Reaction #47437

Reaction equation

(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

Yield 53.5%

Solvents

N,N-dimethylformamide

Conditions

Workup

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

Procedure

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).

Source