Реакция #47289

Уравнение реакции

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

(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

6-amino-nicotinic acid methyl ester

bromotripyrrolidinophosphonium hexafluorophosphate

N,N-diisopropylethylamine

→

6-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester

Выход 24.0%

Растворители

ethyl acetate

dichloromethane

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 50% 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 (prepared as in Example 72, 510 mg, 1.28 mmol) in dichloromethane (20 mL) was treated with 6-amino-nicotinic acid methyl ester (252 mg, 1.67 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (1.20 g, 2.57 mmol) and N,N-diisopropylethylamine (438 mg, 2.52 mmol). The reaction mixture was stirred for 5 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 50% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (160 mg, 24%) as a tan solid: HR-ES-MS m/z calculated for C26H26ClF2N3O5 [M+H]+ 534.1602, observed 534.1606; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.73-1.36 (m, 6H) 1.37-1.93 (m, 7H) 3.86 (s, 3H) 4.33 (d, J=18.5 Hz, 1H) 4.64 (d, J=18.5 Hz, 1H) 5.04 (dd, J=11.3, 5.0 Hz, 1H) 5.27 (s, 1H) 7.45 (td, J=9.5, 2.1 Hz, 1H) 7.68 (ddd, J=9.5, 8.1, 5.6 Hz, 1H) 8.13-8.19 (m, 1H) 8.29 (dd, J=8.8, 2.4 Hz, 1H) 8.87 (dd, J=2.4, 0.8 Hz, 1H) 11.32 (s, 1H).

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