Conversion of Racemic Profens to (S)-Profens

Conversion of Racemic Profens to (S)-Profens

Saideh Mortazavi, Chemistry Doctoral Student

Abstract

Some non-steroidal anti-inflammatory drugs (NSAIDs) such as profens (ibuprofen, naproxen, fenoprofen, ketoprofen, or flurbiprofen) can exist and are sold worldwide as a mixture of mirror image compounds called enantiomers (a racemic mixture) where one mirror image has the desired pain, fever, and inflammation reducing effects (referred to as (S)-enantiomer) and the other undesired mirror image (referred to as (R)-enantiomer) does not or may even have harmful side effects.  Thus the efficacy of profen drugs can be improved and side effects reduced by isolating and administering only the desired (S)-profen as opposed to consuming its racemic mixture, (R) and (S)-profens.  In addition, the manufacture of pure single enantiomer pharmaceuticals is a multibillion dollar a year industry and is now required by the Food and Drug Administration (FDA).

Whereas previous methods wasted the undesired profen enantiomer, (R)-profens, we propose to convert several examples to the desired mirror image drug, (S)-profens, using a combination of relatively inexpensive chemical and enzymatic methods. 

The Candida rugosa lipase catalyzed Dynamic Kinetic Resolution of racemic ibuprofen methyl ester was optimized to produce (S)-ibuprofen in 3 days.  The best concentration of various buffers for these reactions was found to be 0.5 M at optimal pH.  The commercial lipase mixture was found to be acidic.  Dimethylformamide was determined to be a better co-solvent to maintain the reaction pH than dimethylsulfoxide, with evidence of the latter functioning as an oxidizing agent.  Lower concentrations of ibuprofen methyl ester and higher stirring rates both led to faster conversions.  The minimal amount of lipase needed was determined to be 20 mg/ml buffer.  Reaction of (R)-ibuprofen methyl ester under the optimized conditions excluding the lipase led to no racemization indicating that conversion of (R)-ibuprofen methyl ester to (S)-ibuprofen is not catalyzed by the base.