反应详情

温度

80 °C

A mixture of NaH (55-65% disp. in oil, 0.55 g, 12.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 2-methyl-4-(morpholin-4-ylmethyl)phenol—see WO 2006133567—(2.0 g, 9.6 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.2 g, 12.5 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The residue was purified by column chromatography on SiO2 using 10-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.6 g (75%) of 12A as an oil. 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.34-2.49 (m, 4H), 3.40 (s, 2H), 3.62-3.76 (m, 4H), 3.94-4.07 (m, 2H), 4.23-4.35 (m, 2H), 4.79-4.92 (m, 1H), 6.38 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).

1. temperaturewas cooled by an ice-bath
2. additionwas added drop-wise over 10 minutes
3. temperaturecooled to RT
4. extractionthe mixture was extracted three times with EtOAc (100 mL)
5. customThe residue was purified by column chromatography on SiO2 using 10-75% EtOAc/heptane as eluent
6. customThe product was further purified