In a 50 mL round-bottom flask, (2S)-3-(2-(3,5-dichlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (prepared in Example 45, 400 mg, 1.16 mmol) was combined in dichloromethane (12 ml) to give a colorless solution. TEA (118 mg, 162 μl, 1.16 mmol) was added. 1-chloro-2-fluoro-4-isocyanatobenzene (219 mg, 1.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. Reaction was not complete by LCMS. Additional 1-chloro-2-fluoro-4-isocyanatobenzene (219 mg, 1.28 mmol) was added. Reaction was stirred at room temperature for 30 min. Complete by LCMS. The reaction mixture was diluted with an equal volume of hexanes and filtered. The precipitate was washed with dichloromethane/hexanes (1:1) twice. The crystalline solid was pure symmetrical urea. The combined filtrate and washes were concentrated. Two major close-running spots of similar intensity could be seen by TLC (silica 10% EtOAc in hexanes eluent), a front-running spot and a later-running spot. The resulting residue was purified by flash chromatography (silica gel, 40 g, 5% to 10% EtOAc in hexanes). The front spot was isolated to provide pure product, assigned as epimer (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3,5-dichloro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester. This product was taken up in ether, treated with 1M HCl in ether (2 mL). Hexane was added and the mixture was concentrated in vacuo to afford (4-chloro-3-fluorophenyl)-carbamic acid (S)-1-[(R)-2-(3,5-dichloro-phenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride as a white powder (193 mg). (M+H)|=515, 517 m/e.
