Acetic Acid → (R)-4-[(1-Methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzonitrile

HRID 1191006Notes

Reaction equation

HRID 1191006 reaction equation
C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].Cl.[CH3:16][C@@H:17]([NH2:22])[C:18]([F:21])([F:20])[F:19].C(O)(=O)C>CO>[CH3:16][C@@H:17]([NH:22][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[C:18]([F:21])([F:20])[F:19]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 660424-CyanobenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 44593757(2R)-1,1,1-Trifluoropropan-2-amine--hydrogen chloride (1/1)

Product 1

HCID 59828823(R)-4-[(1-Methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzonitrileYield 27.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Add sodium cyanoborohydride (3.36 g, 53.5 mmol) to a solution of 4-cyanobenzaldehyde (1.75 g, 13.35 mmol) and (R)-1-methyl-2,2,2-trifluoro-ethylamine hydrochloride (2 g, 13.37 mmol) in methanol (17 mL) containing acetic acid (1.53 mL, 26.75 mmol). Stir the mixture at room temperature overnight. Partition the mixture between 1N aqueous NaOH/DCM (1:1, 500 mL) and extract the aqueous layer twice with DCM. Dry the combined organic extracts over MgSO4, concentrate in vacuo and purify by chromatography on silica gel (120 g) eluting with hexane/EtOAc (19:1, 9:1, 85:15 and 4:1) to obtain the desired intermediate (0.83 g, 27%). MS (ES+) m/z: 229 (M+H)+.

Workup

  1. customPartition the mixture between 1N aqueous NaOH/DCM (1:1, 500 mL)
  2. extractionextract the aqueous layer twice with DCM
  3. dry with materialDry the combined organic extracts over MgSO4
  4. concentrationconcentrate in vacuo
  5. custompurify by chromatography on silica gel (120 g)
  6. washeluting with hexane/EtOAc (19:1, 9:1, 85:15 and 4:1)

Sources & evidence

ORD record
ord-e6d71cbd1e324fadb2d0c77c10a71133
Source dataset
uspto-grants-2014_03
Patent number
US08680091B2

Reaction notes

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