Anti-inflammatory enantiomerically pure acids

The hydrolysis of racemic non-natural amides has led to useful products and intermediates for the fine chemical industry. Thus hydrolysis of the racemic amide (2) with an acylase in Rhodococcus erythrolpolis furnished the (S)-acid (the anti-inflammatory agent Naproxen) in 42 % yield and > 99 % enantiomeric excess1201. Obtaining the 7-lactam (—)-(3) has been the subject of much research and development effort, since the compound is a very versatile synthon for the production of carbocyclic nucleosides. An acylase from Comamonas acidovor-ans has been isolated, cloned and overexpressed. The acylase tolerates a 500 g/ litre input of racemic lactam, hydrolyses only the (+)-enantiomer leaving the desired intermediate essentially optically pure (E > 400)[211. 

Further, [2.2]paracyclophane-4-acetic acid, a potential drug candidate tested for its anti-inflammatory activity (NSAID could be resolved on the 0-9-(tert-butylcarbamoyl)quinine-based CSP with a = 1.12 Rs = 2.6) and elution order (R)-(-)- before (5)-(- -)-enantiomer [125]. Samples that were assessed to be enan-tiomerically pure by an enantioselective H-NMR spectroscopic method contained 6% and 8% enantiomeric impurity in S- and/ -enantiomers, respectively. This clearly reveals that enantioselective HPLC is a more powerful technique than NMR-methods to assess stereoisomeric purity, in particular, if the enantiomeric impurity amounts to less than 10%. 

Arylpropionic acids are important class of non-steroidal anti-inflammatory drugs (NSAID). Their pharmacological activity is mainly in one of both enantiomers. Thus, efforts had been made to access to the enantiomerically pure substance. The kinetic resolution of racemic 2-(2-fluoro-4-biphenyl) propanoic acid 56 and 2(4-isobutylphenyl) propanoic acid 59 (Ibuprofen) was performed via enzymatic esterification and transesterification using an alcohol and vinyl acetate, respectively in a membrane reactor. The unreacted acid is obtained in highly enantiomerically enriched form. A consecutive approach consisting of the enzymatic hydrolysis of the resulted esters is needed to achieve the alcohol in optically pure form.77... 

Ruthenium(binap) complexes effectively catalyze asymmetric hydrogenation of a-amidocinnamic acids [172], allylic alcohols [173] and acrylic acids with almost quantitative enantiomeric excess [174]. For example, one of the largest-selling anti-inflammatory agents, Naproxen should be supplied as the enantiomerically pure 5-isomer, because the R-isomer is expected to be toxic to the liver. Asymmetric hydrogenation of the precursor by RuCL[(5)- binap] produces 5-Naproxen with 96-98 % ee (eq (47)) [175-176]. 

Arylpropionicacids such as ibuprofen 105 are important NS AIs (non-steroidal anti-inflammatories). Only one enantiomer is active and some are administered as enantiomerically pure compounds through there is a problem with racemisation in the body by enolisation. This can be turned to advantage in deracemisation . Weak bases are enough to convert the acid chloride 106 into an enolate that eliminates 107 to form the achiral ketene 108. Addition of, say, ethanol then gives racemic esters 109 R = Et of ibuprofen. 

Ibuprofen and naproxen as 2-arylpropionic acids belong to an important new class of nonsteroidal anti-inflammatory agents42. Asymmetric hydrocarboxylation of styrenes thus represents a direct access to optically active or enantiomerically pure probes. 

The Zambon synthesis of the non-steroidal anti-inflammatory agent (5)-2-(6-methoxy-2-naphthyl)propanoic acid (naproxen) is a landmark-setting application of the chiral auxiliary approach in the industrial stereoselective synthesis of an enantiomerically pure drug [51]. The chiral auxiliary employed, a (2f ,Jf )-dialkyltartrate, is a paradigmatic representative of this class of stereocontroller, being cheap, readily available, easily introduced on the substrate and removed from the product, and eventually recycled (although as its parent acid). 

In this framework, the class of lipases is made up of enzymes largely employed in pharmaceutical productions, whose product is specific enantiomeric forms of organic compounds (alcohols, adds, esters, amines). The enantioselective hydrolysis of racemic esters and simultaneous separation of the corresponding optically pure (5)-add as pure isomer is of considerable interest to the pharmaceutical industry as a route to non-steroidal anti-inflammatory drugs. In this field, studies have been devoted to the feasibility analysis of MBRs to produce (5)-ibuprofen esters and acids. Studies related to the modeling of the lipase-catalyzed hydrolysis of (S)-ibuprofen acid in MBRs show the feasibility of EMRs for the stereo-selective production of (S )-ibuprofen add indeed, the model indicates a high effidency of the EMR in the kinetic resolution of racemic solutions. ... 

It follows that other types of relatively unhindered alkenes could show potential as hydrogenation substrates, 1,1-disubstituted alkenes being an excellent example (5). Ru-BINAP catalysts (Chart 1) have been shown to reduce alkenes of this type, provided that the olefin in question contains an appropriate coordinating group. Enol ethers, enol carbonates, and Q ,jS-unsaturated esters that contain the 1,1-disubstituted alkene moiety are all functional substrates for this type of catalyst and give enantiomeric excesses of 80-90% in many cases. A well-known example is the commercial production of enantiomerically pure (S)-naproxen, otherwise known as Aleve, an over-the-counter anti-inflammatory drug. In this case, the relevant a,/3-unsaturated carboxylic acid is reduced in the presence of Ru(OAc)2[(S)-BINAP] and Ha (6). 

The asymmetric aUcoxycarbonylation of aUcenes is a reaction of particular interest, especially for vinylarenes, because it gives a two steps access (alkoxycarbonyla-tion, ester hydrolysis) to enantiomerically pure carboxylic acids from alkenes. For instance, a few arylpropionic acids such as (S j-Ibuprofen, (5)-Ketoprofen, and (5)-Naproxen, are popular non-steroidal anti-inflammatory agents [99]. Although good regio- and enantioselectivities have already been reported for asymmetric aUcoxycarbonylation, no systems, to the best of our knowledge, possesses both types of selectivities [100-104]. We tested ligands 7 in the asymmetric... 

Chemoenzymatic Preparation of Enantiomerically Pure S(+)-2-Arylpropionic Acids with Anti-Inflammatory Activity... 

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