Sodium hydride → 4-[2-Cyano-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid

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A mixture of sodium 4-hydroxy-4-(2-methyl-phenyl)butanoate, thought to be the (R)-enantiomer, (3 g) and sodium hydride (1.5 g; 60% w/v dispersion in mineral oil; 37.5 mmol) in tetrahydrofuran (50 mL) is stirred at ambient temperature for 1 hour under an atmosphere of argon, and is then warmed to 55° C. It is then treated with 2-fluoro-4-(3-thienylmethoxy)benzonitrile (3 g), in one portion, and stirring is continued at 55° C. for 15 hours. The mixture is then cooled, diluted with hydrochloric acid (200 mL; 1 N) and extracted with ethyl acetate (4×100 mL). The combined extracts are dried over magnesium sulphate and concentrated in vacuo, to give an oily residue. This residue is boiled in isopropyl ether, and the resulting mixture is filtered while hot, and then allowed to cool. The yellow solid which separates is collected and recrystallized from a mixture of ethyl acetate and hexane, to give 4-[2-cyano-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (1.5 g) in the form of a white fluffy solid, m.p. 145° C. Chiral HPLC assay showed a 98% enantiomeric excess. [Elemental analysis:- C,67.82;H,5.18; N,3.24%; Calculated:- C,67.80;H,5.19;N,3.44%].

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