2-Bromo-6-methoxynaphthalene Naproxen

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

An example of an industrial Heck reaction of an aryl bromide is the announced synthesis of Naproxen by Albermarle. Toward that end, 2-bromo-6-methoxynaphthalene is reacted with ethylene in the presence of a homogeneous palladium catalyst. Apparently, as a ligand a sterically hindered basic phosphine is used. Known Pd-catalyzed hydro-carboxylation of 2-methoxy-6-vinylnaphthalene and subsequent resolution give access to Naproxen (Scheme 3). In addition, it was shown that Ketoprofen can be produced by a similar reaction sequence. 

The organic layer contains small amoimts of imreacted 2-bromo-6-methoxynaphthalene, 2-methoxynaphthalene, dicydohexylamine, and a very small amount of unhydrolyzed terf-butyl ester of naproxen. 

Weight of the racemic naproxen, and percentage yield based on the 2-bromo-6-methoxynaphthalene. 

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