Lithium Hydroxide → N-[(4aR,7aS)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride

温度

100 °C

To a solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide hydrochloride (95 mg, 0.25 mmol) and 2-(2-chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (195 mg, 0.57 mmol) in 1,4-dioxane (5.0 mL) is added diisopropylethylamine (150 μL, 0.86 mmol). The resulting solution is heated at 100° C. for 23 hours, cooled to room temperature, and concentrated. The residue is dissolved in methanol (5.0 mL), followed by the addition of lithium hydroxide (100 mg, 4.11 mmol). The resulting solution is heated at 55° C. for 16 hrs and then cooled to room temperature and concentrated. The residue is purified with a 5 g SCX column, eluting first with MeOH/DCM (¼, 50 mL), followed by elution with ammonia in MeOH (7.0 N)/DCM (¼, 50 mL). The basic filtrate is concentrated, and further purified by silica gel flash chromatography, eluting with a gradient of ammonia in MeOH (2.0 M) in dichloromethane (0% to 10%) to give the free base form of the title compound as a colorless oil. El/MS (m/e): 402.00 (M+H). 19F-NMR (CDCl3): δ (ppm) −154.62. 1H-NMR (CDCl3): δ (ppm) 7.38 (m, 5H), 4.11 (d, 1H), 4.01 (d, 1H), 3.83 (m, 2H), 3.05 (dd, 1H), 2.92 (dd, 1H), 2.81 (m, 1H), 2.37 (s, 3H), 1.53 (s, 6H). The purified material is dissolved in dichloromethane (2 mL), followed by the addition of HCl (1.0 M in diethyl ether, 60 μL, 0.06 mmol) and then concentrated to give the title compound as a white solid (22 mg, 20%).

1. temperaturecooled to room temperature
2. concentrationconcentrated
3. dissolutionThe residue is dissolved in methanol (5.0 mL)
4. temperatureThe resulting solution is heated at 55° C. for 16 hrs
5. temperaturecooled to room temperature
6. concentrationconcentrated
7. customThe residue is purified with a 5 g SCX column
8. washeluting first with MeOH/DCM (¼, 50 mL)
9. washfollowed by elution with ammonia in MeOH (7.0 N)/DCM (¼, 50 mL)
10. concentrationThe basic filtrate is concentrated
11. customfurther purified by silica gel flash chromatography
12. washeluting with a gradient of ammonia in MeOH (2.0 M) in dichloromethane (0% to 10%)

ORDレコード

ord-459019e342314b1da511af024f3b285a

出典データセット

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08772282B2