Hydrochloric Acid → (2R)-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 886488Notes

Reaction equation

HRID 886488 reaction equation
C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:31]=[CH:30][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=1)[N:13]=3)[CH3:6])C.O.[OH-].[Li+].Cl.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O>[F:27][C:26]([F:29])([F:28])[CH2:25][N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:30]=[CH:31][C:8]([O:7][C@H:5]([CH3:6])[C:4]([NH2:38])=[O:3])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 168937Lithium hydroxide, monohydrateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67050759(R)-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 ethyl ester

Product 1

HCID 58204941(2R)-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 40%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

To a solution (R)-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 ethyl ester in methanol (3 mL) was added water (1 mL) and lithium hydroxide monohydrate (11 mg, 0.42 mmol). The reaction mixture was stirred at RT for 16 h then HCl (1N, aq.) added until pH˜4. The reaction mixture was concentrated in vacuo. The resultant residue was dissolved in DMF (3 mL) and HATU (217 mg, 0.56 mmol), ammonium chloride (45 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) added. The reaction mixture was stirred at RT for 1 h before being concentrated in vacuo. The residue was 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 resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give 487 as a white solid (49 mg, 40%). 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 (2H, q, J=8.9 Hz), 4.64 (1H, q, J=6.6 Hz), 4.51-4.38 (4H, m), 1.40 (3H, d, J=6.4 Hz)

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutionThe resultant residue was dissolved in DMF (3 mL)
  3. stirringThe reaction mixture was stirred at RT for 1 h
  4. concentrationbefore being concentrated in vacuo
  5. dissolutionThe residue was dissolved in ethyl acetate (10 mL)
  6. washthe mixture washed with water
  7. extractionextracting with ethyl acetate (3×10 mL)
  8. washThe combined organic extracts were washed with brine
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-09f8c9e9868b452b95b3d498684c35ac
Source dataset
uspto-grants-2012_08
Patent number
US08242104B2

Reaction notes

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