Methanol → 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(1-isopropylazetidin-3-yl)ethoxy)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

HRID 1530566Notes

Reaction equation

HRID 1530566 reaction equation
C(OC([N:8]1[CH2:11][CH:10]([CH:12]([O:14][C:15]2[CH:36]=[CH:35][C:18]3[C:19]4[N:23]([CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:22]=[C:21]([C:27]2[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=2)[N:20]=4)[CH3:13])[CH2:9]1)=O)(C)(C)C.[CH3:37]O.O1[CH2:44][CH2:43]OCC1>Cl>[CH:32]([N:28]1[C:27]([C:21]2[N:20]=[C:19]3[C:18]4[CH:35]=[CH:36][C:15]([O:14][CH:12]([CH:10]5[CH2:9][N:8]([CH:43]([CH3:44])[CH3:37])[CH2:11]5)[CH3:13])=[CH:16][C:17]=4[O:26][CH2:25][CH2:24][N:23]3[CH:22]=2)=[N:31][CH:30]=[N:29]1)([CH3:33])[CH3:34]

Participants

5

Reactant 3

HCID 887MethanolHCID 312751,4-DioxaneHCID 683128283-{1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}azetidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 665587592-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(1-(1-isopropylazetidin-3-yl)ethoxy)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineYield 23%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

A solution of 3-{1-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}azetidine-1-carboxylic acid tert-butyl ester (312 mg, 0.63 mmol) in 4M HCl in dioxane (2 mL) and MeOH (5 mL) was stirred at RT for 1 h then concentrated in vacuo. The resulting residue was combined with Pd/C (150 mg) and NEt3 (0.5 mL) in MeOH (3 mL) and acetone (5 mL) and stirred under an atmosphere of H2 for 18 h. The reaction mixture was filtered and the filtrate partitioned between H2O and EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) then reverse phase HPLC (Phenomenex Gemini 5 μm C18, on a gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford 166 (63 mg, 23%). LCMS: RT 2.92 min [M+H]+ 437.3. 1H NMR (CDCl3, 400 MHz): δ 8.63 (1H, s), 8.45 (1H, d, J=8.95 Hz), 7.87 (1H, s), 7.60 (1H, s), 6.74 (1H, dd, J=8.97, 2.56 Hz), 6.57 (1H, d, J=2.52 Hz), 6.00-5.93 (1H, m), 4.52-4.47 (3H, m), 4.44-4.42 (2H, m), 3.95-3.92 (2H, m), 3.61 (1H, t, J=8.14 Hz), 3.44 (1H, t, J=8.17 Hz), 2.89-2.87 (1H, m), 1.59 (6H, d, J=6.64 Hz), 1.24 (3H, d, J=6.14 Hz), 1.17 (3H, d, J=6.36 Hz), 1.14 (3H, d, J=6.41 Hz)

Workup

  1. concentrationthen concentrated in vacuo
  2. filtrationThe reaction mixture was filtered
  3. customthe filtrate partitioned between H2O and EtOAc
  4. dry with materialThe combined organic phases were dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customThe resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc)

Sources & evidence

ORD record
ord-71d7d145bff8416b9450c4df86c20739
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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