1,1'-Carbonyldiimidazole → (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide

HRID 19404

Reaction equation

HRID 19404 reaction equation
[F:1][C:2]1[C:22]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[N:29]1[CH:30]=[CH:31][N:32]=[CH:33][C:28]=1[NH:27][C:11](=[O:13])[C@@H:10]([N:8]1[CH2:9][C:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:26])([CH3:24])[CH3:25])[C:2]=2[F:1])=[CH:6][C:7]1=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17]

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 78747AminopyrazineHCID 66899241(S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid

Product 1

HCID 57920185(S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamideYield 53%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (prepared as in Example 143, 400 mg, 1.10 mmol), 2-aminopyrazine (208 mg, 2.18 mmol) and carbonyldiimidazole (186 mg, 1.15 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 12 h. At this time the mixture was transferred to an Emrys Optimizer microwave tube and microwaved at 120° C. for 5 h. The mixture was concentrated in vacuo and the residue partioned between ethyl acetate and 0.1N aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, aqueous sodium bicarbonate solution, and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by ISCO flash chromatography (RediSep silica 40 g, 70% to 100% ethyl acetate/hexanes) to afford (S)-2-{4-[2-fluoro-3-(1-hydroxy-1-methyl-ethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (256 mg, 53%) as an off-white fluffy powder: HR-ES-MS (m/z) calculated for C23H27FN4O4 [M+H]+ 443.2089, observed 443.2088. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=6.8 Hz, 6H), 1.41-1.54 (m, 1H), 1.49 (s, 6H), 1.56-1.73 (m, 1H), 1.73-1.91 (m, 1H), 4.25 (d, J=18.4 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.04 (dd, J=11.0, 4.4 Hz, 1H), 5.42 (br. s., 1H), 7.24 (t, J=7.7 Hz, 1H), 7.32-7.40 (td, J=7.7, 1.5 Hz, 1H), 7.56 (td, J=7.7, 1.5 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.42 (s, 1H), 9.28 (s, 1H), 11.19 (s, 1H).

Workup

  1. custommicrowaved at 120° C. for 5 h
  2. concentrationThe mixture was concentrated in vacuo
  3. customThe layers were separated
  4. washthe organic layer was washed with water, aqueous sodium bicarbonate solution
  5. dry with materialdried over sodium sulfate
  6. filtrationThe mixture was filtered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by ISCO flash chromatography (RediSep silica 40 g, 70% to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-ec47902571594f7e800fd48f7aebfc2c
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

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