Naproxen catalysis

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]. 

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... 

The hydrocyanation of vinylarenes ° has been studied by a DuPont team using nickel catalysis. The hydrocyanation of 6-methoxy-2-vinylnaphthalene (2.219) affords the product (2.220), where the enantiomeric excess is strongly dependent upon the electronic nature of the bisphosphinite ligand (2.12). Hydrolysis of the nitrile (2.220) affords the nonsteroidal anti-inflammatory drug Naproxen. This nickel-catalysed procedure has also been applied with some success to the regiose-lective, asymmetric hydrocyanation of 1,3-dienes such as 1-phenyl-1,3-butadiene (2.221) to give the 1,2-adduct (2.222) with ees between 50 and 83%. ... 

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 ... 

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. 

Several analgesic and anti-inflammatory drugs such as ibuprofen and naproxen belong to the general class of a-arylalkanoic acids. An often used synthetic route to these molecules is the C-C bond cleavage by Lewis acid catalyzed rearrangement of the ketals of aryl a-haloalkyl ketones (Rieu et al., 1986). Methods based on asymmetric catalysis have also been developed (see Chapter 9). It has recently been shown (Baldovi et al., 1992) that zinc-exchanged Y-zeolites can catalyze the transformation of the ethylene ketal (14) of 2-bromopropiophenone to the a-phenylpropanoic ester (15) (reaction 6.8). 

As described later in Chapter 9, it is necessary to sulfonate an asymmetric catalyst to produce a water-soluble version. In supporting this on a solid as described, the water is first evacuated. However, an exact amount is reintroduced by contact with water vapor because the presence of water is necessary and the extent of enantioselectivity depends on the amount of water. A useful application of SAP catalysis is the use of SAP-Ru-BINAP-4SOjNa supported on controlled pore glass GPG-240 (supplied by CPG Inc.) in the enantioselective hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid to naproxen (Wan and Davis,... 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

Once the gas flow in the manifold is adjusted, one of the stopcocks on the manifold is opened, and the needle is inserted into a rubber septum on the reaction flask. The gas flow into the reaction flask is controlled with the stopcock on the manifold. Excess gas is vented through another syringe needle inserted into the rubber septum. Often the rate of bubbling observed in the Gas Exit Port will slow when the stopcock to the reaction flask is opened. The gas flow from the Gas Inlet Port will need to be increased in order to maintain bubbling in the Gas Exit Port. A complete description of the use of a gas manifold assembly is given in Experiment 59, Synthesis of Naproxen by Palladium Catalysis. 

Synthesis of Naproxen (Aleve ) by palladium catalysis Green Epoxidation of Chalcones Cyclopropanation of Chalcones... 

The best example of supported aqueous phase catalysis, in which a homogeneous catalyst is embedded in an aqueous layer over silica, is the use of tetrasulfonated BINAP ligand to reduce 2-(6 -methoxy-2 -naphthyl)acrylic acid (31 Fig. 6.4). The ee is dependent on the supported organic phase, and in this case, ethylene glycol on a porous glass gave up to 95% ee for the hydrogenation product (naproxen). 

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. ... 

Wan, K.T. Davis, M.E. (1994) Asymmetric-synthesis of naproxen by supported aqueous-phase catalysis, J. Catal, 148,1-8. 

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