反应详情

温度

50 °C

In a 50 mL round-bottom flask, (2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (218 mg, 704 μmol) was combined with dichloromethane (12 ml) to give a colorless solution. TEA (71.2 mg, 98.1 μl, 704 μmol) was added. 1-Chloro-2-fluoro-4-isocyanatobenzene (157 mg, 915 μmol) was added. The reaction mixture was heated to 50° C. and stirred for 3 h and filtered. The solid was washed with dichloromethane (2×). The combined filtrate and washes were concentrated to a reduced volume and loaded onto a silica column. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in hexanes). The fractions that contained product were re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes). The fractions from the back peak were pooled and concentrated and the resulting colorless film was dissolved in 2:1 hexanes ether and treated with 1M HCl in ether (1 mL). The resulting sticky solid was concentrated in vacuo to afford the salt, which was foamed to a white solid with ether (120 mg). The foam was triturated with ether/hexanes to afford ca. 90% pure (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(S)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride. LCMS: M+1=481;

1. customto give a colorless solution
2. filtrationfiltered
3. washThe solid was washed with dichloromethane (2×)
4. concentrationThe combined filtrate and washes were concentrated to a reduced volume
5. customThe crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in hexanes)
6. customwere re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes)
7. concentrationconcentrated
8. dissolutionthe resulting colorless film was dissolved in 2:1 hexanes ether
9. additiontreated with 1M HCl in ether (1 mL)
10. concentrationThe resulting sticky solid was concentrated in vacuo
11. customto afford the salt, which
12. customThe foam was triturated with ether/hexanes