Реакция #47437

Уравнение реакции

(S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine

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

→

(S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide

Выход 53.5%

Растворители

N,N-dimethylformamide

Условия реакции

Обработка

1. 1
   Другоеthe solvents were evaporated
2. 2
   workup.ADDITIONThe residue was treated with ethyl acetate and ammonium chloride solution
3. 3
   Другоеthe organic layer separated
4. 4
   ПромывкаThe organic layer was washed with brine
5. 5
   Сушкаdried over sodium sulfate
6. 6
   ДругоеThe solvents were evaporated
7. 7
   Другоеthe residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 0% to 80% ethyl acetate/hexanes) which

Методика

To a solution of (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.140 g, 0.37 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.090 g, 0.46 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.655 g, 1.48 mmol). The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 0% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.110 g, 53%) as a white solid: HR-ES-MS m/z calculated for C29H38FN5O5 [M+H]+ 556.2930, observed 556.2928, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.25 (s, 3H), 1.29, 1.31 (2×s, 3H), 1.35-1.64 (m, 2H), 1.66-1.83 (m, 1H), 1.84-1.95 (m, 4H), 3.29-3.39 (m, 4H), 3.73 (dd, J=8.3, 5.9 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.14 (m, 2H), 4.18 (d, J=18.4 Hz, 1H), 4.25-4.41 (m, 1H), 4.56 (d, J=18.4 Hz, 1H), 4.84-4.93 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 6.59-6.70 (m, 2H), 7.03 (t, J=8.2 Hz, 1H), 7.60 (br. s., 1H), 10.79 (s, 1H).

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