6-Chloro-N-methylnicotinamide → 6-[(3-Boc-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)oxy]-N-methylnicotinamide

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Reaction Steps

7-Hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (8.7 g, 33 mmol) was dissolved in tert-butanol and treated with potassium-tert-butoxide (4 g, 36 mmol). After stirring for 30 minutes at room temperature, 6-chloro-N-methyl-nicotinamide (D10) (5.1 g, 30 mmol) was added and the reaction mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Ice/water was added to the crude residue resulting in a precipitate which was collected by filtration. The solid precipitate was dissolved in ethyl acetate, washed with brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:1) to afford the title compound (D39). NMR (CDCl3) 8.52 (1H, d, J=2.4), 8.12 (1H, dd, J=8.8), 7.16 (1H, m), 6.95-6.81 (3H, m), 6.02 (1H, br), 3.57 (4H, br), 3.02 (3H, d, J=2.4), 2.89 (4H, br), 1.49 (9H, s).

Provenance & Evidence