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

HRID 19411Notes

Reaction equation

HRID 19411 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 86635248(r)-2-Amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt

Product 1

HCID 66895190(R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl esterYield 46%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
60 °C

Procedure

A suspension of (R)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride salt (1.57 g, 7.50 mmol) in acetonitrile (9 mL) was treated with N,N-diisopropylethylamine (1.62 mL) and stirred at 60° C. for 15 min. At this time the solution was treated with N,N-diisopropylethylamine (1.62 mL) and a solution of (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 61, 2.39 g, 7.49 mmol) in acetonitrile (4 mL) via a dropping funnel and refluxed for 20 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (8 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 80 g, 20% to 80% ethyl acetate/hexanes) which afforded (R)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (1.26 g, 46%).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. customthe residue partitioned between ethyl acetate and water
  3. customThe layers were separated
  4. dry with materialthe organic layer was dried over anhydrous 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. temperatureThe mixture was cooled
  10. concentrationconcentrated in vacuo
  11. customthe residue was purified by ISCO flash chromatography (RediSep silica 80 g, 20% to 80% ethyl acetate/hexanes) which

Sources & evidence

ORD record
ord-d41b863d595d44ba808e4a9608388e8f
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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