Naproxen magnesium salt

Fig. 2 Solubility-pH profiles, 5x of naproxen and four salts A, potassium salt o, sodium salt , magnesium salt and V, calcium salt. (From Ref. l)...

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]. 

---