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. triethylamine (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 gradient). The fractions that contained product were re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes gradient). The front peak was collected and pooled and concentrated in vacuo. TLC corresponded to the free base of (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride prepared in Example 6. 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 to give 107 mg of (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride. LCMS: M+1=481; 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.83 (br. s., 1H) 3.03 (br. s., 1H) 3.16 (br. s., 1H) 3.48 (t, J=6.99 Hz, 1H) 3.68 (br. s., 2H) 4.21 (d, J=11.71 Hz, 1H) 4.52 (br. s., 1H) 5.61 (br. s., 1H) 5.71 (br. s., 1H) 7.17 (d, J=7.55 Hz, 1H) 7.29-7.45 (m, 5H) 7.50 (d, J=10.58 Hz, 1H) 8.83 (br. s., 1H).

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 gradient)
6. customwere re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes gradient)
7. customThe front peak was collected
8. concentrationconcentrated in vacuo
9. dissolutionThe resulting colorless film was dissolved in 2:1 hexanes ether
10. additiontreated with 1M HCl in ether (1 mL)
11. concentrationThe resulting sticky solid was concentrated in vacuo
12. customto afford the salt, which