Potassium ethyl malonate → (S)-6-[2-(4-Acetylaminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one

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Reaction Conditions

Reaction Steps

Potassium ethyl malonate (12.9 g) and magnesium chloride (7.6 g) are added to a flask followed by acetonitrile (70 mL) and tetrahydrofuran (45 mL) and the resulting mixture stirred at 15° C. for 3 hours under an inert atmosphere. To a second flask is added (S)-3-[2-(N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (23a) (9.6 g, 31 mmol correcting for 4.9% water content) and tetrahydrofuran (296 mL) followed by carbonyl diimidazole (8.0 g) and the resulting solution stirred at ambient temperature for 3 hours. The latter solution is then added over a 2 hour period to the potassium ethyl malonate-magnesium chloride complex in the first flask and the resulting mixture stirred overnight at 20° C. The mixture was concentrated under vacuum to remove solvent while maintaining the temperature below 40° C. Cold ethyl acetate (116 mL) and water (60 mL) are added to the residue followed by 37% hydrochloric acid (7 g) with agitation while maintaining the temperature below 10° C. The layers are allowed to settle and the aqueous layer separated. The organic layer is extracted twice with a solution of 37% hydrochloric acid (2.5 g) in water (22 mL) followed by a solution of sodium bicarbonate (2 g) in water (20 mL). The remaining organic layer is concentrated under vacuum to remove solvent. The residue is dissolved in methanol (10 mL) and a solution of sodium hydroxide pellets (3.0 g) dissolved in methanol (25 mL) is added and the resulting solution stirred at ambient temperature for 3 days. The solution was concentrated under vacuum to remove solvent. Water (60 mL) was added to the residue and then removed by concentrating under vacuum while maintaining the temperature below 45° C. The remaining oil is dissolved in water (60 mL) and the resulting solution added over 45 minutes to a solution of 3.9 g acetic acid in methanol (10 mL) and water (10 mL). The mixture is stirred overnight at ambient temperature and then cooled to 5° C. and filtered and the solid washed with water (100 mL) and vacuum dried at 60° C. to give 8.0 g (23 mmol; 74% correcting for HPLC purity and water content) of (S)-6-[2-(4-acetylamino-phenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (24a): HPLC: 95.1 %; Water (KF): 4.4%.

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