反应详情

温度

80 °C

To a stirred solution of 3,3-difluoro-1-methylcyclobutanecarboxylic acid (0.047 g, 0.311 mmol) in toluene (2.0 mL) was added TEA (0.167 mL, 1.195 mmol), followed by DPPA (0.104 mL, 0.478 mmol) and the reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 3481 (0.08 g, 0.239 mmol) in THF (1.0 mL) and stirred at RT for 14 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 1% MeOH in CHCl3) to afford the racemic compound. The individual isomers were separated by preparative Chiral SFC (Column: Lux cellulose-4 (250×4.6) mm, 5 μm, flow rate 4 mL/min, Mobile Phase A: CO2, Mobile Phase B: 0.2% DEA in methanol, back pressure: 100 bar. Retention time: 3.84 min. and 8.08 min. respectively for Compounds 348 and 349.

1. temperatureThe reaction mixture was cooled to RT and to it
2. stirringstirred at RT for 14 h
3. washwashed with water and brine
4. dry with materialThe organic layer was dried over Na2SO4
5. filtrationfiltered
6. concentrationthe filtrate concentrated under reduced pressure
7. customThe crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 1% MeOH in CHCl3)
8. customto afford the racemic compound
9. customThe individual isomers were separated by preparative Chiral SFC (Column
10. customRetention time: 3.84 min. and 8.08 min.