Acetic Anhydride → rel-1-(1,1-Dimethylethyl) 3-methyl (3R,5S)-1,3,5-piperidinetricarboxylate

Participants

Reaction Conditions

Reaction Steps

(3R,5S)-1-(tert-Butoxycarbonyl)piperidine-3,5-dicarboxylic acid (222 g) was suspended in acetic anhydride (2 L), and the suspension was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure. Toluene (200 ml) was added and the mixture was concentrated under reduced pressure. This operation was repeated twice. The obtained residue and quinidine (142 g) were dissolved in THF (900 ml), and the mixture was cooled to −40° C. A solution of methanol (161 ml) in THF (100 ml) was added dropwise over 30 min, and the mixture was stirred at the same temperature for 7 hr. THF (about 700 ml) was evaporated under reduced pressure, ethyl acetate was added, and the mixture was washed with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, the organic layer was combined and the mixture was washed successively with 2 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue (106 g) was suspended in ethanol (410 ml). (R)-(+)-1-Phenylethylamine (45 g) was added, and the mixture was dissolved by heating to 75° C. The hot ethanol solution was rapidly filtered, and the filtrate was allowed to stand at room temperature for 12 hr. The resulting colorless crystals were collected by filtration, washed with ethyl acetate-hexane, and then with hexane and air-dried. The obtained solid was suspended in water (490 ml). Saturated aqueous potassium hydrogen sulfate solution (490 ml) was added and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness to give the object compound (148 g) as a solid.

Provenance & Evidence