Hydrochloric Acid → (2R)-2-[[2-(2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]oxy]propanamide

HRID 1629514Notes

Reaction equation

HRID 1629514 reaction equation
C(O[C:4](=[O:30])[C@H:5]([O:7][C:8]1[CH:29]=[CH:28][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]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=3)[CH3:6])C.O.[OH-].[Li+].Cl.C[N:36](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>[CH:25]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:28]=[CH:29][C:8]([O:7][C@H:5]([CH3:6])[C:4]([NH2:36])=[O:30])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1)([CH3:26])[CH3:27]

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 58204720(R)-2-[2-(2-isopropyl-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 58204369(2R)-2-[[2-(2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]oxy]propanamideYield 26%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid ethyl ester (315 mg, 0.77 mmol) in methanol (10 mL) was added water (1 mL) and lithium hydroxide monohydrate (46 mg, 1.15 mmol). The reaction mixture was heated at 50° C. 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 (5 mL) and HATU (583 mg, 1.53 mmol), ammonium chloride (122 mg, 2.29 mmol) and triethylamine (320 μL, 2.29 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) and the product crystallised from acetonitrile to give 485 as a white solid (75 mg, 26%). LCMS: RT=3.25 min, [M+H]+=383

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutionThe resultant residue was dissolved in DMF (5 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
  10. customthe product crystallised from acetonitrile

Sources & evidence

ORD record
ord-2070f41ef1b746eea34b0587d5c2817f
Source dataset
uspto-grants-2014_07
Patent number
US08785626B2

Reaction notes

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