Naproxen, synthesis using asymmetric

Fig. 35. The optimization of S-Naproxen synthesis using Ru-BINAP asymmetric hydrogenation...

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

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... 

Hydroformylation has been extensively studied since it produces optically active aldehydes which could be important precursors for pharmaceutical and fine chemical compounds. Thus, asymmetric hydroformylation of styrene (Scheme 27) is a model reaction for the synthesis of ibuprofen or naproxen. Phosphorus ligands were used for this reaction with excellent results, espe-... 

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... 

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... 

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]. 

We describe the extension of this class of bisphosphite catalysts to asymmetric hydroformylation and hydrocyanation of vinylarenes.(3) These enantiose-lective catalytic transformations are employed for the asymmetric synthesis of S-Naproxen, a widely used non-steroidal anti-inflammatory drug (NSAID). Factors which influence regioselectivity and enantioselectivity, as well as characterization of the catalyst resting states, are discussed. 

The asymmetric dihydroxylation has been applied in many synthetic sequences and is discussed further in Part B, Chapter 12. For example the dihydroxylation was the starting point for enantioselective synthesis of 5-ibuprofen and a similar route was used to prepare -naproxen, which contains a methoxynaphthalene ring. Ibuprofen and naproxen are examples of the NSAID class of analgesic and anti-inflammatory agents. 

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. 

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,... 

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... 

This reaction was used in the highly successful commercial production of the drug l-DOPA by hydrogenation of the alkene 9. l-DOPA is effective against Parkinson s disease. Another commercial process is the asymmetric synthesis of the pain reliever, naproxen. ... 

The most important advantage of using neutral ionic liquids is that the reaction products can be easily separated from the ionic liquids and the catalyst. Using the neutral ionic liquids, cyclohexene can be reduced to cyclohexane." Even benzene could be reduced to cyclohexane. An interesting asymmetric hydrogenation using a chiral catalyst [RuClj-(S)-BINAP]j,NEt has enabled the synthesis of (S)-Naproxen (Scheme 5). ... 

In 2015, this principle was applied on an asymmetric version [17a, b]. As chiral modifier (S,S)-Ph-BPE was used, whereas other prominent ligands like (S)-BINAP, (fJ,S)-BINAPHOS, or (S,S)-BDPP performed clearly inferior in terms of conversion, yield, as well as regio- and enantioselectivity. The optimized conditions were used for the synthesis of aldehydic precursors of ibuprofen and naproxen (Scheme 3.6). By the addition of external CO, the reaction was decelerated. In the same... 

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