2-aryl propionic acids

It is by now apparent that the nature of the aryl group in the aryl acetic and aryl propionic acid antiinflammatory agents can be varied quite widely without loss of activity. The corresponding derivatives of homologous xanthones and thioxanthones thus both show activity as nonsteroid antiinflammatory agents. 

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Francois, Y, Varenne, A., Juillerat, E., Servais, A.-C., Chiap, R, and Gareil, R., Nonaqueous capillary electrophoretic behavior of 2-aryl propionic acids in the presence of an achiral ionic liquid A chemometric approach, /. Chromatogr. A,... 

Aryl propionic acid non-steroidal anti-inflammatory HSA 45... 

An important example is the resolution of the enantiomers of naproxen. Naproxen is a member of a family of compounds known as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) which are 2-aryl propionic acids. This class also includes ibuprofen, the painkiller developed by Boots and marketed as Nurofen. 

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. 

In addition to aryl carboxylic acids, including profens (2-aryl propionic acid NS AIDs) (see Fig. 9.36) [393,398], the terguride-based CSP has shown the potential to re.solve the enantiomers of 2-aryloxypropionic acids [394] and of A-dansyl, A-3,5-dinitrobenzoyl, A-benzoyl, A-P-naphthoyl amino acid derivatives [395]. 

Fig. 9.36. Enantioscparation of a-aryl propionic acids on 1-allyl-tcrguride-ba.scd WAX type CSP (a) fenoprofen. (b) flobufen. (c) naproxen, and (d) ketoprofen. Exp. cond., 20 mM potassium acetate (pH 3.6)-ttcetonitrile (50 50, v/v( How rate. I.O ml/min detectum. 255 nm (reprinted with permission from Ref. 1.3971).

The palladium-catalyzed coupling of silyl ketene acetals with aryl bromides in the presence of TlOAc has been applied to the asymmetric synthesis of 2-aryl-propionic acids (40—50% ee) by the use of BPPFA and several other chiral phosphine ligands (Scheme 2-16) [35]. 

Aryl propionic acid nonsteroidal antiinflammatory drugs. The compounds from this class of agents that have been stereochemically resolved include ibuprofen, flurbiprofen, naproxen, benoxaprofen, pirprofen, su-profen, fenoprofen, indoprofen, and ketoprofen (94). 

T. A. G. Noctor, G. F61ix, and I. W. Warner, Stereochemical resolution of enantiomeric 2-aryl propionic acid non-steroidal anti-inflammatory drugs on a human serum albumin based high-performance liquid chromatography chiral stationary phase, Chtmiatogra ia, 31 55 (1991). 

Table 12.3 Chiral resolution of 2-aryl propionic acid non-steroidal anti-inflammatory drugs on the HSA-CSP...

Immobilized forms or reticulated crystals of Candida antarctica lipase are effective biocatalysts for the synthesis of pure enantiomers utilized as anti-inflammatory agents. For example, one route for produetion of the 5-isomers of 2-aryl propionic acids (ibuprofen, naproxen, ketoprofen, and flurbprofen) involves enantioselective hydrolysis of the corresponding raeemie esters. Arroyo has indicated that an immobilized form of C. antarctica lipase (fraetion B) is used to mediate the selective acetylation of a diol to form the 5-enantiomer of a monoaeetate (Fig. 5), which is further proeessed to obtain an antifungal agent. ... 

A novel class of complexes, Ir-(5 )-26a, with chiral spiro aminophosphine ligands was found to be effective catalyst for the asymmetric hydrogenation of a-substituted acrylic acids (Scheme 11) [62]. Under mild reaction conditions and at ambient pressure, various a-aryl and alkyl propionic acids were produced with extremely high efficiency (TONS up to 10 000 TOFs up to 6000h ) and excellent enantioselectivity (up to 99% ee). This reaction provides a practically useful method for the preparation of a-aryl propionic acids, a popular class of non-steroid anti-inflammtory reagents. 

One compound which did not work well in our system was our original model, a-phenylacrylic acid. A number of these aryl propionic acids are valuable as nonsteroidal antiarthritics. Here, as is typically the case, only one enantiomer is active and thus a process to prepare one isomer directly was needed. We tried hard to solve this problem, even using ruthenium-ligand systems, but without success. It took Professor Noyori with his BINAP-ruthenium complex to solve this problem [4]. This is just another example in the history of invention. The one who makes the first discovery seldom makes the second. On a grander stage, this may explain why there are so few double Nobel Laureates. 

Important examples of this last type are the 2-aryl propionic acids, widely used as anti-inflammatory drugs. The active enantiomer of ibuprofen 14 can be formed by hydrolysis of esters 13 with the lipase from Candida cylindracea. The natural enzyme gives E = 10 but if it is refolded by precipitation from solution in 1 1 EtOH/Et20 with sodium cholate the E value rises to >100. The unnatural substrate 13 fits the refolded enzyme better than it fits the native enzyme.7... 

Owing to the simplicity, selectivity and economy of this new procedure, the a-bromo alkyl aryl acetals have been proposed as starting materials for the industrial production of some 2-aryl propionic acids such as the important pharmaceutical drugs, Ibuprofen and Naproxen. For instance, the preparation of enantiomerically pure Naproxen has been carried out, in one step, by means of the highly stereoselective Lewis acid catalyzed rearrangement of a starting a-bromo acetal, involving a 1,2-aryl shift (ref. 3) (Fig. 3) ... 

Sharma, A. K., Subramani, A. V., and Gorman, C. B. 2007. Efficient synthesis of halo indanones via chlorosulfonic acid mediated Friedel-Crafts cycliza-tion of aryl propionic acids and their use in alkylation reactions. Tetrahedron 63 389-395. 

The synthesis of other important pharmaceutical products including the PCA (noted in Section 4.1.1) has been successfully realized by using enzymes or active cells extract instead of whole cells [4.68]. The racemic resolution or synthesis of the (5)-(+)-2-(6-methoxy-2-naphtyl) propionic acid (naproxen), which is an important member of the family of 2-aryl-propionic acid derivatives used as non-steroidal anti-inflammatory drugs, has been also realized with a MBR. 

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