反应详情

温度

60 °C

(S)-3-((R)-2-(4-chloro-3-fluorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (338 mg, 1.03 mmol) was combined with 1-chloro-2-fluoro-4-isocyanatobenzene (212 mg, 1.24 mmol) in 4 mL of dichloromethane. DIPEA (160 mg, 1.24 mmol) was added. The reaction tube was sealed and reaction mixture stirred at 60° C. for 5 h. TLC indicated complete consumption of the starting material. The mixture was evaporated and the residue was extracted with ether/hexanes (1:2 ratio) and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (0% to 25% ethyl acetate in hexanes gradient). The desired fraction was concentrated and dissolved in ether/hexanes (1:2 ratio) and treated with 1N HCl in ether. Solvents were evaporated the residue was triturated with ether/hexanes (1:2 ratio) and the clear top layer solution was decanted. The resultant white solid residue was dried under heated vacuum to provide (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(4-chloro-3-fluoro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride as a white solid (330 mg). (M+H)+=499 m/e.

1. customThe reaction tube was sealed
2. customreaction mixture
3. customconsumption of the starting material
4. customThe mixture was evaporated
5. extractionthe residue was extracted with ether/hexanes (1:2 ratio) and water
6. washThe organic layer was washed with brine
7. customdried
8. customSolvents were evaporated
9. customthe residue was purified by ISCO flash column chromatography (0% to 25% ethyl acetate in hexanes gradient)
10. concentrationThe desired fraction was concentrated
11. dissolutiondissolved in ether/hexanes (1:2 ratio)
12. additiontreated with 1N HCl in ether
13. customSolvents were evaporated the residue
14. customwas triturated with ether/hexanes (1:2 ratio)
15. customthe clear top layer solution was decanted
16. customThe resultant white solid residue was dried
17. temperatureunder heated vacuum