Hydrochloric Acid → 2-methyl-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 886475Notes

Reaction equation

HRID 886475 reaction equation
C([O:3][C:4](=O)[C:5]([CH3:32])([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:39](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>[CH3:6][C:5]([O:7][C:8]1[CH:31]=[CH:30][C:11]2[C:12]3[N:16]([CH:15]=[C:14]([C:20]4[N:21]([CH2:25][C:26]([F:28])([F:29])[F:27])[N:22]=[CH:23][N:24]=4)[N:13]=3)[CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)([CH3:32])[C:4]([NH2:39])=[O:3]

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 670507542-methyl-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 582043282-methyl-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 50%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 2-methyl-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 (5 mL) was added water (2 mL) and lithium hydroxide monohydrate (25 mg, 0.62 mmol). The reaction mixture was heated at 50° C. for 30 min then HCl (1N, aqueous) 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 472 as a white solid (61 mg, 50%). LCMS: RT=3.74 min, [M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.21 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.52 (1H, br s), 7.25 (1H, br s), 6.68 (1H, dd, J=8.9, 2.8 Hz), 6.47 (1H, d, J=2.8 Hz), 5.85 (2H, q, J=8.9 Hz), 4.49-4.39 (4H, m), 1.44 (6H, s)

Workup

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

Sources & evidence

ORD record
ord-f627a8e516f04488a7a5bcc7bcc39941
Source dataset
uspto-grants-2012_08
Patent number
US08242104B2

Reaction notes

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