Expanding Access to Optically Active Non-Steroidal Anti-Inflammatory Drugs via Lipase-Catalyzed KR of Racemic Acids Using Trialkyl Orthoesters as Irreversible Alkoxy Group Donors

Abstract

Studies into the enzymatic kinetic resolution (EKR) of 2-arylpropanoic acids (‘profens’), as the active pharmaceutical ingredients (APIs) of blockbuster non-steroidal anti-inflammatory drugs (NSAIDs), by using various trialkyl orthoesters as irreversible alkoxy group donors in organic media, were performed. The enzymatic reactions of target substrates were optimized using several different immobilized preparations of lipase type B from the yeast Candida antarctica (CAL-B). The influence of crucial parameters, including the type of enzyme and alkoxy agent, as well as the nature of the organic co-solvent and time of the process on the conversion and enantioselectivity of the enzymatic kinetic resolution, is described. The optimal EKR procedure for the racemic profens consisted of a Novozym 435-STREM lipase preparation suspended in a mixture of 3 equiv of trimethyl or triethyl orthoacetate as alkoxy donor and toluene or n-hexane as co-solvent, depending on the employed racemic NSAIDs. The reported biocatalytic system provided optically active products with moderate-to-good enantioselectivity upon esterification lasting for 7–48 h, with most promising results in terms of enantiomeric purity of the pharmacologically active enantiomers of title APIs obtained on the analytical scale for: (S)-flurbiprofen (97% ee), (S)-ibuprofen (91% ee), (S)-ketoprofen (69% ee), and (S)-naproxen (63% ee), respectively. In turn, the employment of optimal conditions on a preparative-scale enabled us to obtain the (S)-enantiomers of: flurbiprofen in 28% yield and 97% ee, ibuprofen in 45% yield and 56% ee, (S)-ketoprofen in 23% yield and 69% ee, and naproxen in 42% yield and 57% ee, respectively. The devised method turned out to be inefficient toward racemic etodolac regardless of the lipase and alkoxy group donor used, proving that it is unsuitable for carboxylic acids possessing tertiary chiral centers.

A New Approach in Lipase-Octyl-Agarose Biocatalysis of 2-Arylpropionic Acid Derivatives

“…The CALB has also been utilized in the kinetic resolution of other non-steroidal anti-inflammatory drugs (NSAIDs). Zdun et al [23] obtained pure (S)-naproxen, which demonstrates ca. 28-fold stronger effect than (R)-naproxen, using the reaction catalyzed by this lipase.…”

On the Use of Orthoformates as an Efficient Approach to Enhance the Enzymatic Enantioselective Synthesis of (S)-Ibuprofen

“…Notably, ibuprofen (Code DB01050 inside DrugBank [11]) has been one of the drugs involved in what is known as the chiral switch, the replacement (either partial or complete) of a chiral drug used in the form of a racemate with its eutomer [12]; for this drug, it is possible to find in the pharmaceutical market, both its racemic and enantiopure version, this later one (named dexibuprofen; DrugBank Code DB09213) is commercialized as Seractil ® , DexOprifen ® , Deltaran ® , Ibusoft ® or Monactil ® . Thus, the relevancy of the pharmacological uses of the (S)-(+)-enantiomer [13] and the higher cost associated with its preparation, compared to racemate, are the driving forces for the considerable efforts that have been made for obtaining enantiopure (S)-profens, being the employ of biocatalysed protocols as one of the preferred options [14][15][16](see also the recent article by Zdun et al [17] and references cited therein illustrating different methodologies).…”

“…of biocatalysed protocols as one of the preferred options [14][15][16](see also the recent article by Zdun et al [17] and references cited therein illustrating different methodologies).…”

Intensification of Double Kinetic Resolution of Chiral Amines and Alcohols via Chemoselective Formation of a Carbonate–Enzyme Intermediate

“…Thus, it is crucial to have access to both enantiomers of chiral compounds. Nevertheless, the predominant method of accessing enantiomerically pure compounds is the kinetic resolution (KR) of racemates promoted by enantioselective enzymes such as lipases, which are able to catalyze acyl transfer reactions [ 3 , 4 , 5 , 6 , 7 ]. To increase reaction yields, DKR (dynamic kinetic resolution) was developed; however, the product configuration is limited by the selectivity of the enzyme.…”