Reaction #47387

Reaction equation

1-(5-amino-1,2,4-thiadiazol-3-yl)-2-propanone

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

(S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

1-hydroxybenzotriazole

→

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

Yield 40.0%

Solvents

dichloromethane

Conditions

Workup

1. 1
   workup.ADDITIONwas added
2. 2
   WashThe mixture was washed with saturated ammonium chloride (1 mL)
3. 3
   Otherevaporated
4. 4
   Otherthe 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

Procedure

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, 90 mg, 0.28 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole (41 mg, 0.30 mmol). The resulting solution was stirred for 5 min before 1-(5-amino-1,2,4-thiadiazol-3-yl)-2-propanone (56 mg, 0.29 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-(2-oxo-propyl)-[1,2,4]thiadiazol-5-yl]-amide (51 mg, 40%) as a light yellow solid: HR-ES-MS m/z calculated for C21H23ClN4O4S [M+H]+ 463.1202, observed 463.1202; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.47 (br. s., 1H), 1.59-1.76 (m, 1H), 1.79-1.95 (m, 1H), 2.18 (s, 3H), 4.00 (s, 2H), 4.29 (d, J=18.4 Hz, 1H), 1.59 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.01 (dd, J=10.9, 4.8 Hz, 1H), 7.37 (td, J=7.5, 1 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.54 (m, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 13.37 (s, 1H).

Source