Trifluoroacetic acid → (2S)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamide

HRID 1629516Notes

Reaction equation

HRID 1629516 reaction equation
C([O:5][C:6](=O)[C@@H:7]([O:9][C:10]1[CH:33]=[CH:32][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH2:27][C:28]([F:31])([F:30])[F:29])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:43](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[CH2:27][N:23]1[C:22]([C:16]2[N:15]=[C:14]3[C:13]4[CH:32]=[CH:33][C:10]([O:9][C@@H:7]([CH3:8])[C:6]([NH2:43])=[O:5])=[CH:11][C:12]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:26][CH:25]=[N:24]1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58204957(S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid tert-butyl ester

Product 1

HCID 58205016(2S)-2-(2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yloxy)propanamideYield 47%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid tert-butyl ester was dissolved in DCM (3 mL), TFA (0.5 mL) added and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) then to yield 486 as a white solid (57 mg, 47%). LCMS: RT=3.52 min, [M+H]+=423; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.95 (1H, s), 7.51 (1H, br s), 7.22 (1H, br s), 6.73 (1H, dd, J=8.9, 2.6 Hz), 6.50 (1H, d, J=2.6 Hz), 5.86 (1H, q, J=8.9 Hz), 4.64 (1H, q, J=6.6 Hz), 4.51-4.38 (4H, m), 1.40 (1H, d, J=6.4 Hz)

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutionthe residue dissolved in DMF (3 mL)
  3. stirringthe reaction mixture stirred at RT for 1 hour
  4. concentrationThe reaction mixture was concentrated in vacuo
  5. dissolutionthe residue dissolved in ethyl acetate (10 mL)
  6. washthe mixture washed with water extracting with ethyl acetate (3×10 mL)
  7. washThe combined organic extracts were washed with brine
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customphase preparative HPLC (C-18, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient)

Sources & evidence

ORD record
ord-6c9b653338ff4e628df17c8f70f952a3
Source dataset
uspto-grants-2014_07
Patent number
US08785626B2

Reaction notes

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