Реакция #47288

Уравнение реакции

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

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

benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate

N,N-diisopropylethylamine

→

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

Выход 34.0%

Растворители

ethyl acetate

N,N-dimethylformamide

Условия реакции

Обработка

1. 1
   Промывкаwashed with saturated ammonium chloride, water
2. 2
   Сушкаa saturated sodium chloride solution and dried over sodium sulfate
3. 3
   КонцентрированиеThe organic layer was concentrated
4. 4
   Другоеthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes)

Методика

A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (143 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 70 mg, 0.45 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (350 mg, 0.79 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium 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)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (65 mg, 34%) as a light yellow solid: HR-ES-MS m/z calculated for C26H31ClF2N4O4 [M+H]+ 537.2075, observed 537.2071; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-1.31 (m, 6H) 1.05 (s, 3H) 1.06 (s, 3H) 1.52-1.85 (m, 7H) 3.89 (s, 2H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 5.0 Hz, 1H) 5.24 (s, 1H) 6.44 (d, J=2.2 Hz, 1H) 7.45 (td, J=9.6, 2.0 Hz, 1H) 7.54 (d, J=2.2 Hz, 1H) 7.67 (td, J=8.7, 5.3 Hz, 1H) 10.81 (s, 1H).

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