反応 #47253

反応方程式

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

(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

1-hydroxybenzotriazole

→

(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

収率 72.0%

溶媒

dichloromethane

dichloromethane

反応条件

後処理

1. 1
   workup.STIRRINGThe reaction mixture was stirred for 18 h at 25° C., under nitrogen
2. 2
   洗浄washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
3. 3
   乾燥a saturated sodium chloride solution and dried over magnesium sulfate
4. 4
   濃縮The organic layer was concentrated
5. 5
   その他the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 100% ethyl acetate/hexanes)

実験手順

A solution of (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (86 mg, 0.55 mmol) and 1-hydroxybenzotriazole (80 mg, 0.58 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, 95 mg, 0.60 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 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (197 mg, 72%) as a white solid: LR-ES-MS m/z calculated for C26H32F2N4O4 [M]+ 502, observed [M+H]+ 503; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.35 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.48-1.85 (m, 7H) 3.89 (s, 2H) 4.26 (d, J=18.8 Hz, 1H) 4.64 (d, J=18.8 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 4.7 Hz, 1H) 5.03 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.20-7.50 (m, 3H) 7.53 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).

出典