Reaction Steps
To a solution of tert-butyl 4-(adamantan-2-yloxy)-5-chloro-2-fluorobenzoate in toluene-water (v/v 20:1, 20 mL) was added cyclopropylboronic acid (0.57 g, 6.65 mmol) and tribasic potassium phosphate (4.10 g, 19.31 mmol). The mixture was then sparged with argon for 5 minutes and was then charged with tricyclohexylphosphine tetrafluoroborate (0.33 g, 0.90 mmol) and palladium acetate (0.11 g, 0.47 mmol) and the reaction mixture was heated at 110° C. for 16 hours. The reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and washed with ethyl acetate, concentrated in vacuo. to give the crude product: 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.5 Hz, 1H), 6.49 (d, J=12.9 Hz, 1H), 4.45 (br s, 1H), 2.18-2.04 (m, 6H), 1.94-1.81 (m, 9H), 1.56 (s, 9H), 0.92-0.86 (m, 2H), 0.67-0.62 (m, 2H). The crude product was dissolved in anhydrous dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 2 hours at ambient temperature; concentrated in vacuo to give the crude carboxylic acid (1.02 g, 72%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.6 Hz, 1H), 6.56 (d, J=13.2 Hz, 1H), 4.49 (br s, 1H), 2.20-1.70 (m, 12H), 1.62-1.53 (m, 1H), 1.34-1.17 (m, 2H), 0.96-0.90 (m, 2H), 0.69-0.64 (m, 2H). The crude carboxylic acid (0.34 g, 1.03 mmol) was dissolved in anhydrous dichloromethane (27 mL) and added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.30 g, 1.56 mmol) and 4-dimethylaminopyridine (0.30 g, 2.42 mmol), after stirring for 5 minutes, azetidine-1-sulfonamide (0.23 g, 1.69 mmol) was added and stirring was continued for 16 hours at ambient temperature. The mixture was then poured into a 5% aqueous solution of hydrochloric acid, the layers separated and the aqueous layer extracted with dichloromethane (3×20 mL). The combined organic layers were then washed with distilled water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 30% ethyl acetate in hexanes) to afford the title compound (0.11 g, 24%): 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=16.5 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 6.56 (d, J=14.8 Hz, 1H), 4.53-4.48 (m, 1H), 4.25 (t, J=7.74 Hz, 4H), 2.32-2.07 (m, 7H), 2.01-1.79 (m, 8H), 1.62-1.58 (m, 2H), 0.97-0.90 (m, 2H), 0.71-0.65 (m, 2H); MS (ES−) m/z 447.2 (M−1).
