반응 #47418

반응 방정식

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

수율 55.0%

용매

N,N-dimethylformamide

반응 조건

후처리

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

실험 절차

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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