Cesium carbonate → (S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester

HRID 19157Notes

Reaction equation

HRID 19157 reaction equation
CC1(C)O[C@H](CN2C=CC(N[C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=N2)CO1.[C:37]1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:83](=[O:86])([O-])[O-].[Cs+].[Cs+].[NH:89]1[CH2:93][CH2:92][CH2:91][CH2:90]1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:83]([O:86][C:14](=[O:35])[C@@H:15]([N:20]1[CH2:24][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:89]3[CH2:93][CH2:92][CH2:91][CH2:90]3)[C:27]=2[F:33])=[CH:22][C:21]1=[O:34])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:37]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 31268PyrrolidineHCID 634876Binap, (A+-)-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]-amide

Product 1

HCID 66894784(S)-2-[4-(2-fluoro-3-pyrrolidin-1-yl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl esterYield 41%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (prepared as in Example 128, 0.300 g, 0.72 mmol), palladium(II) acetate (0.023 g, 0.10 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.124 g, 0.20 mmol), and cesium carbonate (0.650 g, 1.99 mmol) in 1,4-dioxane (10 mL) was added pyrrolidine (0.103 g, 1.45 mmol) and the resulting mixture heated to 100° C. in a sealed tube under argon for 6 h. The resulting mixture was taken up in ethyl acetate and water, separated and the organic phase washed with a saturated sodium chloride solution and concentrated. The residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 50 g, 5% to 40% 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 ethyl ester (0.120, 41%) as an oil.

Workup

  1. customwater, separated
  2. washthe organic phase washed with a saturated sodium chloride solution
  3. concentrationconcentrated
  4. customThe residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 50 g, 5% to 40% ethyl acetate/hexanes) which

Sources & evidence

ORD record
ord-4f0c604320e94356b3f4fb63d8b9d85e
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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