Реакция #47517

Уравнение реакции

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

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

1-hydroxybenzotriazole

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

(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

N,N-diisopropylethylamine

→

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

Выход 30.3%

Растворители

dichloromethane

ethyl acetate

Условия реакции

Обработка

1. 1
   Другоеat room temperature
2. 2
   Промывкаwashed with a saturated aqueous ammonium chloride solution
3. 3
   ПромывкаThe organic layer was then washed with a saturated aqueous sodium chloride solution
4. 4
   Другоеseparated
5. 5
   Сушкаdried over sodium sulfate
6. 6
   Концентрированиеconcentrated in vacuo
7. 7
   Другоеto afford the crude product, which
8. 8
   Другоеwas purified by flash column chromatography (silica gel (100-200 mesh)) which

Методика

To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (160 mg, 0.4 mmol) in dichloromethane (5 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82 mg, 0.4 mmol) and N,N-diisopropylethylamine (210 mg, 1.6 mmol) at room temperature, under nitrogen. After 15 min,, 1-hydroxybenzotriazole (61 mg, 0.4 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 160 mg, 0.4 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (0.065 g, 30%) as a brown sticky liquid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-1.01 (m, 2H), 1.05 (s, 3H), 1.06 (s, 3H), 1.07-1.20 (m, 3H), 1.50-1.84 (m, 8H), 3.89 (s, 2H), 4.19 (d, J=18.1 Hz, 1H), 4.60 (d, J=18.1 Hz, 1H), 4.66 (s, 1H), 4.92 (dd, J=10.5, 5.1 Hz, 1H), 4.95 (s, 1H), 6.44 (d, J=2.0 Hz, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 10.76 (s, 1H).

Источник