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

HRID 19154Notes

Reaction equation

HRID 19154 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.C1(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(=O)([O-])[O-].[Cs+].[Cs+].[CH3:89][NH:90][CH3:91].[O:92]1CC[CH2:94][CH2:93]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:93]([O:92][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:90]([CH3:91])[CH3:89])[C:27]=2[F:33])=[CH:22][C:21]1=[O:34])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:94]

Participants

9

Reactant 5

HCID 674DimethylamineHCID 8028TetrahydrofuranHCID 10796Cesium carbonateHCID 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 66894887(S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl esterYield 34%

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, 0.850 g, 2.05 mmol), palladium(II) acetate (0.050 g, 0.22 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.250 g, 0.40 mmol), and cesium carbonate (1.90 g, 5.83 mmol) in 1,4-dioxane (5 mL) was added a dimethylamine solution in tetrahydrofuran (2M, 3 mL, 6.00 mmol) and the resulting mixture was sealed in a tube and heated at 100° C. for 6 h. The cooled solution was poured into ethyl acetate (100 mL), filtered and the filtrate washed with water, brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered, evaporated and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 10% to 60% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-dimethylamino-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.261 g, 34%) as a yellow oil.

Workup

  1. customthe resulting mixture was sealed in a tube
  2. filtrationfiltered
  3. washthe filtrate washed with water, brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationThe resulting mixture was filtered
  6. customevaporated
  7. customthe residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 10% to 60% ethyl acetate/hexanes) which

Sources & evidence

ORD record
ord-f846ea16b1d64146a3a55f1198b9b177
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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