Acetic Acid → Methyl 4-{[(4-tert-butylcyclohexyl)amino]methyl}benzoate

HRID 229982

Reaction equation

HRID 229982 reaction equation
[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].CC(O)=O.[BH3-]C#N.[Na+]>CO>[C:13]([CH:17]1[CH2:18][CH2:19][CH:20]([NH:23][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][CH:6]=2)[CH2:21][CH2:22]1)([CH3:16])([CH3:14])[CH3:15]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 15294Methyl 4-FormylbenzoateHCID 793964-tert-ButylcyclohexylamineHCID 5003444Sodium cyanoborohydride

Product 1

HCID 16100290Methyl 4-{[(4-tert-butylcyclohexyl)amino]methyl}benzoate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of methyl-4-formylbenzoate (73 mmol, 12 g) in 200 mL of MeOH was added 4-tert-butylcyclohexylamine (74 mmol, 13.2 mL) via syringe. The reaction mixture was heated to reflux for 0.75 h, then was cooled in an ice bath. The resulting precipitate was filtered and the filter cake was washed with 2×20 mL of cold MeOH. The solid was dried under reduced pressure, then suspended in 224 mL of MeOH. HOAc (652 mmol, 37.4 mL) was added to the solution, followed by NaBH3CN (42.7 mmol, 2.68 g) in several portions. The reaction mixture was stirred at ambient temperature for 1.5 b, then concentrated under reduced pressure to ca. 25% of the initial volume. 400 mL of EtOAc was added to the solution and the mixture was washed with 3×200 mL of 5% NaHCO3 followed by brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes to afford the trans isomer as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.00 (d, 2H), 7.40 (d, 2H), 3.92 (s, 3H), 3.88 (s, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.79 (m, 2H), 0.95-1.15 (overlapping m, 5H), 0.85 (s, 9H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux for 0.75 h
  3. temperaturewas cooled in an ice bath
  4. filtrationThe resulting precipitate was filtered
  5. washthe filter cake was washed with 2×20 mL of cold MeOH
  6. customThe solid was dried under reduced pressure
  7. concentrationconcentrated under reduced pressure to ca. 25% of the initial volume
  8. addition400 mL of EtOAc was added to the solution
  9. washthe mixture was washed with 3×200 mL of 5% NaHCO3
  10. dry with materialThe organic phase was dried over MgSO4
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by flash chromatography on silica eluting with 1:1 EtOAc/hexanes
  13. customto afford the trans isomer as a white solid

Sources & evidence

ORD record
ord-bc4a737dd4814381a71565da94a979b8
Source dataset
uspto-grants-2009_07
Patent number
US07563815B2

Linked notes

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