Cinchonidine naproxen resolution

Acetyl-6-methoxy-naphthalene may be prepared by the acylation of 6-methoxynaphthalene. The resulting product is then subjected to a series of reactions, namely Wilgerodt-Kindler reaction, esterification, alkylation and hydrolysis ultimately yields /)Z-Naproxen. Resolution of the resulting racemic mixture is caused through precipitation of the more potent /)-enantiomer as the cinchonidine salt. 

For racemic resolution of naproxen the use of cinchonidine, A/-alkyl-D-glucamine, dehydroabietylamine or (S)-a-phenylethylamine has been described. 

Perhaps, one of the most important industrial processes using cinchonidine (or quinidine) as the resolving agent was the production of (S)-naproxen (3) by resolution of racemic naproxen. It is not clear whether it is still in use (Figure 13.4) [12],... 

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]. 

Naproxen is prepared (13) by the acylation of 6 substituted naphthalenes by AcCI forming the 2-acetyl derivative, which is further converted to 2-naphthyl acetic acid. Esterification and alkylation of 2-naphthyl acetic acid in the prescence of H2SO4, MeOH, NaH, Mel and with NaOH gave after hydrolysis the naphthyl propionic acid. Resolution of 2-(6-methoxy-2-naphthyl) propionic (Naproxen) was readily achieved by crystallization of the cinchonidine salt. 

Weight of the (S, R) diastereomer obtained in the resolution of racemic naproxen with cinchonidine. 

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