Methyl iodide → 6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide

HRID 1187381Notes

Reaction equation

HRID 1187381 reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([S:17][CH2:18][CH2:19][CH3:20])[N:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH3:23])[CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[O:7])=[C:4]([S:17][CH2:18][CH2:19][CH3:20])[N:3]=1

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 598306896-chloro-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide

Product 1

HCID 580008806-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamideYield 116.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

6-chloro-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.410 g, 1.3 mmol) in DMF (4 mL) was added portionwise to sodium hydride (60% dispersion in oil) (0.063 g, 1.56 mmol) in DMF (2 mL) cooled to 0° C. over a period of 2 minutes under nitrogen and stirred for 25 minutes. Methyl iodide (0.069 ml, 1.1 mmol) was added in one portion and the suspension was warmed and stirred at 20° C. for 72 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) then diluted with EtOAc (50 mL), and washed sequentially with water (10 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM. Pure fractions were evaporated to dryness to afford 6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (0.422 g, 99%) as a colourless clear gum.

Workup

  1. temperaturethe suspension was warmed
  2. stirringstirred at 20° C. for 72 hours
  3. customThe reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL)
  4. additionthen diluted with EtOAc (50 mL)
  5. washwashed sequentially with water (10 mL) and saturated brine (10 mL)
  6. dry with materialThe organic layer was dried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customto afford crude product
  10. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in DCM
  11. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-470a869371f445d1956ba20dd469ee5c
Source dataset
uspto-grants-2014_03
Patent number
US08673938B2

Reaction notes

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