Naproxen methyl ester

Table using 3-3. Enantioseparation of 2-methylnaphthoyl-AW-diethylamide and naproxene methyl ester CSPs 1-11. ... 

Recent studies in the pharmaceutical field using MBR technology are related to optical resolution of racemic mixtures or esters synthesis. The kinetic resolution of (R,S)-naproxen methyl esters to produce (S)-naproxen in emulsion enzyme membrane reactors (E-EMRs) where emulsion is produced by crossflow membrane emulsification [38, 39], and of racemic ibuprofen ester [40] were developed. The esters synthesis, like for example butyl laurate, by a covalent attachment of Candida antarctica lipase B (CALB) onto a ceramic support previously coated by polymers was recently described [41]. An enzymatic membrane reactor based on the immobilization of lipase on a ceramic support was used to perform interesterification between castor oil triglycerides and methyl oleate, reducing the viscosity of the substrate by injecting supercritical CO2 [42],... 

The racemic resolution of this molecule is very important because the 5 -enantiomer is 28-fold more active than the R-enantiomer. Sakaki and co-workers [4.69] realized the production of (5)-naproxen from the racemic naproxen methyl ester using lipase immobilized in hollow fibers. Their results showed that the MBR had good enzyme stability and enantiomeric excess of up to 0.92. The stereoselective hydrolysis of racemic 2-substituted propionates catalyzed by carboxyl esterase has been performed by Cretich and coworkers... 

Xin JY, Li SB, Xu Y et al. (2001) Dynamic enzymatic resolution of naproxen methyl ester in a membrane bioreactor. J Chem Technol Biotechnol 76(6) 579-585... 

More recently, Hartwig reported on the use of a zinc variant of LHM DS, namely Zn(HMDS)2, as a mild ammonia equivalent in combination with LiCl or R,NX as additives and P(t-Bu)3 as ligand [173]. This protocol has the advantage of extended functional group tolerance, allowing the use of substrates with, for example, eno-Hzable groups. Hence, when (S)-naproxen methyl ester was deliberately added to the amination reactions no racemization occurred, yet addition of the stronger base LHMDS led to almost complete racemization. 

A simplified MBR [94]-a laboratory scale CSTR with CrL immobibzed on moderate polar support and a dialysis membrane tube forming a continuous-flow loop for extracting the product-has been appbed for the KR of the racemic naproxen methyl ester to yield (S)-15 with >90% ee and overall conversion of 30%. 

Fig. 27.22 Enantioselective hydrolysis of racemic-Naproxen methyl ester by the encapsulated lipase in the presence of an additive...

Table 27.9 Enantioselective efficacy of the encapsulated lipases in the hydrolysis reaction of (R/ 5)-Naproxen methyl ester...

Table 27.11 The enantioselective hydrolysis of Naproxen methyl ester of using encapsulated lipases as catalysts...

Hydrolysis of racemic naproxen methyl ester by C. rugosa lipase [31]. 

The enantioselective hydrolysis of racemic naproxen methyl ester by C. rugosa lipase (CRL) was studied in an aqueous buffer solution/isooctane reaction system in the presence of supercritical CO (Figure 3.21) [31]. The conversion reached 41.3% at 120 bar at 37°C after 2 h of reaction and provided enantiomeric purities of product and substrate of 97.9 and 68.8%, respectively. This corresponded to an enantiomeric ratio (E value) of 193. The lipase remained active for at least 12hat37°C and 120 bar in the supercritical CO medium. 

U. Salgm, S. Salgin, S. Takag, Hydrolysis of racemic naproxen methyl ester by Candida rugosa lipase, I. Supercrit. Fluids 43 (2007) 310-316. 

Profens are an important group of NSAIDs. The biological activity of these drugs resides exclusively in the (S)-enantiomer, so considerable effort has been invested in developing efficient routes for their preparation. For instance, (S)-naproxen has been prepared via recrystallization of diastereomeric mixtures. The carboxylesterase-catalyzed kinetic resolution of R/S)-naproxen methyl ester achieves excellent optical purity of the product. Nevertheless, the AMDase-catalyzed as5unmetrizahon of prochiral a-aryl-a-methylmalonates gives rise to a 100% theoretical 5deld of profens, a clear improvement from kinetic resolution (50%). Unfortunately, wild-type AMDase produces only the undesirable (R)-enantiomers. 

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