1-Hydroxybenzotriazole → (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-methyl-[1,2,4]thiadiazol-5-yl)-amide

Participants

Reaction Conditions

Reaction Steps

To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 67 mg, 0.21 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 1-hydroxybenzotriazole (29 mg, 0.22 mmol). The resulting solution was stirred for 5 min before 5-amino-3-methyl-1,2,4-thiadiazole (50 mg, 0.43 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water gradient) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-methyl-[1,2,4]thiadiazol-5-yl)-amide (37 mg, 43%) as a light yellow solid: HR-ES-MS m/z calculated for C19H21ClN4O3S [M+H]+ 421.1096, observed 421.1095; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.35-1.54 (m, 1H), 1.56-1.72 (m, 1H), 1.76-1.93 (m, 1H), 2.44 (s, 3H), 4.28 (d, J=18.4 Hz, 1H), 4.49 (d, J=18.4 Hz, 1H), 4.81 (s, 1H), 5.00 (dd, J=10.6, 4.2 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 13.24 (s, 1H).

Provenance & Evidence