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

HRID 19040Notes

Reaction equation

HRID 19040 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 66898549(2S,4R)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochlorideHCID 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 hydrochloride

Product 1

HCID 668990993-(2,3-dichloro-phenoxy)-4-{(1S,3R)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester

Procedure

(2S,4R)-2-Amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (125 mg, 0.33 mmol) was dissolved in methanol (5 mL) and N,N-diisopropylethylamine (0.25 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 (0.25 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, 143 mg, 0.40 mmol). The mixture was refluxed for 7 h. Solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic layer was dried and concentrated. The crude product was purified by flash column chromatography (silica gel, 20-100% ethyl acetate/hexanes) to afford 3-(2,3-dichloro-phenoxy)-4-{(1S,3R)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester (60 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 (0.25 mL)
  5. temperatureThe mixture was refluxed for 7 h
  6. customSolvents were evaporated
  7. extractionthe residue was extracted with ethyl acetate and water
  8. customThe organic layer was dried
  9. concentrationconcentrated
  10. customThe crude product was purified by flash column chromatography (silica gel, 20-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-d58d974b55d24f7884efb9082db5537a
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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