Resolution of rac‐ketoprofen esters by enzymatic reactions in organic media

Abstract

Enzyme-catalyzed reactions in organic media of ruc-ketoprofen esters with different nucleophiles such as alcohols, amines, and water have been studied. Among the parameters optimized are the enzyme, the activated substrate, and the solvent. With the enzymes used in this study the preferred substrate was the trifluoroethyl ester of YUCketoprofen (ruc-2), whose (Rbenantiomer reacted preferentially. The enzyme of choice was the lipase M-AP-10 from Mucor miehei and best results were obtained with diisopropyl ether as solvent. Three different methods have been scaled-up for the resolution of 75-150 g of substrate: transesterification with l-butano1(90% yield of (S)-ketoprofen, 88% ee), transesterification with 2-(2-pyridyl)ethanol (94% yield, 92% ee), and hydrolysis in wet organic solvent (93% yield, 97% ee). Despite the comparable chemical and optical yields obtained with these three methods, the use of 2-(2-pyridyl)ethanol and the hydrolysis allowed a much easier work-up and isolation of the desired (+)-(S)-ketoprofen.o 1993 Wiey-Liss, Inc. KEY WORDS: lipases, amano M-AP-10, transesterification, hydrolysis, aminolysisThe pharmacological properties of racemic compounds are considerably more complex than those of enantiomerically pure substances. It is now widely recognized that the stereochemistry of drugs must be considered in all stages of drug development and that pure enantiomers must be used whenever the pharmacodynamic or pharmacokinetic data so warrant. ' The synthetic chemists are meeting this goal by developing new technologies to obtain optically pure compounds in preparative amounts. 2-Arylpropionic acids are an important classof nonsteroidal antiinflammatory drugs (NSAIDs) which are used in therapeutics as racemic mixtures, with the exception of (+)-(3-naproxen and (+)-(3-flunoxaprofen. However, the pharmacological activity of this class is mainly due to the 6)-enantiomers, their (R)-antipodes being essentially inactive as inhibitors of prostaglandin synthesis.2 Thus, considerable efforts have been made to synthesize pure enantiomers of 2-arylpropionic acids. One described method is the kinetic resolution of 2-arylpropionic acid esters by stereoselective hydrolysis in aqueous media, catalyzed by enzymes (lipases, 3-7 esterases,' or proteases') or by microorganisms. 'u-" In particular, enzymatic hydrolysis has been applied to the resolution of ruc-ketoprofen, one of the most potent and widely used members of this class of drugs.14 These biotransformations have been carried out in aqueous buffer giving the R-or S-acid with low enantiomeric excess. 5*73 To enhance the enantioselectivity of the reaction, a costly and time-consuming purification of the commercial L-1754 Candiaiz cylindraceu lipase is required.7 Recently, it has been shown that many biocatalytic reactions can proceed with high enantioselectivity when carried out i~i organic media. 14, l5 Lipases are stable and active in apolar organic solvents, being able to catalyze reactions of the ester function with several nucleophiles. ' %' ' Thes...

Lipase-catalyzed dynamic resolution of naproxen 2,2,2-trifluoroethyl thioester by hydrolysis in isooctane

“…Considerable efforts are made in relation to the lipase-catalyzed enantioselective resolution of (S)-profens or synthesis of their ester prodrugs by using racemic profens or their ester derivatives as the substrate (Arroyo and Sinisterra, 1994;Chang and Tsai, 1997;Morrone et al, 1995;Mustranta, 1992;Palomer et al, 1993;Sih et al, 1988;Tsai and Wei, 1994;Tsai et al, 1997). However, to the best of our knowledge, there are still no reports on employing profen thioesters as the starting material via a dynamic resolution procedure to improve the yield and optical purity of the desired (S)-profens.…”

Modulation by stereoselective inhibition of cyclo‐oxygenase of electromechanical coupling in the guinea‐pig isolated renal pelvis

“…The (S)-and (R)-enantiomers of ketoprofen were synthesized in the Chemistry Department of Laboratories Menarini by enzymatic resolution of the racemic trifluoroethylester (Palomer et al, 1993). The optical purity was determined by a direct enantiospecific h.p.l.c.…”

“…The optical purity was determined by a direct enantiospecific h.p.l.c. method, using a Chiralcel OJ column (Daicel, Japan), as described previously (Palomer et al, 1993 …”

Stereoselective inhibition of rat brain cyclooxygenase by dexketoprofen

“…The optical purity of both enantiomers, measured by a direct enantiospecific highperformance liquid chromatographic (HPLC) method using a Chiracel-OJ TM column (Daicel Chemical Industries Ltd., Japan) was >99%. 15,16 Bovine serum albumin (BSA) (fatty acid poor), ethylenediaminotetracetic acid (EDTA), epinephrine, reduced glutathione (GSH), arachidonic acid, as well as all of the inorganic salts employed in buffers were obtained from Sigma (St. Louis, MO). Prostaglandin F 2␣ (PGF 2␣ ) was measured by the Prostaglandin F 2␣ -Monoclonal Enzyme Immunoassay Kit from Cayman Chemical Company (Ann Arbor, MI).…”