Triethylamine → (s)-2-[4-(2,3-Dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-n-[1-(2-hydroxy-2-methyl-propyl)-1h-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide

HRID 19034

Reaction equation

HRID 19034 reaction equation
Cl.[NH2:2][C@@H:3]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)CC)C.Cl.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=3[Cl:60])=[CH:49][C:48]2=[O:61])CC(C)C)=N1>CO>[Cl:60][C:54]1[C:55]([Cl:59])=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][C:50]1[CH2:51][N:2]([C@@H:3]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:48](=[O:61])[CH:49]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 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 67504601(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride

Product 1

HCID 57920027(s)-2-[4-(2,3-Dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-n-[1-(2-hydroxy-2-methyl-propyl)-1h-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamideYield 3.7%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (118 mg, 0.30 mmol) was dissolved in methanol (2 mL) and triethylamine (0.2 mL) was added. The mixture was evaporated to dryness. The residue was dissolved in acetonitrile (5 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, 109 mg, 0.30 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to give a crude product (180 mg). One part of the crude product (30 mg) was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide as a white powder (6 mg): LR-ES-MS m/z calculated for C25H30Cl2N4O5 [M]+ 536, observed [M+H]+ 537; 1H-NMR (CDCl3) δ ppm 1.16 (s, 6H), 1.25-1.73 (m, 5H), 1.73-2.00 (m, 2H), 2.17-2.34 (m, 1H), 3.29-3.49 (m, 2H), 3.88-4.06 (m, 3H), 4.24 (d, J=17.8 Hz, 1H), 4.42 (d, J=17.8 Hz, 1H), 4.89 (s, 1H), 5.02-5.16 (m, 1H), 6.70 (br s, 1H), 7.14-7.23 (m, 1H), 7.28-7.37 (m, 3H), 7.42 (d, J=8.2 Hz, 1H), 8.76 (br s, 1H).

Workup

  1. customThe mixture was evaporated to dryness
  2. dissolutionThe residue was dissolved in acetonitrile (5 mL)
  3. temperatureThe mixture was refluxed for 40 h
  4. customThe mixture was evaporated
  5. additionthe residue was treated with ethyl acetate and water
  6. customThe layers were separated
  7. dry with materialthe organic layer was dried over sodium sulfate
  8. concentrationconcentrated
  9. customto give a crude product (180 mg)
  10. customOne part of the crude product (30 mg) was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient)

Sources & evidence

ORD record
ord-bfbb81b677a2437da9cee6c0e70db2a5
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

Loading…