2- arylpropionic acid derivatives

Styrene 20 mmols in benzene. [Rh] = O.OlOmmol. L = 0.040 mmol. The e.e. s were determined by GLC analysis of the corresponding 2-arylpropionic acids derived by Jones oxidation of the products... 

The arylpropionic acid derivatives are useful for the treatment of rheumatoid arthritis and osteoarthritis, for reduction of mild to moderate pain and fever, and for pain associated with dysmenorrhea. Side effects of the drugs are similar to but less severe than those described for the salicylates. Those who are sensitive to salicylates also may be sensitive to and have adverse reactions when taking ibuprofen and related drugs. Acute hypersensitivity to ibuprofen has been reported in patients with lupus. The hypersensitivity reaction to sulindac can be fatal. The use of sulindac has also been linked to cases of acute pancreatitis. The use of dimethylsulfoxide (DMSO) topically in combination with sulindac has been reported to induce severe neuropathies. The concurrent use of ibuprofen with aspirin reduces the antiinflammatory effects of both drugs. Ibuprofen is contraindicated in patients with aspirin sensitivity leading to bronchiolar constriction and in patients with an-gioedema. As with all NSAIDs, renal and liver function should be normal for adequate clearance of the drugs. 

Ketoprofen is an arylpropionic acid derivative that contains a single asymmetrical carbon atom and therefore exists in two enantiomeric forms that differ in their pharmacokinetic and pharmacodynamic properties (96). It is available for veterinary use in products containing the racemic mixture, and is indicated for treatment of respiratory infections in sheep and mastitis-metritis-agalactia syndrome in the sow. The recommended dosage is 3 mg/kg bw in a single injection (97). 

The 2-arylpropionic acid derivatives (profens) are important classes of NSAIDs that have been in clinical use for over 20 years. The profens have been used clinically as racemic agents with the exception of (S)-(+)-naproxen, which has been developed and used only as a single enantiomeric drug. 

A wide series of oxidants, spanning from TiCLj to iodine, has been used in the oxidative homocoupling of chiral 3-arylpropionic acid derivatives aimed at the preparation of lignans. The /f,/f-selectivity in the reactivity of 34 has been explained by a radical coupling mechanism (equation 20). The initially formed lithium (Z)-enolate may transform into the titanium enolate 35, which undergoes oxidation to the radical intermediate 36 via a single electron transfer process. The iyw-Z-type radicals 36 couple each other at the less hindered S-side si face) to give the R,/f-isomers 37 stereoselectively. 

The arylpropionic acid derivatives often cause allergic and photoallergic contact dermatitis, and photoallergic dermatitis to ketoprofen, with cross-photosensitivity to benzophenone and tiaprofenic acid, has been reported (188). Photopatch tests to these substances were positive but patch tests were negative. 

The monomethylation reactions of arylacetonitriles and arylacetoesters start from readily available intermediates and produce 2-arylpropionic acid (antiinflamatory drugs, e.g. ketoprofen, naproxen, etc.). Using a 10-30 molar excess DMC, either under GL-PTC (5) or batch conditions (6), it is possible to synthesize 2-arylpropionic acid derivatives with >99% purity in monomethyl derivatives (Eq. 3). 

Figure 7 Chiral HPLC separation of 2-arylpropionic acid derivatives on nonimprinted (a) and (5)-naproxen-imprinted stationary phase (b). (1) Racemic ketoprofen, (2) racemic ibu-profen, (3) (R)-naproxen, (4) (5)-naproxen. Mobile phase, 20 mM phosphate buffer pH 3.2 -acetonitrile 1 + lv/v. Columns 100 x 4.6 mm. Flow rate, ImL/min. Detection, UV 254 nm. Reproduced from Ref. 45, with permission.

In addition to their beneficial effects, some medications may actually cause cellular injury and disease. An example of this phenomenon involves nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs include aspirin (a derivative of salicylic acid), ibuprofen (arylpropionic acid, Advil ), and acetaminophen (para-aminophenol derivative, Tylenol ). Because of their beneficial pharmacological effects, consumption of these agents has increased significantly in recent years. NSAIDS have the ability to treat fever, pain, acute inflammation, and chronic inflammatory diseases such as arthritis. They are also used prophylactically to prevent heart disease, stroke, and colon cancer. 

As previously observed, for most free amino acids and small peptides unbuffered hydroorganic mixtures are enough to yield good enantioseparations however, for some bifunctional amino acids and most other compounds, an aqueous buffer is usually necessary to enhance resolution. TEAA and ammonium nitrate are the most effective buffer systems, while sodium citrate was also effective for the separation of 2-arylpropionic acids (profens) on vancomycin CSPs [78], and ammonium acetate is the most widely used and appropriate in view of LC-MS applications (see Section 2.3.1.4). Small changes in ammonium acetate concentration of MeOH-water (90 10) mobile phases scarcely affected retention and— to a lesser extent—enantioselectivity of carnitine derivatives [61]. 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory dmgs (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by hydroxycarbonylation [51,53] (several more listed in [52]). The carbonylation of styrene itself serves as a useful test reaction in order to learn the properties of new catalytic systems, such as activity, selectivity to acids, regioselectivity (1/b ratio) and enantioselectivity (e.e.) in the branched product. In aqueous or in aqueous/organic biphasic systems complexes of palladium were studied exclusively, and the results are summarized in Table 5.2. 

Cleavage at the benzylic position has likewise been observed in a variety of (hetero) aromatic derivatives such as chloramphenicol (Sch. 13) (31) or methotrexate (32). An important case is that of the decarboxylation of arylacetic or arylpropionic acids used as non-steroidal anti-inflammatory agents (Sch. 14) (33-35). 

Multiatomic [6] as well as cationic [7] rhodium catalysts also display a high preference for linear hydroformylation products. However, a catalyst system which generally yields branched hydroformylation products has not yet been found. Vinylarenes, such as styrene (16), form preferentially the (.vo-aldehyde 20 and not the n-aldehydes. The possibility to form a relatively stable Rh- -allyl complex 18 is most likely the decisive factor for this result [8]. Subsequent oxidation of 20 leads to 2-arylpropionic acids 21, of which some derivatives like 22-24 are of great importance as non-steroidal inflammatory drugs (NSID) (Scheme 3) [9]. For their synthesis by the hydroformylation of styrenes, not only a regioselective but also an enantioselective reaction process is... 

The enantiomeric purity of 2-arylpropionic acids used as pharmaceuticals was determined after derivatizing to the corresponding amides with various PAA and HAA. End analysis was by HPLC-UVD, with simultaneous measurement at 230 and 254 nm, using a cellulose-based stationary phase. The best derivative for routine determinations was chosen in each case after establishing the chromatographic parameters of the enantiomeric pair of derivatives197. 

Recent works in asymmetric induction has yielded two new ways (1) the electroenzymatic reduction [179, 180] and (2) the use of oreganometallic complexes as mediators (like complexes of Ni11, Pd11, or Co11 [181, 182]. For example, nickel-catalyzed cross coupling between aryl halides and a-chloropropionic acid derivatives bearing chiral auxiliaries affords arylpropionates in high yield and excellent enantiomeric excess [183],... 

For example, the photochemistry of non-steroidal anti-inflammatory drugs (NSAIDs) derived from 2-arylpropionic acid, has been studied because these compounds are known to exhibit phototoxicity (see Special Topic 6.22) and skin photosensitivity in some patients. The photodecarboxylation of ketoprofen (325), a benzophenone... 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory drags (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by... 

Biischges, R. Linde, H. Mutschler, E. Spahn-Langguth, H. Chloroformates and isothiocyanates derived from 2-arylpropionic acids as chiral reagents synthetic routes and chromatographic behaviour of the derivatives. J.Chromatogr.A, 1996, 725, 323-334... 

Spahn, H. Langguth, P. Chiral amines derived from 2-arylpropionic acids novel reagents for the liquid chromatographic (LC) fluorescence assay of optically active carboxylic acid xenobiotics. Pharm.Res., 1990, 7, 1262-1268... 

Van Overbeke, A. Baeyens, W. Van den Bossche, W. Dewaele, C. Enantiomeric separation of amide derivatives of some 2-arylpropionic acids by HPLC on a cellulose-based chiral stationary phase. J.Pharm.Biomed.Anai, 1994, 12, 911-916 [chiral derivatization also, flurbiprofen, ketoprofen, tia-profenic acid]... 

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