Triethylamine → 2-(5-methoxy-2-pyridinyl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone

Participants

Reaction Steps

To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 8.90 g, 53.2 mmol) in dichloromethane (225 mL) was added 1,1′-carbonyldiimidazole (8.63 g, 53.2 mmol) and the reaction was stirred for 2 hours at room temperature. In a separate flask, triethylamine (28.3 mL, 203 mmol) was added to a mixture of 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 22.5 g, 50.7 mmol) in dichloromethane (113 mL). The activated acid was added to the amine solution and the reaction was stirred at room temperature for 2 hours. Aqueous sodium hydroxide (1N, 80 mL) and 100 mL of water were added and mixture was stirred for 10 minutes. The aqueous layer was washed with 150 mL of dichloromethane. The combined organic layers were washed with aqueous NH4Cl (3×) to remove the residual amine starting material. The organic solution was concentrated to a light green-amber oil and was stirred at 50° C. in EtOAc (150 mL) until a solution was obtained. The solution was cooled to room temperature with stirring. A solid formed and the thick slurry was diluted with 50 mL of EtOAc and 50 mL of heptanes. The slurry was stirred for 1 hour and filtered under nitrogen to afford 2-(5-methoxy-pyridin-2-yl)-1-{2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]non-7-yl}-ethanone (22 g, 89.7%) as an off-white solid. MS (ES+) 484.4 (M+H)+. 1H NMR (CDCl3) δ 1.74 (dt, 4H), 1.95-1.99 (m, 1H), 2.25-2.36 (m, 1H), 2.59 (s, 3H), 2.89-2.99 (m, 1H), 3.11-3.21 (m, 1H), 3.34-3.46 (m, 4H), 3.51-3.61 (m, 4H), 3.83-3.92 (m, 5H), 4.17 (dd, 1H), 7.29 (d, 1H), 7.38 (dd, 1H), 7.53 (d, 1H), 7.88 (s, 1H), 8.00 (d, 1H), 8.06 (s, 1H), 8.16 (d, 1H), 9.02 (s, 1H). [α]D20=+55.0 deg (c=1 mg/mL, MeOH).

Provenance & Evidence