Arylpropionic acids products

Asymmetric catalytic hydrogenation is one of the most efficient and convenient methods for preparing a wide range of enantiomerically pure compounds, and Ru-BINAP-catalyzed asymmetric hydrogenation of 2-arylacrylic acids has attracted a great deal of attention,11 as the chiral 2-arylpropionic acid products constitute an important class of nonsteroidal antiinflammatory drugs. 

Although the Rh-catalyzed asymmetric hydrogenations of prochiral enamides have been extensively studied and excellent results have been frequently achieved, the catalytic asymmetric hydrogenations of 2-arylacrylic acids have been less successful. Until recently most catalyst systems gave only moderate optical yields for the 2-arylpropionic acid products (77). An important breakthrough in the study of these reactions was reported by Noyori et al. By using Ru(BINAP)(OAc)2 as a catalyst precursor, these researchers obtained excellent optical yields in the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid (72). 

At the beginning of the 1970s a convenient procedure was described for converting olefins into substituted butanedioates, namely through a Pd(II)-cata-lysed bisalkoxycarbonylation reaction. So far various catalytic systems have been applied to this process, but it took twenty years before the first examples of an enantioselective bisalkoxycarbonylation of olefins were reported. Ever since, the asymmetric bisalkoxycarbonylation of alkenes catalysed by palladium complexes bearing chiral ligands has attracted much attention. The products of these reactions are important intermediates in the syntheses of pharmaceuticals such as 2-arylpropionic acids, the most important class of... 

Electrochemistry offers new routes to the production of several commercially relevant a-arylpropionic acids, used as non-steroidal anti-inflammatory agents (NSAI) [178,182]. A preparative method based on sacrificial Al-electrodes has been set up for the electrocarboxylation of ketones [117,183-187] and successfully applied to the electrocarboxylation of aldehydes, which failed with conventional systems. The electrocarboxylation of 6-methoxy-acetonaphthone to 2-hydroxy-2-(6-methoxynaphthyl)propionic acid, followed by chemical hydrogenation to 2-(6-methoxynaphthyl)-2-propionic acid - one of the most active NSAI acids - has been developed up to the pilot stage [184,186],... 

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 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. 

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). 

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... 

Applications to Products of Commercial Interest. (5)-Ethyl lactate has been incorporated in chiral syntheses of (5)-2-arylpropionic acids, an important class of nonsteroidal anti-inflammatory agents, including ibuprofen and naproxen (eq 12). These syntheses, though elegant in concept, are unlikely to compete with existing industrial methods for production of the (5) enantiomers of these drugs. 

Moreover, hydrocarboxylation reactions have been expanded to include functionalized olefins as substrates, leading to arylpropionic acids [16], fluorinated acids [17], silylated esters [18], and y5-amino acids [19] as products (Structures 1-6). 

Typical kinetic resolutions of the arylpropionic acids are those of flurbiprofen 16 and ketoprofen 18 with a cell-free extract of Pseudomonas fluorescens. Note the special ester (trifluoroethyl) selected for maximum efficiency and how successful that is perfect ee in the hydrolysed products at close to 50% conversion.8 The unreacted esters 15 and 17 can of course be racemised by enolisation and added to the next resolution. 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

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... 

Thus, considerable effort is necessary to achieve a wide and synthetically useful application of this method. Nevertheless, the first examples of interesting target molecules obtainable via asymmetric hydroformylation have appeared (amino acids, arylpropionic acids)180. Thus, if appropriate catalytic systems and reaction conditions can be found, even industrial applications might be realized within the near future. Thus, asymmetric hydroformylation is considered to be a powerful tool for the preparation of a large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutical activity180. Examples are the essential and non-essential amino acids, 2-arylpropanoic acids, aryloxypropyl-and /1-phenylpropylamines. modified /1-phenylethylamines, pheniramines and others180. 

Many kinetic resolutions of rac-nitriles were performed in search of a method to produce (S)-configurated a-arylpropionic acids, such as ketoprofen, ibuprofen, or naproxen, which are widely used as nonsteroidal antiinflammatory agents. Overall, enantioselectivities depended on the strain used, and whether a nitrilase- or nitrile hydratase-amidase pathway was dominant, which determines the nature of (enantiomeric) products consisting of a mixture of nitrile/carboxylic acid or amide/ carboxylic acid, respectively [687, 693-696]. 

R)-4-Methyl-5-phenyl-oxazolidin-2-one, a chiral auxiliary for an electrochemical approach to the preparation of a-arylpropionic acids, has been obtained in one step by fusing above the melting point (R)-2-phenylglycinol with urea [570]. The urea first decomposes to free cyanic acid, which then reacts with the amino group to form a j5-hydroxyethylurea derivative. This subsequently cyclizes with loss of ammonia to afford the product [571]. 

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). 

In this case, a reaction temperature of 50°C was needed to increase the racemization rate of the substrate and achieve an efficient DKR. Ru catalyst 3a in combination with CAL-B or subtilin Carlsberg has been used to carry out the DKR of the allylic alcohol rac-49, which is a precursor of the pharmacologically important 2-arylpropionic acids. Bearing in mind that these two enzymes display opposite stereopreference, both enantiomers could be prepared. Scheme 57.12 shows the reaction conditions. DKR with CAL-B was conducted at 80°C to obtain an acceptable rate of product formation, the corresponding acetate (R)-50... 

De la Pena, D., Marti, C., NoneU, S., Martinez L. A., and Miranda M. A., Time-resolved near infrared studies on singlet oxygen production by the photosensitizing 2-arylpropionic acids, Photochem. Photobiol, 65, 828, 1998. 

Although there were some trials to prepare optically active carboxylic acids via asymmetric decarboxylation, the optical yields of the products were not high enough for practical use. Thus, it is strongly desirable to find an enzyme which catalyzes asymmetric decarboxylation of arylmethylmalonates to give optically pure arylpropionates. 

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