Reacción #47271

Ecuación de reacción

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

(S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

1-hydroxybenzotriazole

→

(S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1-H-pyrazol-3-yl]-propionamide

Rendimiento 24.0%

Disolventes

dichloromethane

dichloromethane

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.STIRRINGThe reaction mixture was stirred for 18 h at 25° C., under nitrogen
2. 2
   Lavadowashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
3. 3
   Secadoa saturated sodium chloride solution and dried over magnesium sulfate
4. 4
   ConcentraciónThe organic layer was concentrated
5. 5
   Otrothe crude product was purified on Gilson HPLC system (C18 column, 10-99% acetonitrile/water gradient)

Procedimiento

A solution of (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (151 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (63 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.38 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, 67 mg, 0.43 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 on Gilson HPLC system (C18 column, 10-99% acetonitrile/water gradient) to afford (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1-H-pyrazol-3-yl]-propionamide (47 mg, 24%) as a white solid: HR-ES-MS m/z calculated for C29H38N4O6 [M+H]+ 539.2864, observed 539.2865; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.99 (m, 2H) 1.05 (s, 3H) 1.07-1.30 (m, 4H) 1.50-1.83 (m, 7H) 3.89 (s, 2H) 3.98 (dd, J=18.1, 4.0 Hz, 1H) 4.09 (dd, J=11.3, 7.5 Hz, 1H) 4.18-4.34 (m, 2H) 4.34-4.45 (m, 1H) 4.53-4.63 (m, 1H) 4.67 (s, 1H) 4.86 (dd, J=11.3, 4.0 Hz, 1H) 5.25 (s, 1H) 6.42 (d, J=2.1 Hz, 1H) 6.79-6.99 (m, 4H) 7.52 (d, J=2.1 Hz, 1H) 10.70 (s, 1H).

Fuente