Naproxen esterase

Other similar lipase/esterase resolution processes have been developed such as the use of Bacillus that esterase to produce the substituted propanoic acids that are precursors of non-steroidal anti-inflammatory drags, snch as naproxen and ibuprofen etc., and the formation of chiral amines by Celgene. Other methods start from prochiral precursors and have the advantage that enantioselective synthesis allows the production of particular isomers in yields approaching 100%, rather than the 50% yields characteristic of resolution processes. For instance Hoechst have patented the production of enantiomers using Pseudomonas fluorescens lipase to either acylate diols or hydrolyse diacetate esters. 

For the enzymatic cleavage of esters of racemic naproxen, cloned esterases, which are cheap and easy to produce, have been developed (a 100 tons per annum process is planned). 

S)-Naproxen and (S)-ibuprofen by enantioselective ester hydrolysis Esterase (bacillus)... 

S)-Naproxen Kinetic resolution by carboxylic ester hydrolysis (recombinant esterase) Development stage Chirotech Sha-sun Chemicals, India [14]... 

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... 

One class of enzymes that has received particular attention in this regard is the esterases, which catalyze the hydrolysis of esters (Section 14.1C) to give an alcohol and a carboxylic acid. We illustrate this method by describing the resolution of (f ,5)-naproxen. The ethyl esters of both (R)- and (5)-naproxen are solids with very low solubilities in water. Chemists then use an esterase in alkaline solution to selectively hydrolyze the (S)-ester, which goes into the aqueous solution as the sodium salt of the (5)-carboxylic acid. The (fl)-ester is unaffected by these conditions. Filtering the alkaline solution recovers the crystals of the (i )-ester. After the crystals are removed, the alkaline solution is acidified to precipitate pure (5)-naproxen. The recovered (J )-ester can be racemized (converted to an f ,S-mixture) and again treated with the esterase. Thus, by recycling the (f )-ester, all the racemic ester is converted to (5)-naproxen. 

Norbomadiene and cyclopentadiene have both been converted into carbocycltc nucleoside precursor SO through cydopentene-ester-amide or ester-add intermediates, respectively. Asymmetry was introduced by use of naproxen esterase. ... 

The recovered R ester is racemized (converted to an R,S mixture) and treated again with the esterase. Thus, by recycling the R ester, all the racemic ester is converted to (S)-naproxen. 

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). 

Naproxen, (S)-2-(6-methoxy-2-naphthyl)propanoic acid 126 is a nonsteroidal anti-inflammatory and analgesic agent first developed by Syntex [220,221]. Biologically active desired S-naproxen has been prepared by enantioselective hydrolysis of the methyl ester of naproxen by esterase derived from Bacillus subtilis Thai 1-8 [222]. The esterase was subsequently clone in Escherichia coli with over 800-fold ipcrease in activity of enzyme. The resolution of racemic naproxen amide and ketoprofen amides has been demonstrated by amidases from Rhodococcus erythropolis MP50 and Rhodococcus sp. C311 (223-226). 5-Naproxen 126 and 5-ketoprofen 127 (Fig. 44) were obtained in 40% yields (theoretical maximum yield is 50%) and 97% e.e. Recently, the enantioselective esterification of naproxen has been demonstrated using lipase from Candida cylindraceae in isooctane as solvent and trimethylsilyl as alcohol. The undesired isomer of naproxen was esterified leaving desired S isomer unreacted [227]. 

The presence of esterases or amidases in many microorganisms has also been employed to resolve racemic mixtures of the esters or amides of these drugs. In this sense, Kluyvera oxytoca SNSM 87 [74] and Bacillus subtilis [75] esterases have been successfully used in die resolution of the racemic esters, while Rhodococcus erythopolis MP50 has been applied for the resolution of the amides of (/ ,5 -2-(6-methoxy-2-naphthyl)propionic acid, yielding 48% yield of naproxen, with an enantiomeric excess more than 99% after 45 h [76]. 

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