Date of Award

2010-01-01

Degree Name

Doctor of Philosophy

Department

Chemistry

Advisor(s)

James M. Salvador

Abstract

Ibuprofen is a common Non-Steroidal Anti-Inflammatory Drug (NSAID) sold as a racemic or equal mixture of (R) and (S) mirror-image enantiomers. Without patent protection, ibuprofen is an orphan drug even though one enantiomer, (S)-ibuprofen, provides relief three times faster than its racemic mixture with fewer side effects. The goal of this research was to develop a facile, environmentally benign (no waste of ibuprofen or catalysts), and inexpensive process to convert a commercially available racemic mixture of ibuprofen to the therapeutically active (S)-ibuprofen.

After many attempts, the most successful conversion of racemic ibuprofen to (S)-ibuprofen was the in situ racemization and enantioselective hydrolysis (a dynamic kinetic resolution) of the methyl ester of racemic ibuprofen in the presence of Candida rugosa lipase and 20 % DMSO at pH 9.8. All reactions started with quantitative extraction of ibuprofen from inexpensive commercial pills. Both esters could be quantitatively isolated after Fischer esterification of racemic ibuprofen with the corresponding alcohol.

The kinetics of the dynamic kinetic resolution of the racemic methyl ibuprofen ester to (S)-ibuprofen were fit to a "consecutive reactions with a reversible step" model to give 0.02583 ± 0.0042 and 0.05253 ± 0.00454 h-1 rate constants for the racemization and hydrolysis steps, respectively. The hydrolysis under these conditions was twice as slow as most hydrolyses where no racemization was occurring. After 144 hours, 94 % of racemic ibuprofen by weight was converted to (S)-ibuprofen with an ee of 94 %.

To complete the purification, racemic ibuprofen was crystallized in methanol from the enriched product of the dynamic kinetic resolution to isolate (S)-ibuprofen in a 93.2 % yield and an ee of 99.7 %. Combining the dynamic kinetic resolution and crystallization steps, and considering that isolation of ibuprofen from pills and forming its racemic methyl ester is also quantitative, the overall conversion of (S)-ibuprofen from racemic ibuprofen pills, is 88 %, with the possibility of recovering all other reagents

Language

en

Provenance

Received from ProQuest

File Size

87 pages

File Format

application/pdf

Rights Holder

David Chavez-Flores

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