High-throughput screening applied to drug synthesis process development.

Combinatorial chemistry and high-throughput screening have greatly increased the rate of lead drug molecule discovery. The increase in the number of compounds in the early phase of the drug development pipeline has, however, created a bottleneck in the development of cost-effective, scalable chemical processes for the manufacture of these drug candidates. Thus, pharmaceutical chemical development groups and their suppliers are implementing their own forms of high-throughput screening to improve their productivity to solve this bottleneck. Developments for implementing high-throughput screening for chemical process development are reviewed.

Synthesis and enantiomeric purity determination of chiral 3-benzylglycidol, a key synthon for HIV protease inhibitors.

The detailed synthesis of (2R,3R)-3-benzylglycidol by the Sharpless asymmetric epoxidation route is described. The enantiomeric purity determination of this compound is complicated by the presence of small quantities of the diastereometric (2R,3S)-3-benzylglycidol from the asymmetric epoxidation of the cis-allylic alcohol, and the unreacted allylic alcohols that are not removed in the product isolation steps. We have developed a direct chiral HPLC method that can resolve all these components for the precise determination of enantiomeric excesses of chiral 3-benzylglycidols.