Hydrogen Peroxide → 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-isobutyramide

HRID 708187Notes

Reaction equation

HRID 708187 reaction equation
[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 784Hydrogen Peroxide2×HCID 962WaterHCID 11430Potassium CarbonateHCID 582038042-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile

Product 1

HCID 582042592-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-isobutyramideYield 49.7%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
45 °C

Procedure

A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.26 g, 0.6 mmol) in DMSO (5 mL) was treated with potassium carbonate (16 mg, 0.12 mmol) followed by hydrogen peroxide (30% aq., 0.33 mL) and the mixture was heated at 45° C. for 18 hours then at 50° C. for a few more hours. Further hydrogen peroxide (33 mL, 30% aq.) was added and the mixture heated at 50° C. for 18 hours. After cooling, water was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo and the residue purified by flash chromatography (SiO2, first time with 0-10% MeOH in EtOAc then second time with 0-5% MeOH in DCM). Further purification was by reverse-phase preparative HPLC (Gemini C18 column, gradient 30-40% MeOH in H2O+0.1% HCO2H). A solution of the product in a mixture of chloroform and DCM was treated with 0.2M HCl in ether (0.32 mL) and then concentrated in vacuo to give 446 (27 mg, 9%). LCMS: RT=7.41 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 10.79 (1H, s), 8.34-8.28 (1H, m), 8.06 (1H, s), 7.82 (1H, d, J=17.45 Hz), 7.65 (1H, d, J=4.94 Hz), 7.27-7.16 (1H, m), 7.07 (1H, d, J=1.80 Hz), 5.80-5.72 (1H, m), 4.47 (1H, td, J=10.76, 4.67 Hz), 4.37-4.26 (3H, m), 4.20-3.94 (3H, m), 3.41 (2H, q, J=4.96 Hz), 1.55-1.45 (12H, m)

Workup

  1. waitat 50° C. for a few more hours
  2. temperaturethe mixture heated at 50° C. for 18 hours
  3. temperatureAfter cooling
  4. extractionthe mixture was extracted with EtOAc (×5)
  5. dry with materialThe combined organic extracts were dried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customthe residue purified by flash chromatography (SiO2, first time with 0-10% MeOH in EtOAc
  8. customFurther purification
  9. additionA solution of the product in a mixture of chloroform and DCM
  10. additionwas treated with 0.2M HCl in ether (0.32 mL)
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-2a989e4d85cc4e358194042e09e35575
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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