Bis(2-chloroethyl)amine → 4-(4-Chlorophenyl)piperidine-4-carbonitrile

HRID 2104229Notes

Reaction equation

HRID 2104229 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 9533Bis(2-chloroethyl)amineHCID 24758Sodium hydrideHCID 2415824-Chlorobenzyl cyanide

Product 1

HCID 229935654-(4-Chlorophenyl)piperidine-4-carbonitrile

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

49 g 4-chlorobenzyl cyanide 1 (323 mmol, 1.00 equiv) and 58 g of bis[2-chloroethyl]amine (323 mmol, 1.00 equiv) were dissolved in 325 mL of anhydrous DMF in a 2 L round bottom flask fitted with a magnetic stir bar, reflux condenser, and N2 inlet. The mixture was cooled in an ice water bath, then 52 g of 60% NaH in mineral oil (1293 mmol, 4.00 equiv) was added to the stirring solution at a rate such that the exothermic reaction did not become violent. After the addition was complete, the apparatus was transferred to an oil bath and the mixture heated to 60° C. and stirred for 48 h under N2 atmosphere. The mixture was cooled to room temperature and the remaining hydride carefully quenched under N2 by dropwise addition of a small amount of H2O. The resultant slurry was poured into 2 L of rapidly stirring H2O and the pH adjusted to ˜1 with concentrated HCl. The mixture was transferred to a 4L separatory funnel and extracted with 3×500 mL of hexane. The organic extracts were discarded and the aqueous extracts was adjusted pH to ˜9 by the addition of solid K2CO3. The resultant precipitate was collected by vacuum filtration and washed with small portions of H2O, followed by hexane. The tan solid was dried under vacuum to yield 4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=221.7, found=221.1.

Workup

  1. customfitted with a magnetic stir bar
  2. temperaturereflux condenser, and N2 inlet
  3. temperatureThe mixture was cooled in an ice water bath
  4. additionAfter the addition
  5. customthe apparatus was transferred to an oil bath
  6. temperatureThe mixture was cooled to room temperature
  7. customthe remaining hydride carefully quenched under N2 by dropwise addition of a small amount of H2O
  8. additionThe resultant slurry was poured into 2 L of rapidly stirring H2O
  9. extractionextracted with 3×500 mL of hexane
  10. additionthe aqueous extracts was adjusted pH to ˜9 by the addition of solid K2CO3
  11. filtrationThe resultant precipitate was collected by vacuum filtration
  12. washwashed with small portions of H2O
  13. customThe tan solid was dried under vacuum

Sources & evidence

ORD record
ord-1f0f0810141f47859071be30b3ceae52
Source dataset
uspto-grants-2009_08
Patent number
US07576218B2

Reaction notes

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