Ibuprofen ester form

The 2-ethoxyethanol was a by-product, as shown in Figure 5.13. The formation rate of 2-ethoxyethanol was the same as the conversion rate of the (S)- or (R)-ibuprofen ester one mole of 2-ethoxyethanol was formed when one mole of ester was catalysed. A known concentration of 2-ethoxyethanol was added in the organic phase before the start of the reaction for product inhibition. The plots of the kinetics for the free lipase system are presented in Figure 5.17 and immobilised enzyme (EMR) in Figure 5.18, respectively. The Kw value was 337.94 mmoFl 1 for the free lipase batch system and 354.20 mmoll 1 for immobilised... 

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. ... 

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

A comparison between carbamoylmethyl and aminoalkyl esters has been reported for a small series of prodrugs of ibuprofen (8.28) [39]. A further interest of this work is the systematic comparison made between the enantiomers of ibuprofen, i. e., the active (+)-(S)-form and the inactive (-)-(/ )-form. As shown in Table 8.4, the ethyl esters were hydrolyzed very slowly in human plasma, with t1/2 values in the order of 100 - 200 h. In contrast, the hydrolysis of the carbamoylmethyl and aminoalkyl esters occurred with t1/2 values in the order of some or several minutes. The carbamoylmethyl esters were hydrolyzed very rapidly with low substrate enantioselectivity, while the 2-(imidazol-l-yl)ethyl esters were hydrolyzed somewhat more slowly and with marked substrate enantioselectivity. 

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... 

Semipinacol rearrangement of a-haloalkyl aryl acetates has produced good yields of 2-aryl alkanoic esters. The acids formed on hydrolysis are important anti-inflammatory agents (such as Ibuprofen) and the reaction has been reviewed in some detail1010. In a similar process, oc-bromoalkyl aryl acetals thermally rearrange in protic solvents (under neutral or slightly basic conditions) via a 1,2-aryl shift (equation 193)1010,1011. 

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. ... 

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. ... 

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. 

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... 

Another example of the use of organic solvents in enzymatic asymmetric synthesis is the development of a new scheme for ibuprofen. Although sound methods for the synthesis of (5)-ibuprofen (the active form) exist, a synthetic scheme based on lipase-catalyzed hydrolysis of organic soluble esters has also been developed in which the (5)-isomer is preferentially produced and leaves the (K) form untouched. In fact, lipase-catalyzed hydrolysis of esters to the desired acids or alcohols is likely to be an increasingly useful technique in asymmetric synthesis. 

Detailed structure-activity studies showed that small structural differences in the agents determined whether or not they caused irreversible inactivation. Particularly striking was the conversion of the free carboxylic acid to the methyl ester which gave an agent that had a similar binding affinity [86], but appeared to be completely devoid of ability to irreversibly inactivate the cyclooxygenase activity. The value of the apparent inactivation constants (K ) for the acidic forms of the compounds ranged from zero for ibuprofen and mefenamic acid to 0.0003, 0.04, 0.4 and 1.1 M min for aspirin, indomethacin, meclofenamate and flurbiprofen, respectively [86]. 

The ketene 25g prepared by dehydrochlorination has been produced on an industrial scale and gives a highly stereoselective reaction with R-panto-lactone forming the product ester in 64% yield (Eqn (4.11)). Related chiral 2-arylacetic acid derivatives have important pharmaceutical appHca-tions, of which ibuprofen, now sold as Advil, and naproxen, now sold as Aleve, are synthesized by this general route.Stereoselective additions to ketenes of appropriate chiral alcohols provide usefiil routes to the particular enantiomers needed for pharmaceutical application. 

In an experimental drug, the NSAID ibuprofen was ester-ified to a polyethylene glycol (Fig. 5.44) in order to reduce gastric irritation and to produce a sustained-release form of the dmg having a longer plasma half-life. 

---