Asymmetric naproxen precursor

The potential naproxen precursor 23 is accessible in 96 % yield and in 85 % ee by asymmetric hydrocyanation (cf. Section 2.5) of the aromatic olefin 22 catalyzed by a Ni° complex with a glucose-derived phosphinite ligand (Scheme 6) [27]. 

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... 

Naproxen precursor nitrile. The best reported results are >90% ee at 25°C. Over 4000 turnovers of catalyst have been shown, without deactivation at 100% conversion. After recrystallization, over 99% optical purity of the nitrile was observed. Although this is only one example, there are many other fine examples of asymmetric catalysis being developed that illustrate the power of catalysis in this area, longer term, particularly for chiral drugs and agrichemicals. 

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-... 

Thus, [HRh(C0)(TPPTS)3]/H20/silica (TPPTS = sodium salt of tri(m-sulfophenyl)phopshine) catalyzes the hydroformylation of heavy and functionalized olefins,118-122 the selective hydrogenation of a,/3-unsaturated aldehydes,84 and the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic add (a precursor of naproxen).123,124 More recently, this methodology was tested for the palladium-catalyzed Trost Tsuji (allylic substitution) and Heck (olefin arylation) reactions.125-127... 

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. 

RajanBabu and Casalnuovo [19, 20] tested diphosphinite ligand systems (5 and 6 in Figure 4) based on carbohydrate backbones. The steric and electronic properties depended on the substituents on the aryl groups on the phosphorus atoms. The use of different chlorophosphine precursors led to the electronically asymmetric ligand 6. This approach resulted in both enantiomers of naproxen nitrile from MVN in 91 % ee (S)-nitrile (ligand 5) and 95 % ee (R)-nitrile (ligand 6) at 0 °C. 

Monsanto also uses a similar process to produce a single enantiomer of the arthritis drug Naproxen, a nonsteroidal anti-inflammatory drug (NSAID). Note that this asymmetrical hydrogenation produces only the (.S )-cnantiomer of the drug in a yield of 98.5% from an achiral precursor ... 

The reaction can be carried out asymmetrically, using nickel complexes of chiral phosphite ligands. Examples are the enantioselective hydrocyanation of norbomene using ligand (22-XVIII),48 and of vinylnaphthalene derivatives with (22-XIX).49 The latter is a precursor for the anti-inflammatory drug naproxen. 

Recently, ee s of 85-90% have been obtained for the asymmetric hydrocyanation of 6-methoxy-2-vinyhiaphthalene using nickel complexes of chiral bidentate phosphinites derived from glucose (abbreviated PP, equation 12). This reaction is of great interest to the pharmaceutical industry because the (S) enantiomer of the product nitrile is a useful precursor for the widely marketed antiinflammatory dmg naproxen (equation 13). The same reaction can be applied to a number of other vinyl aromatic compounds, including the precursor for the antiinflammatory drug ibuprofen (6) however, the ee is not as high. 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

S-Naproxen is being produced by Syntex by resolution with a chiral auxiliary. The main patents from Syntex expired in 1993, which represents the main drive for an increase in the efforts to find alternative synthetic routes which may lead directly to an asymmetric carbohydroxylation of the styrene precursor. Asymmetric hydrogenation of molecules of this type has been successfully accomplished by Noyori using ruthenium complexes of the ligand BINAP (Fig. 6.30). With this system a high enantioselectivity can be achieved (97%) albeit at rather high pressures (135 bar). Monsanto [79] claims a similar route that operates at a much lower pressure. The reaction scheme is shown in Fig. 6.31. 

Ruthenium(binap) complexes effectively catalyze asymmetric hydrogenation of a-amidocinnamic acids [172], allylic alcohols [173] and acrylic acids with almost quantitative enantiomeric excess [174]. For example, one of the largest-selling anti-inflammatory agents, Naproxen should be supplied as the enantiomerically pure 5-isomer, because the R-isomer is expected to be toxic to the liver. Asymmetric hydrogenation of the precursor by RuCL[(5)- binap] produces 5-Naproxen with 96-98 % ee (eq (47)) [175-176]. 

Asymmetric hydrogen transfer from EtOH, /-PrOH or triethylammonium formate to Z-a-acetamidocinnamic acid Z-3.32 (R = Ph, Z = COMe, R = H) or to itaconic acid 7.7 (R = H) is highly enantioselective when the catalyst is a binap-Ru complex [873, 1333] (Figure 7.14). The relationship between the absolute configuration of the saturated add and the binap ligand is the same as in the catalytic hydrogenation. However, hydrogen transfer to other a,P-unsaturated acids, such as the precursor of naproxen (7.15), is less enantioselective [1333],... 

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. 

One example of the potential use of asymmetric catalysis comes from our work on asymmetric hydrocyanation (4). The world s fifth largest prescription drug is Naproxen, which is a popular anti-inflammatory compound. Asymmetric hydrocyanation technology offers the potential to produce a precursor to Naproxen, equation 4 ... 

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... 

Profenes or aryl-2-propionic acids are a family of antiinflammatory agents representing an enormous market in pharmacy. Several approaches of syntheses of these compounds using asymmetric catalysis have been used with success. For example, asymmetric hydrocyanation (see Chap. 14) of an olefin by nickel(O) to which a phosphinite ligand derived from glucose is coordinated leads to a nitrile precursor of naproxene with a 96% yield and 85% e.e. ... 

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