Ibuprofen isomers

The individual events are summarized in Fig. (4). Since the decrease of the molecular mass of HA is the prime effect of the action of HO radicals, while functional groups are retained, methods enabling determination of the molecular mass were primarily applied in order to study the HO radical-induced depolymerization of HA. For instance, Soltes and coworkers used viscosimetry in order to study the effects of H2O2 and Cu " on HA solutions [242] as well as to study the inhibitory ("scavenging") effect of the ibuprofen isomers (ibuprofen is an anti-inflammatory drug). 

Chemical reactions are used in separation processes for selective removal of components. Liquid reactive extraction and reactive distillation are examples. The solubility of reactants in supercritical gases makes available a tool to remove products from the reaction mixture. Reaction equilibrium can be shifted, and at even relatively small yields, a total conversion of educts can be achieved. Among the most selective catalysts are enzymes. These biocatalysts can selectively catalyze the reaction of one isomer. It has been shown that some enzymes are stable at high pressures and in carbon dioxide atmosphere [19]. If the reaction is carried out in a supercritical gas atmosphere and the product is soluble in the supercritical gas, a separation of the isomers is possible. As an example the separation of ibuprofen isomers will be discussed. 

Most of the vanillic acid was reduced by E. coli containing Car in 2 h to vanillin (80 %) and vanillyl alcohol (20 %). Car does not reduce aldehydes to alcohols. However, E. coli s endogenous aldehyde reductase/dehydrogenase reduces vanillin to vanillyl alcohol. The broad substrate specificity of Car enables the wide application of this biocatalyst to other important applications, such as enantiomeric resolution of isomers such as ibuprofen and the reductions of many other natural and synthetic carboxylic acids. 

Ibuprofen is an interesting case, in that the (5)-(+)-form is an active analgesic, but the ( )-(—)-enantiomer is inactive. However, in the body there is some metabolic conversion of the inactive (I )-isomer into the active (5 )-isomer, so that the potential activity from the racemate is considerably more than 50%. Box 10.11 shows a mechanism to account for this isomerism. 

Other similar lipase/esterase resolution processes have been developed such as the use of Bacillus that esterase to produce the substituted propanoic acids that are precursors of non-steroidal anti-inflammatory drags, snch as naproxen and ibuprofen etc., and the formation of chiral amines by Celgene. Other methods start from prochiral precursors and have the advantage that enantioselective synthesis allows the production of particular isomers in yields approaching 100%, rather than the 50% yields characteristic of resolution processes. For instance Hoechst have patented the production of enantiomers using Pseudomonas fluorescens lipase to either acylate diols or hydrolyse diacetate esters. 

The enzymatic enantioselective hydrolysis of esters of naproxen and ibuprofen has attracted considerable attention because the (S)-enantiomers of these nonsteroidal anti-inflammatory drugs (NSAIDs) are the pharmacologically active isomers. These reactions have been successfully performed in a range of ionic liquids (Figure 10.10) [60, 65, 121]. 

Manufacture of optically pure (5)-(+)-ibuprofen (13), an NSAID similar to naproxen, is another example demonstrating the role of resolution in production of chiral fine chemicals, although from a somewhat different angle. Unlike naproxen, ibuprofen (14) was introduced to the market as a racemate almost 30 years ago.30 31 At the time of the introduction, it was thought that both R- and 5-isomers of ibuprofen had the same in vivo activity.32 It has been demonstrated that the R-isomer is converted to the 5-isomer in vivo29 by a unique enzyme system called invertase.34 Based on these data, ibuprofen has since been marketed as a racemate and has achieved sales of more than a billion... 

Amides of (S)-lactic acid have been used as chiral auxiliaries in the dynamic kinetic resolution of racemic ibuprofen (Scheme 23.9).56 The therapeutically effective (S)-isomer 33 was obtained in 80% yield, with complete recovery of the pyrrolidine-derived (S)-lactamide auxiliary 34. 

Concentration of the Organic Solvent in the Eluent. As in other reversed-phase systems, the solute retention curves (log k vs. % organic modifier) on cyclodextrin-silicas are quasi-linear, at least over a limited concentration range. Such curves are shown in Figs. 2-4 for the positional isomers of nitrophenol (Fig. 2) and chloroaniline (Fig.3), and the enantiomers of Ibuprofen (Fig.4). Similar retention curves were observed and published for other positional iscmers (67), cis/trans isomers (68) and enantiomers (69). ... 

Aromatic phenols and alcohols were also found to act as good displacers on cyclodextrin-silica columns (67,69). Since the retention studies discussed above indicate that p-nitrophenol is more retained (Fig. 2) than the chloroaniline isomers (Fig. 3), and 4-t-butyl cyclohexanol is more retained than the Ibuprofen enantiomers (Fig. 4), p-nitrophenol and 4-t-butylcyclohexanol were selected as possible displacers for the separations discussed below. 

The ultimate goal in most industrial research is to develop economically attractive processes or products. The technology of asymmetric hydrogenation of 2-arylacrylic acids is probably most useful for the production of naproxen and S-ibuprofen. Naproxen is currently one of the top ten prescription drugs in the world S-ibuprofen is the active isomer in the popular anti-inflammatory drug ibuprofen. Figures 5 and 6 summarize two commercially feasible processes for the manufacturing of these products. 

Ibuprofen, the anti-inflammatory (see Figure 2.19 for its structure), has two isomers but, cleverly, our bodies metabolize the inactive isomer to the active one so a simple mixture of the two forms is sold over the counter. Can you spot the asymmetric carbon atom ... 

A commercial synthesis (Albemarle) of naproxen (a 2-aryl propionic acid anti-inflammatory related to ibuprofen) involves palladium catalyzed hydroxycarbonylation of an aryl olefin which is itself made in a palladium catalyzed Heck coupling reaction (Figure 6b). Resolution is needed to obtain the (5)-enantiomer of naproxen since its optical isomer is a liver toxin. 

How differences in the three-dimensional structure of starch and cellulose affect their shape and function (Section 5.1) The three-dimensional structure of thalidomide, the anti-nausea dmg that caused catastrophic birth defects (Section 5.5) How mirror image isomers can have drastically different properties— the analgesic ibuprofen, the antidepressant fluoxetine, and the anti-inflammatory agent naproxen (Section 5.13)... 

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... 

For the clinical pharmacologist, neither of these racemic drug mixtures is problematic for drug therapy in the clinic if a pharmacodynamic endpoint (e.g., decrease in blood pressure with propranolol or improvement in arthritic pain with ibuprofen) is used to establish drug dose. However, to effectively characterize the pharmacokinetics of the active isomer, an endeavor that may be useful during drug development, administration, and/or specific determination of the active isomer is required. Such data... 

S. S. Adams, F. Bresloff, and G. G. Mason, "Pharmacological difference between the optical isomers of ibuprofen Evidence for the metabolic inversion of the (-) isomer," /. Pharm. Pharmacol, 28 256-257 (1976). 

Parameter Isomer Warfarin Ibuprofen Disopyramide PropranoF Verapamil ... 

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