Reaction #47384

Reaction equation

(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

(5-amino-[1,2,4]thiadiazol-3-yl)-acetic acid

→

(5-{(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester

Yield 70.0%

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) 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, 132 mg, 0.41 mmol) in dichloromethane (2.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.47 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46 mmol). The resulting solution was stirred for 5 min before (5-amino-[1,2,4]thiadiazol-3-yl)-acetic acid ally ester hydrochloride (1:1) (100 mg, 0.50 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) which afforded (5-{(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoylamino}-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester (145 mg, 70%) as a light yellow solid: HR-ES-MS m/z calculated for C23H25ClN4O5S [M+H]+ 505.1307, observed 505.1306; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.4 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H), 1.36-1.57 (m, 1H), 1.58-1.76 (m, 1H), 1.77-1.96 (m, 1H), 3.97 (s, 2H), 4.30 (d, J=18.0 Hz, 1H), 4.50 (d, J=18.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 4.83 (s, 1H), 5.01 (dd, J=11.3, 5.6 Hz, 1H), 5.16-5.35 (m, 2H), 5.77-6.01 (m, 1H), 7.37 (ddd, J=8.0, 1.5 Hz, 1H), 7.47 (td, J=8.0, 1.5 Hz, 1H), 7.54 (dd, J=8.0, 1.5 Hz, 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 13.43 (s, 1H).

Source