Hexanal → Methyl 5-[{4-[(4-ethylphenyl)ethynyl]benzyl}(hexyl)amino]-2-fluorobenzoate

HRID 551970Notes

Reaction equation

HRID 551970 reaction equation
[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26].[CH:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=3)[C:25]([O:27][CH3:28])=[O:26])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2]

Participants

9

Reactant 5

HCID 6184HexanalHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 11276380HCID 11276380, compoundHCID 15621043Methyl 5-amino-2-fluorobenzoate

Product 1

HCID 57554472Methyl 5-[{4-[(4-ethylphenyl)ethynyl]benzyl}(hexyl)amino]-2-fluorobenzoateYield 131.4%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolvent2×HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 4-[(4-ethylphenyl)ethynyl]benzaldehyde (530 mg; 2.26 mmol, intermediate which may be prepared according to methods disclosed in EP03103780.7) in toluene (35 mL) were added methyl 5-amino-2-fluorobenzoate (382 mg; 2.26 mmol) and AcOH (194 μL) and the reaction mixture was refluxed with azeotropic removal of water until complete consumption of, the aldehyde (determined by 1H NMR of aliquots). Toluene was concentrated under reduced pressure and the residue dissolved in DCE (25 mL). Hexanal (Aldrich, 818 μl; 6.79 mmol), acetic acid (194 μL) and sodium triacetoxyborohydride (1,4 g, 6.79 mmol) were added to the solution, which was then heated at 60° C. for 3 hrs. The reaction mixture was poured into a saturated solution of NaHCO3 and extracted twice with DCM. Combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated to give 1.4 g of a brown solid. Purification by flash chromatography using silica gel (EtOAc/c-Hex, gradient from 97:3 to 95:5) yielded to 330 mg (30%) of the title compound as a white solid. HPLC, Rt: 6.27 min (purity: 61%), LC/MS, M+(ESI): 472.2, 1H NMR (CDCl3) δ: 7.43 (t, J=7.7 Hz, 4H), 7.17 (m, 5H), 6.90 (t, J=10.7 Hz, 1H), 6.73 (m, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.35 (t, J=7.8 Hz, 2H), 2.63 (qd, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.28 (m, 6H), 1.22 (t, J=7.6 Hz, 3H), 0.85 (t, J=5.1 Hz, 3H).

Workup

  1. concentrationToluene was concentrated under reduced pressure
  2. dissolutionthe residue dissolved in DCE (25 mL)
  3. extractionextracted twice with DCM
  4. washCombined organic layers were washed with brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltrated
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-5696c77c09d14cf7b3fa7df6adbfee78
Source dataset
uspto-grants-2011_05
Patent number
US07947851B2

Reaction notes

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