Resolutions Naproxen

FIGURE 6.2 Block flow diagram of the naproxen resolution process. 

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. 

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

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%). 

Applications. In the last decade a lot of research has been devoted to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acetamido ligand as additional functionality. In Figure 4.17 four are listed, which are important as anaesthetics for rheumatic diseases. Their sales in beat many bulk chemicals the turnover of Naproxen (retail) in 1990 was 700 million for 1000 tons. S-Naproxen is now being produced by Syntcx via resolution with a chiral auxiliary. The main patents from Syntex expired in the U.S. in 1993, the reason for a lot of activity to study alternative synthetic routes. Routes leading to an asymmetric centre are o asymmetric hydrogenation of an unsaturated acid, o asymmetric carbohydroxylation of a styrene precursor, o asymmetric hydroformylation of a styrene precursor and oxidation. 

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

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. 

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. 

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. 

S)-3-Methyl-2-phenylbutylamine, a new versatile synthetic resolving agent we have proposed, is effective for the resolution of chrysanthemic acid, ibuprofen, ketoprofen, naproxen and others.19... 

The resolution of (7i,. S )-naproxen 54 using lipase-catalyzed esterification of the free acid with different diols and organic solvents was reported. The (.S)-naproxcn ester 55 was obtained in > 99 % ee when using 1,4-butandiol.79... 

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... 

Other resolving agents are readily prepared from inexpensive chiral starting materials such as glucose, aspartic acid, or glutamic acid. A literature example is the use of /V-methylglucamine 6, obtained by reductive amination of D-glucose, in the resolution of naproxen (Chapter 6).13... 

Silica-base stationary phases have also been employed for enantiomeric separations in CEC [6,72-81]. In the initial work on chiral CEC, commercially available HPLC materials were utilized, including cyclodextrins [6,74,81] and protein-type selectors [73,75,80] such as human serum albumin [75] and ai-acid glycoprotein [73]. Fig. 4.9, for example, depicts the structure of a cyclodextrin-base stationary phase used in CEC and the separation of mephobarbital enantiomers by capillary LC and CEC in a capillary column packed with such a phase. The column operated in the CEC mode affords higher separation efficiency than in the capillary LC mode. Other enantiomeric selectors are also use in CEC, including the silica-linked or silica-coated macrocyclic antibiotics vancomycin [82,83] and teicoplanin [84], cyclodextrin-base polymer coated silicas [72,78], and weak anion-exchage type chiral phases [85]. Relatively high separation efficiency and excellent resolution for a variety of compounds have also been achieved using columns packed with naproxen-derived and Whelk-0 chiral stationary phases linked to 3 pm silica particles [79]. Fig. 4.10 shows the... 

An important example is the resolution of the enantiomers of naproxen. Naproxen is a member of a family of compounds known as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) which are 2-aryl propionic acids. This class also includes ibuprofen, the painkiller developed by Boots and marketed as Nurofen. 

This approach was studied for naproxen trifluoroethylthioester [55], feno-profen trifluoroethylthioester [56], naproxen trifluoroethylester [57] and ibupro-fen 2-ethoxyethyl ester [58] (Scheme 6.15). Some of these reactions were not performed in water only, but in biphasic mixtures, due to solubility problems. This is a drawback from a green point of view, but the much higher yield and the fact that no recycling step is needed is a clear indication of the high efficiency of dynamic kinetic resolutions. 

A commercial synthesis (Albemarle) of naproxen (a 2-aryl propionic acid anti-inflammatory related to ibuprofen) involves palladium catalyzed hydroxycarbonylation of an aryl olefin which is itself made in a palladium catalyzed Heck coupling reaction (Figure 6b). Resolution is needed to obtain the (5)-enantiomer of naproxen since its optical isomer is a liver toxin. 

Sotalol, metoprolol, propranolol, carvedilol, nifedipine, captopril, cilazapril, milrinone, ticlopidine, acenocoumarol, furosemide, acetylsalicylic acid, salicylic acid, ibuprofen, naproxen, ketoprofen, diclofenac, paracetamol, dipyrone, mildronate, sildenafil, dexa-methasone, carbamazepine, terbinafine/urine UHPLC MS/MS Column Zorbax Rapid Resolution High Definition SB-C18 (50 x 2.1 mm, 1.8 pm) Mobile phase Solvent A 0.1 % HCOOH in water Solvent B MeOH (gradient elution) Detection MS/MS, ionization ESI Protein precipitation LOQ 0.05-0.60 ng/mL [71]... 

R.S)-Naproxen.achiral amine base (37) Recycled to resolution... 

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). 

Type I CSPs have also been used with aqueous mobile phases. Pirkle et al. (32) have reported on the resolution of N-(3,5-dinitrobenzoyl) derivatives of M-amino adds and 2-aminophosphonic adds on an (l )-N-(2-naphthyl)-alanine-derived CSP using a mobile phase composed of methanol-aqueous phosphate buffer. The utility of achiral alkyltrimethylammoruum ion-pairing reagents was also investigated. Other examples include the following (1) The recently commercialized ot-Burke 1 CSP resolves the enantiomers of a number of underivatized p-blockers using an ethanol-dichlorornethane-ammonium acetate mobile phase (33) (2) an (R)-l-naphthylethylurea CSP was used to resolve N-(3,5-dinitrobenzoyI)-substituted amino adds and 3,5-dinitrobenzoyl amide derivatives of ibuprofen, naproxen, and fenoprofen with acetonitrile-sodium acetate mobile phases (34). 

---