Acetone → rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide

HRID 1041397Notes

Reaction equation

HRID 1041397 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10]2)[C:5]([Cl:20])=[CH:4][N:3]=1.CC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]#[N:34]>>[C:33]([CH2:32][N:15]([C@@H:11]1[CH2:12][CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)[S:16]([CH3:19])(=[O:18])=[O:17])#[N:34]

Participants

5

Reactant 4

HCID 180AcetoneHCID 10796Cesium carbonateHCID 11534Bromoacetonitrile2×HCID 87330136HCID 87330136, compound

Product 1

HCID 87330211rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamideYield 58.5%

Procedure

rel-N-[(1R,3R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (400 mg, 1.18 mmol) was dissolved in acetone (15.0 mL, 204 mmol) and cesium carbonate (576 mg, 1.77 mmol) was added. After 15 min, bromoacetonitrile (130 uL, 1.86 mmol) was added and the mixture stirred at room temperature for 4 days. LCMS analysis showed that the reaction had only gone to 50% completion. A second aliquot of bromoacetonitrile (90.4 uL, 1.30 mmol) was added and the reaction was heated at 45° C. overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in DCM (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain rel-N-cyanomethyl-N-[(1R,3R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide as a white foam (261 mg, 58%). LCMS (m/e) 378 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 5.32 (d, 1H, J=7.3 Hz), 4.34-4.07 (m, 3H), 3.97-3.85 (m, 1H), 3.08 (s, 1H), 2.49-2.39 (m, 1H), 2.17-2.08 (m, 1H), 2.03-1.94 (m, 2H), 1.62-1.45 (m, 3H), 1.30-1.15 (m, 1H).

Workup

  1. temperaturethe reaction was heated at 45° C. overnight
  2. concentrationThe reaction was then concentrated under reduced pressure
  3. washwashed with water (30 mL)
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-8488c5ae676243ce8e94f6d8a82f2fe5
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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