تفاعل #47512

معادلة التفاعل

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

المردود 40.0%

المذيبات

dichloromethane

ethyl acetate

ظروف التفاعل

المعالجة

1. 1
   أخرىat room temperature
2. 2
   غسيلwashed with a saturated aqueous ammonium chloride solution
3. 3
   غسيلThe organic layer was then washed with a saturated aqueous sodium chloride solution
4. 4
   أخرىseparated
5. 5
   تجفيفdried over sodium sulfate
6. 6
   تركيزconcentrated in vacuo
7. 7
   أخرىto afford the crude product, which
8. 8
   أخرىwas purified by flash column chromatography (silica gel (100-200 mesh)) which

الإجراء التجريبي

To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (125 mg, 0.34 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (195 mg, 1.0 mmol) and N,N-diisopropylethylamine (220 mg, 1.7 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (157 mg, 1.1 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl US2008021032 Example 80, 53 mg, 0.34 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-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (68 mg, 40%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.81-1.08 (m, 3H), 1.14 (s, 6H), 1.16-1.32 (m, 2H), 1.65-1.96 (m, 8H), 3.64 (br. s., 1H), 3.92 (s, 2H), 4.12 (d, J=18.0 Hz, 1H), 4.34 (d, J=18.0 Hz, 1H), 4.89 (dd, J=8.8, 6.8 Hz, 1H), 5.00 (s, 1H), 6.67 (d, J=1.5 Hz, 1H), 7.01-7.15 (m, 3H), 7.28 (d, J=1.5 Hz, 1H), 8.64 (br. s., 1H).

المصدر