Chiral synthesis naproxen

A Chiral Synthesis Route to Naproxen Using Asymmetric Hydroformylation... 

The use of an analogous (S)-BINAP-Ru-diacetate catalyst with axial chirality has led to important industrial applications, such as the synthesis developed by Monsanto where the asymmetric hydrogenation is involved in the last step to yield naproxen, a widely prescribed, non-steroidal, anti-inflammatory drug (Equation (9)).96... 

With a rhodium complex catalyst containing a chiral ligand dispersed in [BMIM]SbFg, the enantioselective hydrogenation of a-acetamidocinnamic acid to (5)-phenylalanine was achieved with 64% enantiomeric excess 112). [RuCl2( S)-BINAP]2 NEt3 in [BMIM]BF4 for (5)-naproxen synthesis gave 80% ee from 2-(6-methoxy-2-naphthyl) acrylic acid and isopropyl alcohol 214). 

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. 

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... 

Naproxen, an anti-inflammatory drug, is synthesized by utilizing an asymmetric enantioselective hydrocyanation of vinylnaphthalene 1.65 utilizing a chiral ligand 1.66. Since the S-enantiomer is medicinally desirable whereas the i -enantiomer produces harmful health effects, the enantioselectivity of this reaction is important. The synthesis of naproxen nitrile (1.67) shown below produces the S-(—)-enantiomer with 75% ee. 

A variety of important drugs contain the chiral substituent 2-propanoic acid, e. g., naproxen, for which the patent has now expired. Using the methodology of enantioselective hydrogenation, the corresponding a-substituted acrylic acids give high optical inductions [69]. However, in most cases the tedious synthesis of the acrylic acid precursor is the obstacle to industrial application (cf. Sections 2.9 and 3.3.1). 

Because the aldehyde group is an extremely versatile functionality, AH constitutes a useful entree into chiral biologically active compounds such as the nonsteroidal antiinflammatory drug (S)-naproxen (32), commonly called Aleve. Section 9-7-1 highlighted a racemic hydrofomylation that was a key step in the synthesis of ibu-profen. naproxen is quite similar to ibuprofen in structure, but the toxic nature of racemic Naproxen in the body demands that it be synthesized and administered as the much less toxic (S)-enantiomer. Scheme 12.14 shows a possible route to 32, first involving AH of the vinyl naphthalene in the presence of BINAPHOS (34, Fig. 12-6) to create the chiral branched aldehyde and then subsequent oxidative conversion of the aldehyde to the carboxylic acid.83 AH of vinylnaphthalene (33)... 

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. 

Transition metal-catalyzed hydrovinylation is one of a few practically useful carbon-carbon bond-forming reactions utilizing feedstock carbon sources for the synthesis of high-value fine chemicals. Asymmetric hydrovinylation has many potential applications in the synthesis of pharmacologically important compounds, such as ibuprofen and naproxen, and has attracted much attention [110]. Recently, chiral monodentate phosphines have proven to be highly efficient ligands for the asymmetric hydrovinylation of a-alkyl vinylarenes [111]. 

Pirkle, W.H. Welch, C.J. Lamm, B. Design, synthesis, and evaluation of an improved enantioselective naproxen selector. J.Org.Chem., 1992, 57, 3854-3860 [chiral also carprofen, cicloprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, pirprofen, tiaprofenic acid]... 

The Zambon synthesis of the non-steroidal anti-inflammatory agent (5)-2-(6-methoxy-2-naphthyl)propanoic acid (naproxen) is a landmark-setting application of the chiral auxiliary approach in the industrial stereoselective synthesis of an enantiomerically pure drug [51]. The chiral auxiliary employed, a (2f ,Jf )-dialkyltartrate, is a paradigmatic representative of this class of stereocontroller, being cheap, readily available, easily introduced on the substrate and removed from the product, and eventually recycled (although as its parent acid). 

One of the few available examples is represented by the synthesis of cilastatine by a chiral Cu complex promoted cyclopropanation reaction developed by Sumitomo Chemical Co. [78]. Another is the catalytic asymmetric hydrocyanation of vinylarenes developed at DuPont [79]. In this process (Fig. 27) sugar-derived phosphinites are used in combination with a Ni catalyst to prepare enantiomerically enriched precursors of the NSAID naproxen. 

NAP ligand. The resulting chiral polymeric phosphine was then used to form a Ru(BINAP)-type complex by reaction with [Ru(cymene)Cl2]2 this complex formed in situ and was used to hydrogenate the naproxen precursor shown in Eq. 75. The activity of this complex in naproxen synthesis in this biphasic system was higher than in pure ethyl acetate or in miscible methanol-water mixtures. This in situ formed catalyst was also more active than a low molecular weight Ru(4-Na03S-BINAP) catalyst in a similar asymmetric hydrogenation of... 

Figure 9.5 lists the more important P-, N-, and S-containing chiral ligands used in asymmetric synthesis. Of these, Noyori s BINAP (axially dissymmetric phosphine-substituted binaphthyl) is probably the most effective and is used, for instance, as a Ru complex in the synthesis of (5)-naproxen (Noyori and Takaya,... 

Pirkle, W.El. Liu, Y. Design, synthesis, resolution, determination of absolute eonfiguration, and evaluation of a chiral naproxen selector. J. Org. Chem. 1994. 59. 6911-6916. 

An interesting example of a chirality pool material used as a chiral auxiliary, is the industrial synthesis of -naproxen, reported by Zambon [15]. Naproxen is the generic name of the non-steroidal anti-inflammatory drug, S-2-(6-methoxy-2-naphthyl) propanoic acid, described originally by Syntex in 1967 [16]. It is interesting to compare the Syntex and Zambon strategies for the production of S-naproxen (Schemes 7.2 and 7.3, respectively). 

The Zambon process also starts from P-naphthol, and affords S-naproxen directly avoiding resolution and recycling. It is one of the few examples of a non-enzymatic, non-fermentation industrial asymmetric synthesis. Clearly, the early stages of the process produce similar waste streams to the Syntex process, with additionally waste from the Friedel-Crafts step. In principle, however, the aluminium salts can be recycled by work-up involving conversion back to aluminium chloride. The key step in this route is the highly diastereoselective (94 6) bromination of the ketal diester, derived from chirality pool 2R, 3R tartaric acid, which is used as an auxiliary. The subsequent acid catalysed 1,2-aryl shift occurs with complete inversion of configuration at the migration terminus [17]. The tartaric acid auxiliary can be efficiently recycled, but clearly there is a... 

---