反応 #47229

反応方程式

(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid

oxalyl chloride

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

N,N-diisopropylethylamine

→

(S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide

収率 55.0%

溶媒

benzene

dichloromethane

反応条件

後処理

1. 1
   濃縮The reaction mixture was concentrated
2. 2
   workup.DISSOLUTIONdissolved in dichloromethane (8 mL)
3. 3
   workup.STIRRINGThe reaction mixture was stirred at 25° C., under nitrogen for 18 h
4. 4
   洗浄washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution
5. 5
   その他dried
6. 6
   濃縮The organic layer was concentrated
7. 7
   その他the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane)

実験手順

A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (643 mg, 2.53 mmol) in benzene (8 mL) was treated with oxalyl chloride (342 mg, 2.7 mmol), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 3 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in dichloromethane (8 mL) and treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 442 mg, 2.8 mmol), and N,N-diisopropylethylamine (497 mg, 3.8 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (542 mg, 55%) as an off-white powder: LR-ES-MS m/z calculated for C20H30N4O4 [M]+ 390, observed [M+H]+ 391; 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.04 (s, 3 H), 1.06 (s, 3H), 1.08 (m, 1H), 1.26 (m, 1H), 1.44 (m, 2H), 1.50-1.86 (m, 7H), 3.78 (s, 3H), 3.88 (s, 2H), 3.95 (d, Jgem=18.0 Hz, 1H), 4.33 (d, Jgem=18.0 Hz, 1H), 4.66 (s, 1H), 4.78 (dd, J=4.6 Hz, 10.6 Hz, 1H), 5.15 (s 1H), 6.42 (d, J=2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 10.70 (s, 1H).

出典