Hydroxylamine → N'-hydroxy-4-[(1R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboximidamide

HRID 1850792Notes

Reaction equation

HRID 1850792 reaction equation
[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[N:23]#[C:24]Br.C(=O)(O)[O-].[Na+].[NH2:31][OH:32].C(N(CC)CC)C>ClCCl.O.CO.C(Cl)Cl.O>[OH:32][N:31]=[C:24]([N:20]1[CH2:21][CH2:22][CH:17]([C@H:15]2[CH2:16][C@H:14]2[CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=2)[CH2:18][CH2:19]1)[NH2:23]

Participants

10

Reactant 5

HCID 787HydroxylamineHCID 8471TriethylamineHCID 10476Cyanogen BromideHCID 516892Sodium BicarbonateHCID 708192275-(methylsulfonyl)-2-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}pyridine

Product 1

HCID 86711209N'-hydroxy-4-[(1R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboximidamide

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 21908982Water methylene chlorideSolvent

Procedure

5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (320 mg, 0.98 mmol) was combined with cyanogen bromide (0.395 mL of a 3.0M solution, 1.19 mmol) and sodium bicarbonate (250 mg, 3.0 mmol) at 0° C. in a 10:1 mixture of DCM/water (5 mL), and the resulting slurry stirred for 30 min and warmed to ambient temperature. After 3 hr, HPLC/MS indicated no starting material. The reaction mixture was diluted with dichloromethane (10 mL), water (3 mL) and the layers separated. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (10-40% acetone/hexanes, 25S+ column) to afford a white film (not weighed). The material was dissolved in 3 mL of methanol and to this solution was added hydroxylamine (82 mg, 1.19 mmol) and triethylamine (0.2 mL, 1.48 mmol). The mixture was then heated to reflux for 2 hrs and then cooled to ambient temperature. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (3.5% methanol/95.5% dichloromethane/1% NH4OH, 25S+ column) to afford title compound as a white foam. HPLC/MS; 0.99 min, 383 (M+H)+.

Workup

  1. customat 0° C.
  2. waitAfter 3 hr
  3. customthe layers separated
  4. dry with materialThe organic layer was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. custompurified by flash chromatography (10-40% acetone/hexanes, 25S+ column)
  8. customto afford a white film (not
  9. temperatureThe mixture was then heated
  10. temperatureto reflux for 2 hrs
  11. temperaturecooled to ambient temperature
  12. concentrationThe mixture was concentrated under reduced pressure
  13. customthe residue was purified by flash chromatography (3.5% methanol/95.5% dichloromethane/1% NH4OH, 25S+ column)

Sources & evidence

ORD record
ord-a50f290e54414f64bd9bed8e60dd5535
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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