Methanol → 3-(2,3-dichloro-phenoxy)-4-{(1S,3S)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester

HRID 19045Notes

Reaction equation

HRID 19045 reaction equation
Cl.[OH:2][C:3]([CH3:22])([CH3:21])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[C@@H:12]([NH2:19])[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])=[N:6]1.C(N([CH2:30][CH3:31])C(C)C)(C)C.Cl.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:52][C:51]([O:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=3[Cl:61])=[CH:50][C:49]2=[O:62])CC(C)C)=N1.C[OH:67]>>[CH2:30]([O:67][C:49](=[O:62])[CH:50]=[C:51]([O:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=1[Cl:61])[CH2:52][NH:19][C@H:12]([C:11](=[O:20])[NH:10][C:7]1[CH:8]=[CH:9][N:5]([CH2:4][C:3]([OH:2])([CH3:22])[CH3:21])[N:6]=1)[CH2:13][C@@H:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH3:31]

Participants

5

Reactant 4

HCID 887MethanolHCID 81531DiisopropylethylamineHCID 66899077(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochlorideHCID 66899130(2S,4S)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

Product 1

HCID 675042483-(2,3-dichloro-phenoxy)-4-{(1S,3S)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester

Procedure

(2S,4S)-2-Amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (150 mg, 0.40 mmol) was dissolved in methanol (5 mL) and N,N-diisopropylethylamine (0.3 mL) was added. The solution was evaporated and the residue was dried. The resulting material was dissolved in acetonitrile (6 mL) containing N,N-diisopropylethylamine (0.3 mL). To this solution was added (E)-4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 77, 286 mg, 0.80 mmol). The mixture was refluxed for 7 h. The solvents were evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 20-100% ethyl acetate/hexanes) to give 3-(2,3-dichloro-phenoxy)-4-{(1S,3S)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester (120 mg): LR-ES-MS m/z calculated for C26H36Cl2N4O6 [M]+ 570, observed [M+H]+ 571.

Workup

  1. customThe solution was evaporated
  2. customthe residue was dried
  3. dissolutionThe resulting material was dissolved in acetonitrile (6 mL)
  4. additioncontaining N,N-diisopropylethylamine (0.3 mL)
  5. temperatureThe mixture was refluxed for 7 h
  6. customThe solvents were evaporated
  7. additionthe residue was treated with ethyl acetate and water
  8. customThe layers were separated
  9. customthe organic layer was dried
  10. concentrationconcentrated
  11. customThe crude product was purified by flash column chromatography (silica gel, 20-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-d1de985d7fd14ff89c8e4ce7cccf4558
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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