Réaction #47264

Équation de réaction

1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol

2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

1-hydroxybenzotriazole

→

2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

Rendement 62.0%

Solvants

dichloromethane

dichloromethane

Conditions de réaction

Traitement

1. 1
   workup.STIRRINGThe reaction mixture was stirred for 18 h at 25° C., under nitrogen
2. 2
   Lavagewashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
3. 3
   Séchagea saturated sodium chloride solution and dried over magnesium sulfate
4. 4
   ConcentrationThe organic layer was concentrated
5. 5
   Autrethe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane)

Mode opératoire

A solution of 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (200 mg, 0.51 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (86 mg, 0.56 mmol) and 1-hydroxybenzotriazole (72 mg, 0.53 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 94 mg, 0.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (166 mg, 62%), as an off-white solid: LR-ES-MS m/z calculated for C26H33ClN4O6 [M]+ 532, observed [M+H]+ 533; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.13-1.30 (m, 2H), 1.37 (br. s., 1H), 1.55-1.73 (m, 3H), 1.72-1.87 (m, 1H), 3.13-3.31 (m, 2H), 3.74-3.87 (m, 2H), 3.89 (br. s., 2H), 3.90 (s, 3H), 4.24 (d, J=18.6 Hz, 1H), 4.60 (d, J=18.6 Hz, 1H), 4.68 (s, 1H), 4.82 (s, 1H), 4.92 (dd, J=10.7, 4.7 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.42 (t, J=8.5 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 10.81 (s, 1H).

Source