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)-1 H-pyrazol-3-yl]-amide

HRID 19140Notes

Reaction equation

HRID 19140 reaction equation
[Br:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)[C:8](=[O:19])[CH:7]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:12](=[O:14])[C@@H:11]([N:9]3[CH2:10][C:6]([O:5][C:4]4[CH:20]=[CH:21][CH:22]=[C:2]([Br:1])[C:3]=4[F:23])=[CH:7][C:8]3=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:32]2)[CH2:27][O:26]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 59344941(R)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-amineHCID 66895436(S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

Product 1

HCID 44252757(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)-1 H-pyrazol-3-yl]-amideYield 55%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

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).

Workup

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

Sources & evidence

ORD record
ord-bcf1c62dfc324076946956b2ea96319e
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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