Naproxen hydrocyanation

Other approaches that have been suggested include catalytic asymmetric hydroformylation of 2-methoxy-6-vinylnaphthalene (6) using a rhodium catalyst on BINAPHOS ligand followed by oxidation of the resultant aldehyde 7 to yield 5-naproxen (Scheme 6.3).22 However, the tendency of the aldehyde to racemize and the co-generation of the linear aldehyde isomer make the process less attractive. Other modifications related to this process include catalytic asymmetric hydroesterification,23 hydrocarboxylation,24 and hydrocyanation.25... 

Other asymmetric synthetic processes used for the manufacturing of (S)-(+)-naproxen can also be applied to the production of (S)-(+)-ibuprofen these include the Rh-phosphite catalyzed hydro-formylation,37 hydrocyanation,25 and hydrocarboxylation reactions.24... 

The alternative potential synthetic routes for the drug Naproxen neatly illustrate the industrial significance of asymmetric hydroformylation and asymmetric hydrocyanation reactions. This is shown in Fig. 9.12. Regio- and en-antioselective hydroformylation or hydrocyanation of 6-methoxy 2-vinyl naphthalene can give the desired enantiomers of the branched aldehyde or nitrile. These two intermediates can be oxidized or hydrolyzed to give 5-Naproxen. 

Figure 9.12 Two alternative synthetic routes for 5-Naproxen. The left-hand route involves asymmetric hydroformylation, while the right-hand one uses asymmetric hydrocyanation.

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. 

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. 

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. 

The features of homogeneously catalyzed hydrocyanations described above prompted attempts to prepare 2-aryl-2-propionitriles 32 (eq. (8)). The development of a synthesis for naproxen demonstrates the successful application of ligand tailoring , the adjustment of the catalyst ligand system to the demands of the reaction. In this case it is of particular importance to achieve a high stereoselectivity because the 7 -enantiomer has a number of undesirable health effects [55],... 

The system was exploited by employing electronically unsymmetrical bis-(diaryl)phosphinites, giving excess of both enantiomers of naproxen nitrile in excellent yields (91 % S, 95 % R). Ligand tuning in the asymmetric hydrocyanation of vinylarenes is comprehensively surveyed by the same authors [57]. Figure 1 illustrates the tunable sites on a sugar-derived ligand. 

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]. 

Keywords Asymmetric hydrocyanation. Hydrogen cyanide, Vinylarenes, 2-Arylpropanoic acids, Naproxen, Arylphosphinites, Carbohydrate ligands. Electronic effects. Electronic asymmetry... 

Naproxen. In addition, the use of chiral bisphosphites in asymmetric olefin hy-drocyanation is described. Details of the structural features responsible for hi b/1 and %ee in asymmetric hydroformylation and hydrocyanation are presented. 

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. 

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. 

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 ... 

More success has been achieved with the enantioselective hydrocyanation of vinylar-enes. For reasons described below, the hydrocyanation of vinylarenes tends to generate the branched, chiral, a-aryl nitrile product, instead of the linear, achiral, P-aryl nitrile product. Much research has focused on the hydrocyanation of 6-methoxyvinylnaphtha-lene because hydrolysis of the nitrile product would lead to the profen drug Naproxen. As shown in Equation 16.9, the hydrocyanation of this vinylarene occurs with high enanti-oselectivity in the presence of a nickel catalyst containing a phosphinite derived from a... 

The hydrocarboxylation of vinylarenes has also been studied extensively as a simple, clean route to the ot-aryl carboxylic acids that are common non-steroidal anti-inflamatory medicines, such as ibuprofen and naproxen. " By this process, a vinylarene undergoes hydrocarboxylation to form the branched a-aryl carboxylic acid. A series of patents and papers describe this hydrocarboxylation process " and the related hydroesteri-fication. Like the hydrosilylations and hydrocyanations presented in Qiapter 16 and the hydroformylations described in this chapter, the regioselectivity for reactions of vinylarenes contrasts with that for reactions of alkenes. The reactions of vinylarenes form branched hydrocarboxylation products. 

Hydrocyanation of vinylarenes provides an interesting access to antiinflammatory and pain killer drugs such as naproxen and dexibuprofen (the pharmacologically active enantiomer of ibuprofen, Scheme 8.3). However, the enantioselective hydrocyanation of these substrate types remains a challenge. In 1994, RajanBabu and Casalnuovo [14] reported the application of glucophosphinite ligands 1 for the hydrocyanation of P-vinylnaphathalene 3. 

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. ... 

The potential of asymmetric catalytic hydrocyanation in the selective synthesis of the drug (S)-naproxen is shown by reaction 5.6.2.1. The aromatic substituents on the phosphorus atoms of 5.68 have a pronounced effect on the enantioselectivity of this reaction. Instead of CFj groups, if the aromatic rings are substituted in the same positions by CHj groups, the ee value drops by 70%. Based on the results of Ni-catalyzed hydrocyanation of 1,3 hexadiene with DCN, reductive elimination appears to be the rate-determining step. 

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