Naproxen hydrocarboxylation

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory dmgs (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by hydroxycarbonylation [51,53] (several more listed in [52]). The carbonylation of styrene itself serves as a useful test reaction in order to learn the properties of new catalytic systems, such as activity, selectivity to acids, regioselectivity (1/b ratio) and enantioselectivity (e.e.) in the branched product. In aqueous or in aqueous/organic biphasic systems complexes of palladium were studied exclusively, and the results are summarized in Table 5.2. 

Asymmetric hydrocarboxylation of styrenes.1 Use of (S)- or (R)-l as a chiral ligand in the palladium-catalyzed hydrocarboxylation of p-isobutylstyrene (2) results in (S)- or (R)-2 (ibuprofen) in 83-84% ee. Similar enantioselectivity obtains in hydrocarboxylation of a 2-vinylnaphthalene to form naproxen. 

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... 

Chiral Ligand for Asymmetric Catalysts. (5)-(+)- and (R)-(—)-BNPPA are efficient chiral ligands for the Pd-catalyzed hydrocarboxylation of alkenes. Naproxen can be obtained re-gioselectively in 91% ee (eq 2). 

Pd -catalyzed hydrocarboxylation of aromatic olefins leads directly to the requisite carboxylic acids (cf. Section 2.1.2.2) under mild conditions (Scheme 5). The reaction, with the aid of (5)-BNPPA (21), a chiral hydrogen phosphate, gives regio- and enantioselectively (S)-ibuprofen and (S)-naproxen, but the turnover efficiency as well as the enantioselectivity can still be improved [26]. 

The hydrocarboxylation of styrene (Scheme 5.12) and styrene derivatives results in the formation of arylpropionic acids. Members of the a-arylpropionic acid family are potent non-steroidal anti-inflammatory drags (Ibuprofen, Naproxen etc.), therefore a direct and simple route to such compounds is of considerable industrial interest. In fact, there are several patents describing the production of a-arylpropionic acids by... 

Thus, ibuprofen and naproxen can be synthesized in 64-89% yield and 83-91 % optical purity via palladium(Il) chloride catalyzed hydrocarboxylation of the corresponding styrenes in the presence of (-)-(/ )- or ( + )-(5)-2,2 -(l,l -binaphthyl)phosphoric acid. The hydrocarboxylation reaction is completely regiospeciftc and proceeds at room temperature under 1.01 bar carbon monoxide pressure25. 

Ibuprofen and naproxen as 2-arylpropionic acids belong to an important new class of nonsteroidal anti-inflammatory agents42. Asymmetric hydrocarboxylation of styrenes thus represents a direct access to optically active or enantiomerically pure probes. 

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. 

The selectivity for formation of the branched isomer and the activity for formation of the carboxylic acid or ester when the catalyst is generated from monodentate ligands, such as PPhj and neomenthyldiphenylphosphine, " is exceptionally high, as shown in Equation 17.34. The use of these ligands led to the development of a particularly efficient method to prepare naproxen by the Albemarle company shown in Equation 17.35. Naproxen was synthesized from 2-bromo-6-methoxynapthalene by a sequence of a Heck reaction (Chapter 19) to form the vinylnapthalene, followed by palladium-catalyzed hydrocarboxylation. Unfortunately, changes in business focus have reduced the use of this process. 

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