期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 98, 期 5, 页码 1804-1812出版社
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.21540
关键词
beta-dicarbonyl carbon acids; dehydroxymethylation; carbon-carbon bond break; pH-rate profile; pK(a)
资金
- Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS
The kinetics of conversion of C-hydroxymethyl derivatives of pharmaceutically relevant beta-dicarbonyl carbon acids of two series, pyrazolidin-3,5-diones and inden-1,3-diones, and a model carbon acid back to the respective carbon acids were studied as a function of pH at 25 degrees C and an ionic strength of 0.15 M. This is a somewhat surprising reaction since it involves the facile breakdown of a carbon-carbon bond. The slopes of the pH-rate profiles for the dehydroxymethylation were approximately unity, which along with the lack of buffer catalysis, indicates a specific-base mechanism involving spontaneous breakdown of the oxymethyl anion. This breakdown generates the conjugate base of the respective carbon acids. Thus within a series, there exists a correlation between the second-order rate constant for dehydroxymethylation and the pK(a) of the corresponding carbon acid with a shorter conversion/dehydroxymethylation half-life (at all given pH values) with decreasing pK(a) of the parent carbon acid. The increasing acidity of the carbon acid affords an increase in the leaving group ability of the carbanion, and therefore facilitation of the rate-determining unimolecular carbon-carbon bond cleavage. Since the hydroxymethyl derivative is an intermediate in the bioconversion of C-phosphoryloxymethyl prodrugs of carbon acids, also under study, the relationship allows one to reasonably predict how facile the dehydroxymethylation would be for any new beta-dicarbonyl carbon acid. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1804-1812, 2009
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