Hydrogen Peroxide → HCID 131729887, compound

HRID 1498375Notes

Reaction equation

HRID 1498375 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:40]CC1.[OH-].[Na+].OO.OC1CCNCC1>COCCOCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:12]([OH:40])[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]

Participants

8

Reactant 5

HCID 784Hydrogen PeroxideHCID 14798Sodium HydroxideHCID 79341Piperidin-4-olHCID 2723981Borane;tetrahydrofuranHCID 58204793HCID 58204793, compound

Product 1

HCID 131729887HCID 131729887, compoundYield 5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8150DiglymeSolvent

Procedure

4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.05 g, 2.21 mmol) was partially dissolved in dry diethyleneglycol dimethyl ether (25 mL) and a solution of borane/THF complex (1M in THF, 13.2 mL, 13.2 mmol) was added dropwise. After stirring briefly at room temperature, the mixture was allowed to stand for 16 h. The mixture was then cooled in ice, and water (2 mL), 2M sodium hydroxide (6.5 mL) and 35% hydrogen peroxide (1.7 mL, 16.24 mmol) were added dropwise in sequence. The mixture was heated at 50° C. for 6 h, then cooled, diluted with water (approx. 45 mL) and extracted three times with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-8.5% methanol in DCM) to give the crude product (0.78 g, 71%), containing approx. 20% of 4-hydroxypiperidine isomer which was recrystallised twice from ethyl acetate/methanol to give racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester containing <5% of the cis isomer (0.38 g). LCMS RT=4.44, [M+H]+=495. 1H NMR 400 MHz (DMSO-d6) δ: 8.39 (1 H, d, J=8.25 Hz), 7.89 (1 H, s), 7.47 (1 H, d, J=2.62 Hz), 7.03 (1 H, dd, J=8.29, 1.80 Hz), 6.77 (1 H, s), 6.07-5.99 (1 H, m), 4.37-4.37 (6 H, m), 4.19-4.18 (1 H, m), 3.73-3.73 (1 H, m), 2.66-2.66 (3 H, m), 1.81-1.81 (1 H, m), 1.61 (6 H, d, J=6.01 Hz), 1.50 (9 H, s)

Workup

  1. temperatureThe mixture was then cooled in ice
  2. temperatureThe mixture was heated at 50° C. for 6 h
  3. temperaturecooled
  4. extractionextracted three times with ethyl acetate
  5. dry with materialThe combined organic extracts were dried (Na2SO4)
  6. concentrationconcentrated
  7. customto give the crude product (0.78 g, 71%)
  8. customwas recrystallised twice from ethyl acetate/methanol

Sources & evidence

ORD record
ord-f7d0adf4f6e041159fb5dcbf69f79aa0
Source dataset
uspto-grants-2015_12
Patent number
US09198918B2

Reaction notes

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