反应详情

To a mixture of (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carboxylic acid (0.420 g, 0.905 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.148 g, 1.06 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.151 g, 1.12 mmol) in DMF (9.0 mL) is added N, N-diisopropylethylamine (0.49 mL, 2.81 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.0.228 g, 1.19 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate, gradient from 0% to 75% to provide (±)-3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ylsulfanyl)-2-methyl-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.347 g, 70%) as a white foam. MS (ES): 548.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak AD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 280 nm) to provide Isomer 1 (0.126 g, >99% ee) and Isomer 2 (0.119 g, 94.5% ee).

1. extractionextracted with EtOAc (3×25 mL)
2. washCombined organic extracts are washed with H2O, brine
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated
6. washeluted