Diisopropylethylamine → (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester

HRID 19407Notes

Reaction equation

HRID 19407 reaction equation
Cl.[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([NH2:12])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3].C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[CH:57]=[CH:56][CH:55]=[CH:54][C:25]=1[O:26][C:27]1[CH2:31]N([C@@H](CC2CCCCC2)C(NC2C=CN(CC(O)(C)C)N=2)=O)[C:29](=[O:53])[CH:28]=1>C(#N)C>[CH2:2]([O:4][C:5](=[O:13])[C@@H:6]([N:12]1[CH2:31][C:27]([O:26][C:25]2[CH:54]=[CH:55][CH:56]=[CH:57][C:24]=2[Cl:23])=[CH:28][C:29]1=[O:53])[CH2:7][CH:8]([CH3:11])[CH2:9][CH3:10])[CH3:3]

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 57920081(S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1-H-pyrazol-3-yl]-propionamideHCID 86635245(S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride

Product 1

HCID 66894874(S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl esterYield 52%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
60 °C

Procedure

A suspension of (S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.05 g, 5.01 mmol) in acetonitrile (6 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and stirred at 60° C. for 15 min. To this mixture was added N,N-diisopropylethylamine (1.2 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 61, 1.6 g, 5.0 mmol) in acetonitrile (4 mL) via a dropping funnel and the resulting mixture refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL). The resulting solution was transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was concentrated in vacuo and the residue purified by ISCO flash chromatography (RediSep silica column 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (950 mg, 52%).

Workup

  1. concentrationThe resulting mixture was concentrated in vacuo
  2. customthe residue was partitioned between ethyl acetate and water
  3. customThe layers were separated
  4. dry with materialthe organic layer was dried over sodium sulfate
  5. filtrationThe mixture was filtered
  6. concentrationconcentrated in vacuo
  7. dissolutionthe residue dissolved in tetrahydrofuran (8 mL)
  8. custommicrowaved at 160° C. for 4 h
  9. concentrationThe mixture was concentrated in vacuo
  10. customthe residue purified by ISCO flash chromatography (RediSep silica column 80 g, 20% to 80% ethyl acetate/hexanes) which

Sources & evidence

ORD record
ord-3dc65d9c8c264c7c9c8e2be65c963895
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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