

The trend in the last couple of decades has been toward the use of single enantiomer drugs over drugs for which it is possible to have a racemic mixture of both enantiomers. 

The top ten best-selling single enantiomer drugs in 1996 are given in Table 31.1.1 Because we are only concerned with small molecules, peptide products such as insulin and erythropoietin have been ignored because they are outside of the realms of chemical approaches. 

Top Ten Best-Selling Single Enantiomer Drugs in 1996a ... 

Sales of single enantiomer drugs exceeded 159 billion in 2002. Some of these come from biological sources, but the majority are synthetic. For this reason, the development of synthetic methods that produce only a single enantiomer of chiral compounds is a very active research area in both academic and pharmaceutical research labs. Chiral or asymmetric syntheses, which produce only the desired enantiomer, are much preferred over resolution processes, in which at least half of the initial compound is discarded. 

Chiral Pharmaceutical Intermediates. The use of biocatalysis for producing chirally pure pharmaceuticals is now an accepted technology that complements alternative chemical and physical methods.23 The size of the current world market for single enantiomer drugs, over 150 billion in 2002, offers plenty of incentive to develop competitive biocatalytic routes for key intermediates. The market for chiral intermediates themselves, although far smaller, is still considerable at over 7 billion... 

TABLE 16.1. Importance of Single Enantiomer Drugs Approved Worldwide in 1994—1998... 

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