Methanol → Methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate

HRID 551931Notes

Reaction equation

HRID 551931 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.[Na+].[Cl-].O>[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:32]=[CH:31][C:28]([CH2:29][NH:1][C:2]3[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]

Participants

8

Reactant 4

HCID 887MethanolHCID 4311764Sodium borohydrideHCID 113345124-[2-(4-Butylphenyl)ethynyl]benzaldehydeHCID 15621043Methyl 5-amino-2-fluorobenzoate

Product 1

HCID 11452740Methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoateYield 76%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 5234Sodium ChlorideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of methyl 5-amino-2-fluorobenzoate (1.20 g, 7.1 mmol, described in J. Chem. Soc. Perkin Trans. I, 1975, 1283-1284 and J. Org. Chem., 1990, 2034-2044) and 4-[(4-butylphenyl)ethynyl]benzaldehyde (1.95 g, 7.4 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) in toluene (30 ml) was heated under reflux for 2.5 hrs with azeotropic removal of water. The reaction mixture was cooled down to 0° C., then MeOH (30 mL) and sodium borohydride (540 mg, 14.2 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min, then at rt for 1 hr. The reaction mixture was diluted with a saturated aqueous solution of NaCl (100 mL) and water (30 mL) and then extracted with Et2O (300 mL+50 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. The residual brown gummy oil was taken up in MeOH (10 mL) and a white solid precipitated out. Filtration and washing with MeOH (2×) gave 2.23 g (76%) of the title compound as a white powder. HPLC, Rt: 5.8 min (purity: 98.2%). LC/MS, M−(ESI): 414.0. 1H NMR (CDCl3) δ: 7.51 (d, J=7.9 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 3H), 6.97 (m, 1H), 6.76 (m, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 2.63 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Workup

  1. waitat rt for 1 hr
  2. extractionextracted with Et2O (300 mL+50 mL)
  3. dry with materialThe combined organic layers were dried over MgSO4
  4. customthe solvents were removed under reduced pressure
  5. customa white solid precipitated out
  6. filtrationFiltration
  7. washwashing with MeOH (2×)

Sources & evidence

ORD record
ord-7778f229cbd544c4ac608ef8fa8358f8
Source dataset
uspto-grants-2011_05
Patent number
US07947851B2

Reaction notes

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