Diisopropylethylamine → (+/-)-3-({5-[1-(4'-Tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester

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Reaction Steps

To a mixture of (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.546 g, 1.34 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.204 g, 1.46 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.217 g, 1.60 mmol) in DMF (12.3 mL) is added N, N-diisopropylethylamine (0.70 mL, 4.01 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.333 g, 1.74 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-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.472 g, 71%) as a white solid. MS (ES): 492.1 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak OD-H 4.6×150 mm; eluent: 10:90 3A alcohol/Heptane; flow rate: 0.6 mL/min; UV absorbance wavelength: 270 nm) to provide Isomer 1 (0.180 g, 98.3% ee) and Isomer 2 (0.190 g, 96.7% ee).

Provenance & Evidence