反应 #47418

反应方程式

triethylamine

(S)-2-[4-(3-bromo-2-fluoro-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-(3-bromo-2-fluoro-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

收率 55.0%

溶剂

N,N-dimethylformamide

反应条件

后处理

1. 1
   workup.STIRRINGThe mixture was stirred at room temperature for 4 h
2. 2
   其他the solvents were evaporated
3. 3
   workup.ADDITIONThe residue was treated with ethyl acetate and ammonium chloride solution
4. 4
   其他the organic layer separated
5. 5
   洗涤The organic layer was washed with brine
6. 6
   干燥dried over sodium sulfate
7. 7
   其他The solvents were evaporated
8. 8
   其他the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 10% to 50% ethyl acetate/hexanes) which

实验过程

To a solution of (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.250 g, 0.65 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.166 g, 0.84 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.576 g, 1.30 mmol). The mixture was stirred at 0° C. and triethylamine (0.140 g, 1.37 mmol) was added. The mixture was stirred at room temperature for 4 h 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 12 g, 10% to 50% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-bromo-2-fluoro-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 (0.200 g, 55%) as a fluffy powder: HR-ES-MS m/z calculated for C25H30BrFN4O5 [M+H]+ 565.1457, observed 565.1457, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.45 (br. s., 1H), 1.50-1.65 (m, 1H), 1.68-1.83 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.03-4.20 (m, 2H), 4.24 (d, J=18.7 Hz, 1H), 4.29-4.41 (m, 1H), 4.61 (d, J=18.7 Hz, 1H), 4.89 (dd, J=10.9, 4.8 Hz, 1H), 5.00 (s, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.27 (td, J=8.2, 1.4 Hz, 1H), 7.49-7.59 (m, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.63-7.74 (m, 1H), 10.81 (s, 1H).

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