Acetic Acid → Methyl 5-{butyl[4-(phenylethynyl)benzyl]amino}-2-fluorobenzoate

HRID 551965Notes

Reaction equation

HRID 551965 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].[C:13]1([C:19]#[C:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C.[CH:33](=O)[CH2:34][CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[CH2:33]([N:1]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([C:20]#[C:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:23]=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])[CH2:34][CH2:35][CH3:36]

Participants

8

Reactant 5

HCID 176Acetic Acid2×HCID 261ButanalHCID 6099084-(Phenylethynyl)benzaldehydeHCID 5049666Sodium triacetoxyborohydride2×HCID 15621043Methyl 5-amino-2-fluorobenzoate

Product 1

HCID 57554483Methyl 5-{butyl[4-(phenylethynyl)benzyl]amino}-2-fluorobenzoateYield 75.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 1140TolueneSolvent

Conditions

Temperature
70 °C

Procedure

A solution of methyl 5-amino-2-fluorobenzoate (500 mg, 2.96 mmol), 4-(phenylethynyl)benzaldehyde (6 10 mg, 2.96 mmol) and acetic acid (0.25 mL, 4.40 mmol) in toluene (20 mL) was heated under reflux for 3 h with azeotropic removal of water. Then the solvent was removed by distillation at atmospheric pressure and replaced by anhydrous DCE (20 mL). Butanal (Fluka, 0.66 mL, 7.39 mmol), sodium triacetoxyborohydride (1880 mg, 8.87 mmol) and acetic acid (0.25 mL, 4.40 mmol) were added and the resulting mixture was heated at 70° C. After 45 min, an additional amount of sodium triacetoxyborohydride (630 mg, 2.96 mmol) was added. After 45 min, the reaction mixture was diluted with water (40 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc): gave. 924 mg (75%) of the title compound as a colorless oil. HPLC, Rt: 5.6 min (purity: 99.8%). LC/MS, M+(ESI): 416.1. 1H NMR (CDCl3) δ: 7.51-7.44 (m, 4H), 7.32 (m, 3H), 7.17 (m, 3H), 6.92 (dd, J=9.8, 9.7 Hz, 1H), 6.73 (m, 1H), 4.49 (s, 2H), 3.88 (s, 3H), 3.36 (t, J=7.2 Hz, 2H), 1.60 (m, 2H), 1.34 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).

Workup

  1. customThen the solvent was removed by distillation at atmospheric pressure
  2. waitAfter 45 min
  3. extractionextracted with DCM (3×20 mL)
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. customthe solvents were removed under reduced pressure
  6. customPurification by flash chromatography on silicagel (cHex/EtOAc)
  7. customgave

Sources & evidence

ORD record
ord-1070f5b0b7db4b6598ffb3e68c69fe06
Source dataset
uspto-grants-2011_05
Patent number
US07947851B2

Reaction notes

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