The title compound has been prepared by two related ways. The alkylation of 2-fluoro-4-hydroxybenzonitrile (I) with 3,4-(methylenedioxy)benzyl chloride (II) afforded ether (III). This was coupled with (R,S)-2-hydroxy-2-(2-methylphenyl)acetic acid (IV) in the presence of NaH in DMSO to produce the racemic adduct (V). Resolution was then achieved by fractional crystallization of the diastereoisomeric salts with (-)-ephedrine to furnish the desired (S)-enantiomer, which was finally isolated as the corresponding sodium salt.
In a related procedure, alkylation of 2,4-dihydroxybenzaldehyde (VI) with chloride (II) gave ether (VII). Subsequent conversion of the aldehyde group of (VII) into the desired nitrile (X) was effected by the following sequence, including formation of the corresponding oxime (VIII), dehydration with concomitant acetylation using Ac2O, and then hydrolysis of acetate (IX) using K2CO3. Alternatively, aldehyde (VII) was directly converted to nitrile (X) by reaction with hydroxylamine-O-sulfonic acid, followed by basic treatment. Racemic alpha-bromo-(2-methylphenyl)acetic acid (XI) was resolved via formation of the corresponding salt with (-)-ephedrine (XII). Hydroxy nitrile (X) was then alkylated with the chiral bromide (XII), and the resulting compound was finally converted to the corresponding sodium salt.
The alkylation of 2-fluoro-4-hydroxybenzonitrile (I) with 4-picolyl chloride (II) afforded ether (III). This was coupled with (R,S)-2-hydroxy-2-(2-methylphenyl)acetic acid (IV) in the presence of NaH in DMSO to produce the racemic adduct (V). Resolution of (V) was then achieved by fractional crystallization of the diastereoisomeric salts with (-)-ephedrine to furnish the desired (S)-enantiomer, which was finally isolated as the corresponding sodium salt.