Acetic Acid → 1-[2-[2-(3-Hydroxy-1-azetidinyl)ethyl]phenyl]-2-piperidinone

Participants

Reaction Steps

To [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1 (1.32 g, 6.09 mmol, 1 eq) in methanol (50 ml) is added azetidin-3-ol hydrochloride al 1-0 (0.76 g, 6.96 mmol, 1.14 eq). After stirring at room temperature for approximately 30 minutes, acetic acid (522 μl, 9.13 mmol, 1.5 eq), then NaBH3CN (1.15 g, 18.26 mmol, 3 eq) are added. The reaction mixture is stirred overnight at room temperature, then filtered and loaded on an ion exchange acidic resin cartridge prewashed with methanol. The cartridge is then washed with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M ammonia in methanol. This eluate is evaporated to dryness. To the residue obtained is added water (50 ml) and dichloromethane (50 ml). After vigorous shaking and addition of brine, the 2 phases are separated. The organic phase is washed with water (50 ml). The aqueous phases are pooled and washed 3 times with iPrOH/CH2Cl2 (25 ml/50 ml). The organic phases are combined, evaporated to dryness to give 212.6 mg of 1-{2-[2-(3-hydroxyazetidin-1-yl)ethyl]phenyl}piperidin-2-one a11-1 (212.6 mg, 0.775 mmole if assumed pure, 12.7% yield), which is used in next step without any further purification.

Provenance & Evidence