S -naproxen

Most of the reactions applied to amines can also be transferred to alcohols (Eig. 7-5). One large group of chiral alcohols are the (i-adrenoreceptor blockers, for which a variety of derivatization agents was developed. One highly versatile reagent for the separation of (i-blockers is A-[(2-isothiocyanato)cyclohexyl]3,5-dinitrobenzoyl-amide (DDITC) [11]. Alternatively, unichiral drugs such as (3-blockers or (S)-naproxen [12] may be used in a reciprocal approach to derivatize racemic amine compounds. 

Mixtures of a nematic liquid crystal (LC or LC ) with small quantities of gold nanoparticles coated with alkylthiolates (<5 wt%) including an alkylthiolate functionalized with a chiral group have been studied (Figure 8.29) [72]. All mixtures show nematic mesophases with transition temperatures and phase stability very similar to those oftheliquid crystal precursors LC or LC. The introduction ofachiral center into the mixtures (mixtures of Au ) produce chiral nematic mesophases. A similar result is obtained in mixtures of Au and LC doped with the chiral dopant (s)-Naproxen. 

With a BINAP-Ru [3d,104], Hg-BINAP-Ru [102], or P-Phos-Ru [25] catalyst, the anti-inflammatory drugs (S)-ibuprofen and (S)-naproxen could be efficiently synthesized via enantioselective hydrogenation (Scheme 26.9). In these cases, high hydrogenation pressure and low temperature are required to achieve good enantioselectivity. With an (R)-BIPHEMP-Ru catalyst, (S)-2-(4-fluorophenyl)-3-methylbutanoic acid, a key intermediate for the synthesis of the calcium antago-... 

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%). 

The asymmetric hydroformylation of aryl ethenes such as substituted styrene or naphthylethene is of industrial interest because the hydroformylation products of these substrates are precursors to important nonsteroidal antiinflammatory drugs such as (S )-ibuprofen and (S )-naproxen. Strong efforts have been made to improve the branched/linear ratio, as well as the enantioselectivity of the product. 

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. 

Figure 4.18. Monsanto route to S-Naproxen hydrogenation step...

Naproxen 4-Vinylpyridine-EDMA (template (S)-naproxen) THF/heptane/acetic acid (250/250/1 v/v/v) 296... 

I Brand Name(s) (naproxen) EC-Naprosyn, Naprelan, Naprelan 375, Naprelan 500... 

The 2-arylpropionic acid derivatives (profens) are important classes of NSAIDs that have been in clinical use for over 20 years. The profens have been used clinically as racemic agents with the exception of (S)-(+)-naproxen, which has been developed and used only as a single enantiomeric drug. 

Other biocatalytic processes for (S)-naproxen production from the academic area are shown below ... 

Enanlioselective hydrogenation of a-aryl-substituted acrylic acids has extensively been studied because of the pharmaceutical importance of the saturated products. Anti-inflammatory (S)-naproxen with 97% ee is obtained by the high-pressure hydrogenation of 2-(6 -methoxy-naphth-2/-yl)acrylic acid by using Ru(OCOCH3)2[(S)-binap] [99]. The hydrogenation rate is... 

Only limited successful examples of asymmetric hydrogenation of acrylic acids derivatives have included the use of chiral Rh complexes (Scheme 1.17). The diamino phosphine (28) utilizes selective ligation of the amino unit to a Rh center and also exerts electrostatic interaction with a substrate. Its Rh complex catalyzes enantioselective hydrogenation of 2-methylcinnamic acid in 92% optical yield [116], Certain cationic Rh complexes can attain highly enantioselective hydrogenation of trisubstituted acrylic acids [ 1171. 2-(6 -Methoxynaphth-2 -yl)acrylic acid is hydrogenated by an (.S ..S )-BIPNOR- Rh complex in methanol at 4 atm to give (.S)-naproxen with 98% ee but only in 30% yield [26]. 

In spite of extensive studies on the asymmetric hydroformylation of olefins using chiral rhodium and platinum complexes as catalysts in early days, enantioselectivity had not exceeded 60% ee until the reaction of styrene catalyzed by PtCl2[DBP-DIOP (l)]/SnCl-> was reported to attain 95% ee in 1982 [8]. Although the value was corrected to 73% ee in 1983 [9], this result spurred further studies of the reaction in connection to possible commercial synthesis of antiinflammatory drugs such as (S)-ibuprofen and (S)-naproxen. The catalyst PtCl2[BPPM... 

V)-2-(4-Isobutylphenyl)propanal (17b) with 92% ee is obtained from p-isobutylstyrene (16b) by using the Rh-BINAPHOS catalyst, which is the precursor of antiinflammatory drug (S)-ibuprofen (entry 15) [19,64,65]. In a similar manner, the precursor of (S)-naproxen is obtained with 85% ee and excellent regioselectivity in the reaction of 16c catalyzed by Rh-(diphosphite 9) complex (entry 16) [25], Pentafluorostyrene (16e) is converted to the corresponding branched aldehyde 17e by the catalysis of the Rh-BINASPHOS complex with... 

S)-ibuprofen (44b Ar = 4-isobutylphenyl), (S)-naproxen (44c Ar = 6-MeO-naphthyl), and (S)-suprofen (44d Ar = 4-(2-thienylcarbonyl)phenyl) (Eq. 7.11) (10]. Thus, the asymmetric hydroformylation of vinylarenes discussed above provides potentially efficient route to these drags. 

Following the hydrophilic surface modification of the MIP beads, the retention factors of the various employed analytes were decreased, whereas similar or (in the case of (,S )-naproxen) even higher enantioselectivities were observed. Furthermore, the recovery of bovine serum albumin was complete on modified MIPs while it was only 10-40% on unmodified MIPs. Although the column efficiency of modified beads was lower, possibly due to mass transfer limitation by hydrophilic external layers in an aqueous-rich eluent, these preliminary results demonstrated the applicability of RAM-MIPs in direct serum injection assays [95]. 

Fig. 11 Mixed monolayer alkylthiol-capped gold nanoparticle end-functionalized with (S)-naproxen chiral dopant moieties [349, 365, 366]...

Related enantioselective protonation reactions based on the use of thiophenol as a nucleophile have also been reported by Kumar et al. these reactions led to enantioselectivity of 45-51% ee [9]. For example in the presence of 20 mol% quinine 11 the adduct 10 was synthesized in 85% yield and with 46% ee (Scheme 9.3, Eq. b). Reaction product 10 has subsequently been used as an intermediate in the synthesis of (S)-naproxen, 12, which was obtained in 85% ee (after recrystallization). 

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