Drug Development Through the Looking Glass

By Angelo De Palma, Ph.D., Contributing Editor If no difference is noted between racemate and pure isomer, fine. In cases where the single enantiomer is more toxic, sponsors must determine why and consider the “implications for human dosing.” Finally, where little difference is observed in activity of the enantiomers — by far the most likely circumstance — then racemates may be safely developed with FDA’s blessing. In the old days there were only three ways to obtain chiral compounds: Although modern pharmacopoeias still include natural products and their simple analogs, medicinal chemists rely on these compounds mostly as starting materials or building blocks. Amino acids, sugars, terpenes and vitamin C often serve as simple starting points for a host of complex chiral intermediates. More detailed chiral structures rely on semi-synthesis. The two best-known examples are Taxol, which is manufactured in four steps from a compound isolated from the English yew, and desogestrel, the steroid contraceptive whose starting material is isolated from dioscorea root and converted, through ten chemical steps, into the drug. But with each new chiral process, it seems that manufacturers must reinvent the wheel. ?Although many synthetic tools are available for introducing chirality in the laboratory, the challenge is to perform these reactions on industrial scale,? says Ronald Gebhard, Ph.D., R&D director at DSM Pharma Chemicals (Geleen, Netherlands). When asymmetric synthesis is impractical at large scale, manufacturers fall back on classical and enzymatic resolutions, which are inherently wasteful since each pass theoretically yields just 50% of the desired product. Unless the undesired isomer can be recycled through re-racemization, it must be discarded as waste, along with spent resolving reagents and solvent. Much effort has therefore been devoted to developing dynamic resolutions which provide high chemical yield and an ee approaching 100%. These work by cycling the unwanted product through