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.
Kiau
Susanne
S
Process Research and Development Department, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, New Jersey 08903-0191, USA. susanne.kiau@bms.com
Discordia
Robert P
RP
Madding
Gary
G
Okuniewicz
Francis J
FJ
Rosso
Victor
V
Venit
John J
JJ