Reaction #47375

Reaction equation

3-cyclopropyl-[1,2,4]thiadiazol-5-ylamine

(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-cyclopropyl-[1,2,4]thiadiazol-5-yl)-amide

Yield 32.4%

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, 95 mg, 0.29 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol) and 1-hydroxybenzotriazole (41 mg, 0.30 mmol). The resulting solution was stirred for 5 min before 3-cyclopropyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.35 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-cyclopropyl-[1,2,4]thiadiazol-5-yl)-amide (42 mg, 32%) as a light orange solid: HR-ES-MS m/z calculated for C21H23ClN4O3S [M+H]+ 447.1252, observed 447.1252; 1H NMR (300 MHz, DMSO-d6) ppm 0.84-0.97 (m, 2H), 0.91 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.97-1.06 (m, 2H), 1.39-1.56 (m, 1H), 1.55-1.75 (m, 1H), 1.76-1.97 (m, 1H), 2.07-2.24 (m, 1H), 4.28 (d, J=18.4 Hz, 1H), 4.51 (d, J=18.4 Hz, 1H), 4.82 (s, 1H), 4.99 (dd, J=11.0, 4.4 Hz, 1H), 7.37 (td, J=8.0, 1.3 Hz, 1H), 7.47 (td, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=8.0, 1.3 Hz, 1H), 7.66 (dd, J=8.0, 1.1 Hz, 1H), 13.26 (s, 1H).

Source