Cyanogen Bromide → 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile

HRID 1850774Notes

Reaction equation

HRID 1850774 reaction equation
[N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22](OCC(C)C)=O)[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[N:37]#CBr>C(Cl)(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:37])[CH2:18][CH2:17]3)=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1

Participants

5

Reactant 3

HCID 10476Cyanogen BromideHCID 11430Potassium CarbonateHCID 66563045isobutyl 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carboxylate

Product 1

HCID 867112014-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step B, Example 1; 300 mg, 0.958 mmol) and potassium carbonate (492 mg, 3.57 mmol) were stirred in chloroform (10 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 8.89 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 4.11 (t, J=6.5 Hz, 2H), 3.50-3.25 (m, 2H), 3.10-2.90 (m, 2H), 2.25-2.10 (m, 1H), 1.90-1.75 (m, 2H), 1.65-1.40 (m, 3H), 1.10-0.80 (m, 2H), 0.80-0.60 (m, 2H), −0.09 (q, J=4.7 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-de4fad05e9674ff6bd9c683a8915af06
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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