反应详情

温度

130 °C

To 2-(carboxymethyl)-5-methylbenzoic acid (100 mg, 0.52 mmol, prepared according to the procedure described in Tetrahedron, 1975, 31(20), 2607-2619) in a microwave reaction vessel was added acetyl chloride (0.5 mL). The tube was sealed and irradiated (Biotage Inc., microwave) while stirring at 130° C. for 20 minutes. The reaction was cooled to room temperature and the excess acetyl chloride was removed in vacuo. Dichloromethane was added to azeotrope the excess acetyl chloride and the crude anhydride was dried under vacuum. The crude anhydride was dissolved in acetonitrile (2 mL) and 2-[(1S)-5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1e, 220 mg, 0.52 mmol) was added followed by triethylamine (0.16 mL, 2.06 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and the desired product was purified using reverse phase chromatography (Biotage SNAP (15 g), water/CH3CN=95/5% to 50/50%) to afford (176 mg, 69%) 5-methyl-2-{2-oxo-2-[2-(5-pyrimidin-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]non-7-yl]ethyl}benzoic acid. MS (ES+) 497.6 (M+H)+. 1H NMR (CDCl3) δ 1.54-1.58 (m, 2H), 1.60-1.64 (m, 2H), 2.15-2.38 (m, 5H), 2.78-3.02 (m, 2H), 3.04-3.24 (m, 1H), 3.26-3.52 (m, 6H), 3.62-3.66 (m, 2H), 4.41-4.45 (m, 1H), 7.06-7.27 (m, 3H), 7.34-7.57 (m, 1H), 7.68 (s, 1H), 8.31 (s, 2H), 8.73-8.79 (m, 2H).

1. customin a microwave reaction vessel
2. customThe tube was sealed
3. customirradiated (Biotage Inc., microwave)
4. temperatureThe reaction was cooled to room temperature
5. customthe excess acetyl chloride was removed in vacuo
6. additionDichloromethane was added
7. dry with materialthe crude anhydride was dried under vacuum
8. dissolutionThe crude anhydride was dissolved in acetonitrile (2 mL)
9. stirringThe reaction was stirred at room temperature overnight
10. concentrationThe reaction was concentrated
11. customthe desired product was purified