Ethyl Acetate → (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester

HRID 19117Notes

Reaction equation

HRID 19117 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C([O:14][C:15](=O)/[CH:16]=[C:17](/[O:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH2:29][CH3:30])[C:22]=1[F:31])\[CH2:18]Br)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:18][C:17]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH2:29][CH3:30])[C:22]=2[F:31])=[CH:16][C:15]1=[O:14])[CH2:7][CH:8]([CH3:10])[CH3:9]

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 2723695Leucine methyl ester hydrochlorideHCID 66894256HCID 66894256, compound

Product 1

HCID 66895064(S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl esterYield 28.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

To a solution of (L)-leucine methyl ester hydrochloride (6.00 g, 0.033 mol) dissolved in acetonitrile (50 mL) was added (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (6.05 g) in acetonitrile (10 mL) and N,N-diisopropylethylamine (7.27 g, 0.056 mol) and the resulting mixture refluxed for 14 h. The reaction mixture was cooled to room temperature and then poured into ethyl acetate. The mixture was filtered to remove salts and the filtrate washed successively with saturated ammonium chloride, water, and brine. The solution was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in tetrahydrofuran (10 mL) and then transferred to an Emry Optimizer microwave reaction vessel and heated at 160° C., for 4 h. The crude product obtained after aqueous work-up, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 100 g, 5% to 60% ethyl acetate/hexanes) to afford (S)-2-[4-(3ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.80 g, 28%) as an oil.

Workup

  1. temperaturethe resulting mixture refluxed for 14 h
  2. filtrationThe mixture was filtered
  3. customto remove salts
  4. washthe filtrate washed successively with saturated ammonium chloride, water, and brine
  5. dry with materialThe solution was dried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated
  8. dissolutionThe residue was dissolved in tetrahydrofuran (10 mL)
  9. customtransferred to an Emry Optimizer microwave reaction vessel
  10. temperatureheated at 160° C., for 4 h
  11. customThe crude product obtained after aqueous work-up
  12. customwas purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 100 g, 5% to 60% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-7c6192635bce49658e35fd65e387b7be
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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