Racemic ibuprofen esterification

Lipase-catalyzed enantioselective esterification of racemic ibuprofen coupled with pervaporation... 

Won K, Hong JK, Kim KJ, and Moon SJ. Lipase catalyzed enantioselective esterification of racemic ibuprofen coupled with pervaporation. Proc. Biochem. 2006 41(2) 264—269. 

Lipase-catalyzed esterifications of racemic carboxylic acids in SCFs have been studied by several groups. The target in all of these studies was the preparation of optically pure anti-inflammatory drugs ibuprofen and naproxen. Rantakyla and Aaltonen reported the kinetic resolution of racemic ibuprofen by esterification catalyzed by immobilized lipase from Mucor miehei [Eq. (1)] (8,74,75) ... 

Scheme 4.9-1 Enantioselective esterification of racemic ibuprofen in SCCO2 [22].

J., and Sola, C. (2000) Highly enantioselective esterification of racemic ibuprofen in a packed bed reactor using immobilised Rhizomucor miehei lipase. Enzyme Microb. Technol., 27, 157 166. doi 10.1016/S0141-0229(00)00207-6... 

Table 9 influence of the Lyophilization and the Presence of Water on the Esterification of Racemic Ibuprofen, Catalyzed by Immobilized Lipase from C. rugosa in Isooctane... 

Table 10 Influence of Water on the Enantioselectivity of Native and Immobilized Lipt e from C. cylindracea in the Esterification of Racemic Ibuprofen with n-Propanol...

Rantakyla and Aaltonen [79] studied the enantioselective esterification of racemic ibuprofen with -propanol by immobilized lipase in SCCO2. The enantiomeric excess of the product was 70% at 15-20% conversion. The enantioselectivity was affected by temperature and concentration of ibuprofen and lipase. The initial reaction rate increased with pressure, but enantioselectivity was not affected by pressure changes. The reaction rates in SCCO2 were similar in n-hexane. 

The functions of chiral drugs in human body are closely related to their configurations. It has been reported that the R- and S-isomers of ibuprofen have quite different biological activities and toxicides. So it is imperative to prepare enan-tiomerically pure ibuprofen. Song el al. conducted a study on the lipase-catalyzed esterification of racemic ibuprofen with octanol in AOT reverse micelles [108,109] and found that the esterification is enantioselective and the main product is the corresponding S (-H)-ibuprofen ester, with the conversion yield and the enantiomer excess being about 36% and 0.9732, respectively. The water content and the concentration of AOT in the medium affected the conversion yield, but they had little influence on the enantiomeric excess (Table 15.7). Also, it was found that the chain lengths of alcohols affected both the rate of the reaction and the enantiomeric excess of the products. 

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... 

An application of lipases in the pharmaceutical industry can he found in the manufacture of Ihuprofen (Houde et al., 2004). Ihuprofen is a racemic mixture, where the (S)-ihuprofen molecules is 160 times more potent that the (R)-ihuprofen one. Resolution of racemic ihuprofen can he achieved hy esterification of (S)-ibuprofen with methanol or hutanol, in organic media using lipase, leading to synthesis of the corresponding (S)-ester. This ester can be separated from (R)-ibuprofen and chemical transformed to (S)-ibuprofen. 

Apart from catalysis, supported IL membranes have also been investigated for a variety of separation applications [23], which ranged from the separation of isomeric amines [24] to the enzyme-fadlitated transport of (S)-ibuprofen through a supported liquid membrane [25], The latter study demonstrated the selective separation of the (S)-enantiomer from the racemic mixture (see Figure 3). The concept was that by employing certain enzymes, such as lipase, it would be possible to catalyze the hydrolysis or the esterification ofibuprofen enantioselectively. In this investigation... 

Another approach for the enzymatic preparation of 5-ibuprofen has been demonstrated by de Zoete et al. [229]. The enantioselective ammonolysis of ibuprofen 2-chlo-roethyl ester by Candida antarctica lipase (lipase SP435) gave the remaining ester 5-(+) enantiomer in 44% yield and 96% e.e. The enantioselective enzymatic esterification of racemic ibuprofan has also been demonstrated using lipase from Candida cylindraceae [230]. The reaction was carried out in a water-in-oil microemulsion [bis(2-ethyl-hexyl)sulfosuccinate (AOT)/isooctane). The lipase showed high preference for the S-(+) enantiomers of ibuprofen which was esterified and R-(—) enantiomer remained unreacted. The reaction yield of 35% was obtained using n-propanol in the reaction mixture as nucleophile. 

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