反应详情

To a degassed solution of 4-(4-bromo-2-chloro-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.255 g, 0.59 mmol, see Ex.#3 step D) in anhydrous THF (2.5 mL) was added dropwise isopropylmagnesium chloride lithium chloride complex solution (2.25 mL, 1.3 M in THF, 2.93 mmol) at about 0° C. After complete addition, the mixture was stirred at rt for about 4 h, then cooled to about −40° C. and acetone (0.3 mL, 4.1 mmol) was added dropwise. Subsequently, the mixture was warmed to rt, treated with methanol (2 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL), washed with saturated aqueous ammonium chloride (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, diethyl ether) to give 2-[3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenyl]propan-2-ol (0.095 g, 0.23 mmol, 39%) as a white foam: LC-MS (Table 1, Method e) Rt=6.53 min; m/z 415 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.52 (3 H, s) 1.53 (3 H, s) 1.69 (1 H, s) 2.71 (1 H, ddd, J=15.0, 5.2, 2.0 Hz) 2.88 (1 H, ddd, J=15.0, 9.3, 2.6 Hz) 3.21-3.29 (1 H, m) 3.57-3.66 (1 H, m) 3.79 (1 H, dd, J=3.8, 5.4 Hz) 3.83 (3 H, s) 6.84 (1 H, s) 7.08 (1 H, ddd, J=7.5, 4.8, 1.1 Hz) 7.20 (1 H, dd, J=8.1, 1.8 Hz) 7.27 (1 H, d, J=8.1 Hz) 7.52 (1 H, d, J=1.8 Hz) 7.59 (1 H, td, J=7.9, 1.8 Hz) 7.73 (1 H, dt, J=7.9, 1.1 Hz) 8.53 (1 H, ddd, J=4.8, 1.8, 1.0 Hz); and 4-(2-chlorophenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.035 mg, 0.10 mmol, 17%) as a white foam: LC-MS (Table 1, Method e) Rt=7.62 min; m/z 357 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.72 (1 H, ddd, J=15.1, 6.1, 2.2 Hz) 2.87 (1 H, ddd, J=15.1, 9.1, 2.5 Hz) 3.23-3.32 (1 H, m) 3.57-3.66 (1 H, m) 3.81 (1 H, br s) 3.84 (3 H, s) 6.82 (1 H, s) 7.05-7.13 (3 H, m) 7.25-7.31 (1 H, m) 7.36-7.42 (1 H, m) 7.59 (1 H, td, J=7.7, 1.5 Hz) 7.72 (1 H, dt, J=8.0, 1.1 Hz) 8.52 (1 H, ddd, J=4.8, 1.5, 0.8 Hz).

1. additionAfter complete addition
2. temperaturecooled to about −40° C.
3. temperatureSubsequently, the mixture was warmed to rt
4. concentrationconcentrated in vacuo
5. dissolutionThe residue was dissolved in ethyl acetate (40 mL)
6. washwashed with saturated aqueous ammonium chloride (10 mL)
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customThe resulting residue was purified by column chromatography (SiO2, diethyl ether)