Arylpropionic Acid Profens

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]. 

Arylpropionic acids (profens), tocainide and analogues, bupivacaine and analogues, bendrofiumethiazide, benzodiazepines, binaphthol. Bz-phenylglycine, mephenytoin 0.0 -bis(4-/m.-butylbenzoyl)-Ai.Ai -diallyl-(/f./ )-tartaric acid diamidc (Kromasil CHI-TBB) 1198]... 

The 2-arylpropionic acid ( profen ) non-steroidal anti-inflammatory drugs, each of which contains a single chiral center, are formulated as racemic (50 50) mixtures of the S(+)- and R(-)-enantiomers, with the exception of naproxen, which is formulated as the S(- -)-enantiomer. Based on inhibition of cyclooxygenase activity, the S(- -)-enantiomer is the eutomer (more potent enantiomer). These drugs differ markedly in both pharmacodynamic activity and pharmacokinetic behavior and, in addition, enantiomer pharmacokinetics of each drug varies among animal species. After intravenous administration of racemic keto-profen to horses, sheep, and 20-week-old calves and measurement of individual enantiomers in plasma, significant differences between the enantiomers were found in systemic clearance in horses and in both systemic clearance and volume of distribution in sheep... 

In 1992 the world market for arylpropionic acids (profenes) which are used as nonsteroidal antiinflammatory agents was > 2.5 billion ( 2500 million). 

Unidirectional chiral inversion of arylpropionic acids (profens)... 

Almost at the same time, Backvall et al. demonstrated that PSL and metal-catalyzed DKR can also be applied to other primary alcohols bearing an unfunctionalized stereo-genic center in the (3-position. The chosen substrates were racemic 2-arylpropan-l-ols (rac-10 is included, as an example, in Scheme 57.4), which are precursors of the nonsteroidal anti-inflammatory 2-arylpropionic acids (profens). DKR processes were performed in toluene at 80 C, with catalyst la, Amano PS-D 1 lipase, and 4-nitrophenyl 3-[4-(trifluoromethyl)phenyl]propanoate as the acyl donor. In this case, the metal catalyst is also indirectly involved in the racemization of the primary alcohol. Initially, metal-catalyzed dehydrogenation of the alcohol takes place, with the resulting aldehyde undergoing enoUzation, which can be facilitated by the elevated temperature. 

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. 

The profens are non-steroidal anti-inflammatory agents based on arylpropionic acids the best known is ibuprofen. The BHC company (Boots-Hoechst-Celanese) developed a commercial route to ibuprofen which involves a... 

A widely used technique for separating racemic mixture is the use of enzyme mediated transesterification or hydrolysis. One important example is the separation of Naproxen (33), which is a member of the 2-arylpropionic acid class of profens that are broadly used as NSAIDs (see Section 2 for the separation of enantiomers using a crystallization approach). The important association between chirality and biological activity of this class of drugs has been extensively researched, where... 

Various arylpropionic acids show similar specificity. For most, if not all, the (5) enantiomer is the pharmacologically active one, whereas the R) enantiomer is usually much less active, although the ratio of iS)/ R) activity varies from drug to drug (and species to species). Only one of these drugs, however, is administered as the separated (S) enantiomer (naproxen, Naprosyn ). Normally these drugs are considered safe, and one cannot readily differentiate between the relative activities of the (S) and (R) forms because the in vivo half-life is very short, typically one or two hours. In patients with impaired renal function, where clearance is much slower, however, problems can arise. From in vivo studies of ibuprofen, it was established that the (S)-(-l-) isomer was responsible for antiinflammatory activity. In vivo, however, the (/ )-(-) isomer may become active because there is stereoselective inversion from R) to (S) (but not from 5 to R) in vivo with a half-life of about two hours. This inversion apparently proceeds by stereoselective formation of the coenzyme A (CoA) ester of the (f )-(-)-arylpropionic acid, followed by epimerization and release of the (S)-(+)-enantiomer. This epimerization is observed in vivo before the oxidative metabolism. Such inversion from (R) to (S) in vivo is also known for fenoprofen and benoxa-profen, and is expected to occur for most of the drugs of this series. ... 

The 2-arylpropionic acid NSAIDs (the profens ) possess a chiral centre at the carbon atom a to the carboxyl function, and it is known that the activity of these drugs resides in the S(+) [szrasferj-enantiomers while the R(-) [rectus]-enantiomers either have low activity or are inactive (Shen, 1981). The NSAIDs of this subclass are formulated as racemic mixtures containing equal quantities of the two enantiomers, with the exception of naproxen which is commercially... 

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]... 

However, in certain cases, charged modifiers are needed, such as octanoic acid, quaternary compounds etc., to induce adequate enantioselectivity. Such additives, have been shown to be necessary when separating arylpropionic acids and profens, i.e. such substances as Ibuprofen and Naproxen. 

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.

The enzymatic activity of lipases is very comparable to that of esterases, with the main difference being the chain length and hydrophobicity of the acid moiety of the substrate. Therefore in fine chemical applications, lipases and esterases are being used as alternatives for several conversions. For instance, for the kinetic resolution of 2-arylpropionic acids such as naproxen and ibu-profen, both a lipase and an esterase have been found that can perform a stereoselective hydrolysis yielding the pharmaceutically preferred enantiomer S-naproxen (Bertola et al. 1992 Hedstrom et al. 1993). High activity and ease of production have made the carboxylesterase from Bacillus subtilis Thai 1-8 the prime choice of industry (Quax and Broekhuizen 1994). 

Arylpropionic acids (APAs, the profen family) derivatives. 

Two groups of chiral aromatic carboxylic acids are important commercial intermediates for the agricultural and pharmaceutical industries. The R enantiomer of a-phenoxypropionic adds confers biological activity for a number of herbiddes. The S enantiomer of a variety of arylpropionic adds is the biologically active form of the nonsteroidal antiinflammatory products labeled profens. Racemic mixtures of the alkyl esters of these propionic add derivatives have been effectiwly resolved to yield the desired optically active carboxylic acids (64-66). Figure 20 shows examples of the resolution of aromatic propionic acid esters. 

Nonsteroidal antiinflammatory drugs. Pirprofen, naproxen, ibuprofen, and keto-profen can occasionally cause microvesicular steatosis in humans (Bravo et al. 1997 Victorino et al. 1980 Danan et al. 1985 Dutertre et al. 1991). These NSAIDS have a 2-arylpropionate structure, with an asymmetric carbon, and exist as either the S(+)- or the R(—)-enantiomers. Only the S(+)-enantiomer inhibits prostaglandin synthesis, whereas only the R( )-enantiomer is converted into the acyl-CoA derivative. However, both the S(+)-enantiomer and the R( )-enantiomer of ibuprofen inhibit the p-oxidation of medium- and short-chain fatty acids (Freneaux et al. 1990). Pirprofen, tiaprofenic acid, and flurbiprofen also inhibit mitochondrial p-oxidation (Geneve et al. 1987a). 

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