A 21st century HPLC workflow for process R&D.

A unique high-performance liquid chromatographic (HPLC) workflow specifically designed for the rigors of process development has been developed. A key feature of the workflow is the creation of an HPLC software-hardware platform designed to automatically and systematically screen samples using a matrix of columns and eluents to aggressively search for impurities. The workflow platform was assembled from commercial hardware components and both custom and commercial HPLC software. The platform can be used to challenge existing HPLC methods or to develop new methods. Three real world examples are provided to illustrate the utility of the platform to rigorously assess the complexity of samples and to develop new and improved HPLC methods.

Crystallization-induced chiral inversion as the key step for synthesis of (S)-2-acetylthio-3-phenylpropanoic acid from l-phenylalanine.

[reaction: see text] A novel crystallization-induced chiral inversion of (S)-2-bromo-3-phenylpropanoic acid to its (R)-enantiomer with excellent enantiomeric excess (96-99%) is achieved. Optically pure (S)-2-acetylthio-3-phenylpropanoic acid can be prepared in good yield from inexpensive and commercially available l-phenylalanine via diazotization/bromination, chiral inversion, and thioacetate substitution reactions.

Efficient crystallization-induced dynamic resolution of alpha-substituted carboxylic acids.

Herein we present a novel route to enantiomerically enriched chiral alpha-substituted carboxylic acids by crystallization-induced dynamic resolution (CIDR) of their diastereomeric salts with chiral amines. Thus, the racemic alpha-bromo acid 3 is converted reliably with (1R,2S)-2-amino-1,2-diphenylethanol in the presence of a catalytic amount of tetrabutylammonium bromide into its R-enantiomer 4 in 90% yield with 88% ee. Similarly, the racemic alpha-thiobenzoyl acid 5 could be resolved to 90% ee in 74% yield. Further enrichment to enantiomeric homogeneity could be achieved in both cases by crystallization. In a telescoped, two-step process, S-alpha-thiobenzoyl acid 6 (>or=99.6% ee) was prepared from the racemic bromide 3 in 63% yield. State-of-the-art parallel experimentation enabled rapid screening for suitable dynamic resolution conditions. Kinetic studies defined the influence of temperature, tetrabutylammonium bromide concentration, molarity, and solvent polarity on the resolution rate, product yield, and enantiomeric excess.