Sodium hydride → 1,1-dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-1'-(phenylmethyl)-4H-spiro[naphthalene-1,4'-piperidin]-3-yl)carbonyl)glycinate

Participants

Reaction Conditions

Reaction Steps

A suspension of NaH (60% dispersion in mineral oil (36 mg, 895 μmol)) in dioxane (5 mL) in an oven-dried round-bottomed flask was treated with a solution of (E)-benzaldehyde oxime (108 mg, 895 μmol) in DMF (4 mL) in a dropwise fashion. The reaction was stirred at 23° C. under nitrogen. After 30 minutes, the reaction was cooled to 0° C., and was then treated with a solution of ethyl 1-benzyl-4-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)piperidine-4-carboxylate (325 mg, 716 mmol) in DMF (4 mL) which was added in a dropwise fashion over 10 minutes. After 1 hour, the solution was diluted with EtOAc (150 mL) and washed with a saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 2-10% MeOH/DCM), affording the cyclized product, a solution of which (160 mg, 376 μmol) in 1,4-dioxane (7 mL) was treated with glycine tert-butyl ester hydrochloride (94.5 mg, 564 μmol) and DIPEA (131 μL, 751 μmol). The reaction was heated to 120° C. After 19 hours, the reaction was cooled to 23° C., diluted with EtOAc (50 mL) and washed with a saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0-5% MeOH/EtOAc+1% TEA), affording 120 mg (62%, 2 steps) of 1,1-dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-1′-(phenylmethyl)-4H-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycinate. MS m/e=512.2 (M+H)+.

Provenance & Evidence