Triethylamine → 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-9-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

Participants

Reaction Steps

A solution of methyl 2-(2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-amino}ethoxy)-3-(propan-2-yloxy)benzoate (123e, 76.2 mg, 0.196 mmol) in methanol (5.0 mL) was stirred with sodium hydroxide (1.0 M aq., 0.800 mL, 0.800 mmol) for 28 hours at room temperature, then 4.0 M aqueous sodium hydroxide solution (0.5 mL, 2.0 mmol) was added and stirring continued for 25 hours at room temperature. LCMS showed that a portion of the material had spontaneously cyclized, while some uncyclized material remained. The solvents were concentrated under vacuum and the residue acidified to pH˜2 with 1N aqueous hydrochloric acid solution. The resulting white precipitate was collected by suction filtration. The mother liquor was extracted with ethyl acetate (2×10 mL), and the combined extracts dried over magnesium sulfate, filtered, concentrated under vacuum, and combined with precipitate. The aqueous layer was lyophilized and the residue suspended in N,N-dimethylformamide (6.0 mL), passed through a 0.2 micron syringe filter to remove inorganic salts, and then treated with triethylamine (0.08 m L) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 87.0 mg, 0.23 mmol) for 20 hours at room temperature. This mixture was partitioned between deionized water (5 mL) and ethyl acetate (3×15 mL); and the combined organics were dried, filtered, and concentrated under vacuum. This batch was combined with the first batch of product and purified by reverse-phase HPLC to give the title compound 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-9-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Example 123, 11 mg, 16% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (br. s., 1H), 7.05-7.18 (m, 3H), 5.93 (s, 1H), 4.60 (s, 2H), 4.51 (spt, J=6.03 Hz, 1H), 4.01 (t, J=5.38 Hz, 2H), 3.43 (t, J=5.38 Hz, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.23 (d, J=6.11 Hz, 6H). MS: 357 [M+H].

Provenance & Evidence