Cyanogen Bromide → 4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile

HRID 1850786Notes

Reaction equation

HRID 1850786 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].C(=O)([O-])[O-].[K+].[K+].[N:29]#[C:30]Br>C(Cl)(Cl)Cl>[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][N:20]([C:30]#[N:29])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]

Participants

5

Reactant 3

HCID 10476Cyanogen BromideHCID 11430Potassium CarbonateHCID 708192275-(methylsulfonyl)-2-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}pyridine

Product 1

HCID 867112044-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carbonitrile

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

5-(Methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step A, Example 11; 310 mg, 0.957 mmol) and potassium carbonate (489 mg, 3.54 mmol) were stirred in chloroform (15 mL). Cyanogen bromide (122 mg, 1.15 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (99:1, 1 L to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.71 (dd, J=0.5, 2.5 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.84 (dd, J=0.6, 8.7 Hz, 1H), 4.48 (t, J=7.2 Hz, 2H), 3.50-3.35 (m, 2H), 3.07 (s, 3H), 3.05-2.90 (m, 2H), 2.15-2.00 (m, 1H), 1.85-1.75 (m, 2H), 1.60-1.35 (m, 3H), 1.00-0.85 (m, 2H), 0.80-0.50 (m, 2H), −0.12 (q, J=5.0 Hz, 1H). MS (Multimode) m/z 339 [M+H]+.

Workup

  1. temperaturerefluxed overnight
  2. temperatureThe mixture was cooled to RT
  3. additionmixed with silica gel (5 g)
  4. concentrationconcentrated to dryness under reduced pressure
  5. washeluted with dichloromethane/methanol (99:1, 1 L

Sources & evidence

ORD record
ord-f780068952d747828e063fb5b17a9d21
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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