Реакция #47541

Уравнение реакции

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

Выход 54.0%

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-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.6 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143 mg, 0.7 mmol) and N,N-diisopropylethylamine (223 mg, 1.7 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (117 mg, 0.8 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 110 mg, 0.7 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-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (150 mg, 54%) as a brown sticky solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.83-1.08 (m, 2H), 1.16 (br. s., 6H), 1.18-1.33 (m, 4H), 1.67-1.81 (m, 5H), 1.81-2.00 (m, 2H), 3.67 (br. s., 1H), 3.94 (s, 2H), 4.09 (d, J=18.1 Hz, 1H), 4.30 (d, J=18.1 Hz, 1H), 4.91 (dd, J=8.8, 6.4 Hz, 1H), 5.05 (s, 1H), 6.69 (br. s., 1H), 6.93 (d, J=8.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 2H), 7.30 (br. s., 1H), 7.34-7.45 (m, 1H), 8.64 (br. s., 1H).

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