Diisopropylethylamine → (S)-2-[4-(2,6-difluoro-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 19035Notes

Reaction equation

HRID 19035 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)C(C)C)(C)C.C1(C[C@H](N2[CH2:58][C:57]([O:59][C:60]3[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=3[F:67])=[CH:56][C:55]2=[O:68])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>CO>[F:66][C:65]1[CH:64]=[CH:63][CH:62]=[C:61]([F:67])[C:60]=1[O:59][C:57]1[CH2:58][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:55](=[O:68])[CH:56]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 44253752(S)-3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamideHCID 67504601(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride

Product 1

HCID 57920164(S)-2-[4-(2,6-difluoro-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 29%

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 (prepared as in Example 92, 300 mg, 0.78 mmol) was dissolved in methanol (5 mL) and N,N-diisopropylethylamine (0.5 mL) was added. The mixture was evaporated to dryness. The residue was dissolved acetonitrile (8 mL). To this solution was added (E)-4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 296 mg, 0.92 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 and concentrated. The crude material was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,6-difluoro-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 (114 mg, 29%): HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2260; 1H NMR (300 MHz, CDCl3) δ ppm 1.16 (s, 6H), 1.24-1.70 (m, 5H), 1.74-1.97 (m, 2H), 2.17-2.30 (m, 1H), 3.29-3.52 (m, 2H), 3.92-4.05 (m, 1H), 3.95 (s, 3H), 4.25 (d, J=17.8 Hz, 1H), 4.43 (d, J=17.8 Hz, 1H), 4.95 (s, 1H), 5.10 (dd, J=8.6, 6.5 Hz, 1H), 6.69 (s, 1H), 6.97-7.10 (m, 2H), 7.14-7.25 (m, 1H), 7.30 (s, 1H), 8.77 (br. s., 1H).

Workup

  1. customThe mixture was evaporated to dryness
  2. dissolutionThe residue was dissolved acetonitrile (8 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. customthe organic layer was dried
  8. concentrationconcentrated
  9. customThe crude material was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient)

Sources & evidence

ORD record
ord-fe8c140c1f3c4a7e8d73f0129e3aae34
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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