Pyridine-2-carbonitrile → 2-Cyclohexyl-1-(pyridin-2-YL)ethanamine

HRID 52568

Reaction equation

HRID 52568 reaction equation
[Mg].[CH:2]1([CH2:8]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:11].[BH4-].[Na+]>C(OC)(C)(C)C.II.CO>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]([NH2:11])[CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1

Participants

8

Reactant 4

HCID 7522Pyridine-2-carbonitrileHCID 137636Cyclohexane, (bromomethyl)-HCID 4311764Sodium borohydrideHCID 5462224Magnesium

Product 1

HCID 97942552-Cyclohexyl-1-(pyridin-2-YL)ethanamineYield 75%

Reagents, catalysts & solvents 3

HCID 807IodineCatalystHCID 887MethanolSolventHCID 15413tert-Butyl methyl etherSolvent3×

Procedure

To a refluxed stirred mixture of 1.34 kg (55.8 moles) of magnesium in 6 L of t-butylmethyl ether (MTBE) and 4 g (0.016 moles) of iodine, a solution of 10 kg (55.9 moles) cyclohexylmethyl bromide in 22 L (MTBE) was added slowly. After approximately 10% to 25% of the solution was added, heating was discontinued and the remainder of the solution was added at a rate to maintain refluxing temperature. After the addition, the reaction was refluxed for an additional 24 hrs, then cooled to 0° to 5° C. and 3.903 kg (37.1 moles) of 2-cyanopyridine in 22 L MTBE was added at 0°-10° C. After the addition, the greenish thick suspension was stirred without cooling for 18-24 hrs. The Grignard reaction mixture was transferred with stirring to 40 L of methanol at 10° to 15° C. To the clear solution was added 1.4 kg (36.8 moles) of sodium borohydride. The mixture was stirred at room temperature 18 hrs., then quenched by the addition of 16 L of water and 36 L of 4N hydrochloric acid. The organic solvents were removed under vacuum and the remaining aqueous solution was washed twice with 6 L of methylene chloride. The aqueous phase was basified with 15 L of ammonium hydroxide solution and extracted three times with 10 L of methylene chloride. The methylene chloride was dried over 6.5 kg of sodium sulfate and concentrated to yield 5.645 kg (75%) of 1-(R,S)-(2-pyridyl)-2-cyclohexylethylamine.

Workup

  1. temperatureheating
  2. additionthe remainder of the solution was added at a rate
  3. temperatureto maintain
  4. temperaturerefluxing temperature
  5. additionAfter the addition
  6. temperaturethe reaction was refluxed for an additional 24 hrs
  7. temperaturecooled to 0° to 5° C.
  8. additionAfter the addition
  9. stirringthe greenish thick suspension was stirred
  10. temperaturewithout cooling for 18-24 hrs
  11. customThe Grignard reaction mixture
  12. stirringThe mixture was stirred at room temperature 18 hrs
  13. custom, then quenched by the addition of 16 L of water and 36 L of 4N hydrochloric acid
  14. customThe organic solvents were removed under vacuum
  15. washthe remaining aqueous solution was washed twice with 6 L of methylene chloride
  16. extractionextracted three times with 10 L of methylene chloride
  17. dry with materialThe methylene chloride was dried over 6.5 kg of sodium sulfate
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-15b2c1744b134af18b4b8558acfe7322
Source dataset
uspto-grants-1997_04
Patent number
US05616717

Linked notes

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