Racemates naproxen resolution

A lipase-immobilized membrane reactor was applied for the optical resolution of racemic naproxen, lipase stability was enhanced by the EMR set-up to > 200 h in comparison with a half-life of 2 h in a stirred tank. Only pure lipase gave the best enantioselectivity (Sakaki, 2001). 

K. Sakaki, L. Giorno, and E. Drioli, lipase-catalyzed optical resolution of racemic naproxen in biphasic enzyme membrane reactors, J. Membrane Sci. 2001, 184, 27-38. 

Perhaps, one of the most important industrial processes using cinchonidine (or quinidine) as the resolving agent was the production of (S)-naproxen (3) by resolution of racemic naproxen. It is not clear whether it is still in use (Figure 13.4) [12],... 

During the same period, eontinuous process improvements on the resolution route to S -naproxen have achieved dramatic cost reductions. The breakthrough comes from in-process racemization and recycle of the R-naproxen byproduct and the recovery of the resolving agent (Figure 2). In this novel and efficient resolution process, the racemic naproxen is reacted with half an equiva-... 

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... 

Acetyl-6-methoxy-naphthalene may be prepared by the acylation of 6-methoxynaphthalene. The resulting product is then subjected to a series of reactions, namely Wilgerodt-Kindler reaction, esterification, alkylation and hydrolysis ultimately yields /)Z-Naproxen. Resolution of the resulting racemic mixture is caused through precipitation of the more potent /)-enantiomer as the cinchonidine salt. 

The use of enzymes in the resolution of racemates was briefly discussed in Chapter 9. In this section, we develop equations for the kinetic analysis of resolution, Lipases have been the most commonly used enzymes for this purpose, such as in the resolution of racemic ibuprofen (Mustranta, 1992), racemic naproxen (Tsai et al., 1996), and 3-hydroxy esters (Capewell et al., 1996). 

Resolution of Racemic Naproxen Isolation of the (S) Enantiomers (3rd Day of Lab Experiment)... 

This part of the experiment involves the resolution of the racemic naproxen to allow the isolation of the (S) enantiomer of naproxen. You will use the following procedure to... 

Weight of the (S, R) diastereomer obtained in the resolution of racemic naproxen with cinchonidine. 

Sakaki, K., Giomo, L., and Drioli, E. (2001). Lipase-catalyzed optical resolution of racemic naproxen... 

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]. 

One of the first applications of the then newly developed Ru-binap catalysts for a,/ -unsaturated acids was an alternative process to produce (S)-naproxen. (S)-Naproxen is a large-scale anti-inflammatory drug and is actually produced via the resolution of a racemate. For some time it was considered to be one of the most attractive goals for asymmetric catalysis. Indeed, several catalytic syntheses have been developed for the synthesis of (S)-naproxen intermediates in recent years (for a summary see [14]). The best results for the hydrogenation route were obtained by Takasago [69] (Fig. 37.15), who recently reported that a Ru-H8-binap catalyst achieved even higher activities (TON 5000, TOF 600 h 1 at 15 °C, 50 bar) [16]. 

The resolution process developed by Syntex is almost ideal (Pope Peachy resolution), with an efficient racemization and recycling of the unwanted (R) -enantiomer (yield >95% of (S)-naproxen from the racemate) and the chiral auxiliary (recovery >98%). 

Isooctane Racemic resolution of several Naproxen analogues combined with the re-racemisation of the second enantiomer [132, 133]... 

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

For racemic resolution of naproxen the use of cinchonidine, A/-alkyl-D-glucamine, dehydroabietylamine or (S)-a-phenylethylamine has been described. 

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],... 

Manufacture of optically pure (5)-(+)-ibuprofen (13), an NSAID similar to naproxen, is another example demonstrating the role of resolution in production of chiral fine chemicals, although from a somewhat different angle. Unlike naproxen, ibuprofen (14) was introduced to the market as a racemate almost 30 years ago.30 31 At the time of the introduction, it was thought that both R- and 5-isomers of ibuprofen had the same in vivo activity.32 It has been demonstrated that the R-isomer is converted to the 5-isomer in vivo29 by a unique enzyme system called invertase.34 Based on these data, ibuprofen has since been marketed as a racemate and has achieved sales of more than a billion... 

Goto et al. (67) synthesized the sucdnimidyl ester [14] of (—)- -methoxy-a-methyl-l-naphthaleneacetic acid for the normal-phase LC resolution of chiral amines. The reagent permitted the determination of the enantiomers of an amphetamine derivative in blood plasma after administration of racemic drug to rabbits. With detection at 280 nm, the lower limit of sensitivity was 5 ng/mL for each enantiomer (67). Several chiral acids from the "profen" group of nonsteroidal antiinflammatory drugs have been adapted as CDAs. One of these, naproxen, [15], is the S enantiomer and is commercially available as the resolved acid several of these acids have the advantage of providing fluorescent derivatives (68,69). 

On an industrial scale, resolution of racemates is still in many cases the preferred way of producing enantiomerically pure compounds. If chiral-pool compounds are not available as optically active starting materials, a cost comparison of asymmetric and resolution processes often attributes advantages to the latter. Among the top 15 optically active pharmaceutical drugs and their intermediates, a chemical asymmetric process could be established only in the case of naproxen. For all others, diastereomeric and biocatalytic resolution are the methods, apart from fermentation, of creating optically pure compounds. 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

So far, the P DC-catalyzed formation of (R)-PAC (whole cell biotransformation) is the only process for fhe synfhesis of chiral 2-hydroxyketones via carlioligallon used on an industrial scale. The transformations depicted in Scheme 4.3 might provide access to chiral intermediates used in fhe synthesis of biologically active compounds, like fhe antifungal Ro 09-3355 [24], the antidepressant bupropion [25], and the analgesic naproxen [26]. So far, such chiral building blocks have mostly been synthesized by racemic resolution using e. g. lipases. 

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) ... 

The synthesis of other important pharmaceutical products including the PCA (noted in Section 4.1.1) has been successfully realized by using enzymes or active cells extract instead of whole cells [4.68]. The racemic resolution or synthesis of the (5)-(+)-2-(6-methoxy-2-naphtyl) propionic acid (naproxen), which is an important member of the family of 2-aryl-propionic acid derivatives used as non-steroidal anti-inflammatory drugs, has been also realized with a MBR. 

H5fun, M.H. Ryoo, J.-J. Cho, Y.J. Jin, J.S. Unusual examples of the liquid chromatographic resolution of racemates. Resolution of n-donor analytes on a ir-donor chiral stationary phase. J.ChromatognA, 1995, 692, 91-96 [chiral also alminoprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen]... 

The production of other profens as well, like the enantiospecific esterification of racemic ketoprofen in non-aqueous solvent under reduced pressure (De Crescenzo et al. 2000 Ong et al. 2005) and the anti-inflammatory drug naproxen by kinetic resolution of the racemic ester in a in an aqueous-organic biphasic system in a stirred tank membrane bioreactor (Xin et al. 2001)... 

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