R and S-Ibuprofens

In this case study, an enzymatic hydrolysis reaction, the racemic ibuprofen ester, i.e. (R)-and (S)-ibuprofen esters in equimolar mixture, undergoes a kinetic resolution in a biphasic enzymatic membrane reactor (EMR). In kinetic resolution, the two enantiomers react at different rates lipase originated from Candida rugosa shows a greater stereopreference towards the (S)-enantiomer. The membrane module consisted of multiple bundles of polymeric hydrophilic hollow fibre. The membrane separated the two immiscible phases, i.e. organic in the shell side and aqueous in the lumen. Racemic substrate in the organic phase reacted with immobilised enzyme on the membrane where the hydrolysis reaction took place, and the product (S)-ibuprofen acid was extracted into the aqueous phase. 

Figure 15 Effect of octanoic acid on the retention and enantioselective resolution of (R)- and (S)-ibuprofen on the HSA CSR where 1 = (S)-ibuprofen and 2 = (R)-ibuprofen. A, Without octanoic acid in the mobile phase. B, With 4 wiM octanoic acid added to the mobile phase, [From Noctor et at. (94).]...

R- and S-ibuprofen with human serum albumin,/. Chromatogr. A, 1995, 693, 23-32. 

Knihinicki, R.D. Day, R.O. Williams, K.M. Chiral inversion of 2-arylpro-pionic acid non-steroidal anti-inflammatory drugs— II. Racemization and hydrolysis of (R)- and (S)-ibuprofen-CoA thioesters. Biochem. Pharmacol. 1991, 42, 1905-1911. 

Each of the molecules below (carvone, ibuprofen anc limonene) incorporates a single chiral center. Identify ii and draw both R and S forms of each. 

Roussel [3] prepared chiral polysaccharide esters by grafting a-phenylpro-pionic acid, (R)-, (IV), and (S)-ibuprofen, or (R)- and (S)-naproxen onto cellulose. These agents were then used for isolating optically active acids. 

A later single-dose study in eight patients with moderate to severe cirrhosis and a PT of 2-5 seconds above the npper limit of normal, showed an approximate doubling of the half-life compared to controls. Metabolic inversion of the inactive R-ibuprofen to the active S-ibupro-fen may also be impaired in hepatic cirrhosis, because the AUC ratio of R- to S-ibuprofen was significantly higher in patients with cirrhosis. Medicinal ibuprofen is supplied as a racemic mixture [39]. 

S)-Naproxen, 18, and S-ibuprofen, 19, are important and widely used analgesics with annual sales of about US 1.4 billion and a production volume of about 8000 tons. A technical feasible use of R,R-tartaric acid as chiral auxiliary was demonstrated in the Zambon Process for S-naproxen manufacture [3]. The diastereoselective bromination is followed by bromine hydrogenolysis and hydrolysis to produce S-naproxen in 75 percent overall yield. 

Some 1- and 2-hydroxyalkanephosphonates have been successfully resolved by a CALB (Candida antarctica lipase B)-catalysed acylation process to give both (R)- and (S)-isomers with high enantiomeric excess (in most cases with 95% ee). (S)-Naproxen and (S)-Ibuprofen chloride are convenient chemical derivatizing agents for the determination of the enantiomeric excess of hydroxy and aminophosphonates by PMR. . New phosphorylating agents, 3-phosphoro-2(-N-cyanoimino)-thiazolidine derivatives (3-phosphoro-NCTS) (316), can be used as a stable alternative to phosphorochloridates. Phosphoryla... 

In contrast to drugs from natural sources, those drugs that are made entirely in the laboratory are either achiral or, if chiral, are often produced and sold as racemic mixtures. Ibuprofen, for example, contains one chirality center, and only the S enantiomer is active as an analgesic and anti-inflammatory agent. The R enantiomer of ibuprofen is inactive, although it is slowly converted in the body to the active S form. Nevertheless, the substance marketed under such trade names as Advil, Nuprin, and Motrin is a racemic mixture of R and S. 

Goals . Resolve S-ibuprofen-S-lysine from a pair of diastereomeric salts of R-ibuprofen-S-lysine and S-ibuprofen-S-lysine... 

Resolution via crystallization is an important method for the synthesis of pure optical isomers on an industrial scale. In the development of a process for the resolution of racemic ibuprofen, S-lysine is used as the resolving agent to accomplish this task. As shown in Fig. 7-22, R/S-ibuprofen reacts with S-lysine to form a pair of diastereomeric salts of R-ibuprofen-S-lysine and S-ibuprofen-S-lysine, and S-ibuprofen-S-lysine is separated via stereospecific crystallization. 

D. S. Hage, T. A. G. Noctor and I. W. Wainer, Characterization of the protein binding of chiral drugs by high-performance affinity chromatography, interaction of R- and 5-ibuprofen with human serum albumin,/. Chromatogr., A, 1995, 693, 23-32. 

The functions of chiral drugs in human body are closely related to their configurations. It has been reported that the R- and S-isomers of ibuprofen have quite different biological activities and toxicides. So it is imperative to prepare enan-tiomerically pure ibuprofen. Song el al. conducted a study on the lipase-catalyzed esterification of racemic ibuprofen with octanol in AOT reverse micelles [108,109] and found that the esterification is enantioselective and the main product is the corresponding S (-H)-ibuprofen ester, with the conversion yield and the enantiomer excess being about 36% and 0.9732, respectively. The water content and the concentration of AOT in the medium affected the conversion yield, but they had little influence on the enantiomeric excess (Table 15.7). Also, it was found that the chain lengths of alcohols affected both the rate of the reaction and the enantiomeric excess of the products. 

Ibuprofen is an analgesic sold under various names including Advil, Motrin, and Nuprin. The material is sole as a racemic mixture, but only one enantiomer acts as ar analgesic. The other enantiomer is inactive. Assign R oi S forms to the two enantiomers of ibuprofen. 

With a BINAP-Ru [3d,104], Hg-BINAP-Ru [102], or P-Phos-Ru [25] catalyst, the anti-inflammatory drugs (S)-ibuprofen and (S)-naproxen could be efficiently synthesized via enantioselective hydrogenation (Scheme 26.9). In these cases, high hydrogenation pressure and low temperature are required to achieve good enantioselectivity. With an (R)-BIPHEMP-Ru catalyst, (S)-2-(4-fluorophenyl)-3-methylbutanoic acid, a key intermediate for the synthesis of the calcium antago-... 

Tixier C., H.P. Singer, S. OUers, and S.R. Muller (2003). Occurrence and fate of carbamaze-pine, clorolibric acid, diclofenac, ibuprofen, ketoprofen, and naproxen in surface water. Environmental Science and Technology 37 1061-1068. 

Specifically, as the IRF flow rate was increased, the transport of (R,S)-ibuprofen from the ILF to the receiving phase decreased. In both the feeding and receiving phases, the transport ratio of (S)-ibuprofen was calculated to... 

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