2-Methoxybenzaldehyde → 2-Chloro-N-(2-methoxybenzyl)pyridin-3-amine

HRID 2380016Notes

Reaction equation

HRID 2380016 reaction equation
[NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9](=O)[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:8][C:3]1[C:2]([NH:1][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=1

Participants

5

Reactant 3

HCID 86582-MethoxybenzaldehydeHCID 805282-Chloro-3-pyridylamineHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 229185282-Chloro-N-(2-methoxybenzyl)pyridin-3-amineYield 112.8%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
25 °C

Procedure

To a 5 L 3-necked round bottom flask fitted with mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 1.6 L of acetic acid and 80.0 grams (0.62 moles) of 3-amino-2-chloropyridine. The mixture was agitated for approx. 10 minutes at 25° C. for dissolution. To the resulting solution was charged 105.9 grams (119.3 mL/0.78 moles/1.25 equivalents) of o-anisaldehyde (2-methoxybenzaldehyde), upon which was obtained a yellow solution after stirring 10 minutes at 25° C. Over a 30 minute period in portions were added 263.7 grams (1.24 moles, 2.0 equivalents) sodium triacetoxyborohydride, while maintaining a temperature of 20° C. The mixture was stirred for 12-18 hours and concentrated to a semi-solid, which was partitioned between methylene chloride and water (800 mL each). The pH was adjusted to 9.5 with 700 mL 25% sodium hydroxide solution while maintaining a temperature of 25°-30° C. by cooling. The layers were separated, the aqueous layer was washed with methylene chloride (3×300 mL each), and the methylene chloride layers were combined. The organic layer was washed with 300 mL of saturated sodium chloride solution, and then dried with magnesium sulfate for 30 minutes. The magnesium sulfate was removed by filtration, and the methylene chloride filtrate was evaporated and displaced with ethyl acetate, leaving an off white tacky material (174 grams). The product was reslurried in 120 mL of fresh ethyl acetate at 0°-5° C. for 1.5 hours, filtered, washed with cold ethyl acetate and dried, giving 133.2 grams (86.1%) of the title compound. M.P. 121° -125° C. 1H NMR (CDCl3) δ 7.70 (dd, 1H, J=1Hz, 2Hz), 7.25 (m, 2H), 7.05 (m, 1H), 6.90 (m, 3H), 4.95 (t, 1H), 4.40 (d, 2H, J=6), 3.85 (s, 3H).

Workup

  1. customTo a 5 L 3-necked round bottom flask fitted with mechanical stirrer
  2. additionthermometer, addition funnel, and nitrogen inlet
  3. customupon which was obtained a yellow solution
  4. stirringafter stirring 10 minutes at 25° C
  5. temperaturewhile maintaining a temperature of 20° C
  6. stirringThe mixture was stirred for 12-18 hours
  7. concentrationconcentrated to a semi-solid, which
  8. customwas partitioned between methylene chloride and water (800 mL each)
  9. temperaturewhile maintaining a temperature of 25°-30° C.
  10. temperatureby cooling
  11. customThe layers were separated
  12. washthe aqueous layer was washed with methylene chloride (3×300 mL each)
  13. washThe organic layer was washed with 300 mL of saturated sodium chloride solution
  14. dry with materialdried with magnesium sulfate for 30 minutes
  15. customThe magnesium sulfate was removed by filtration
  16. customthe methylene chloride filtrate was evaporated

Sources & evidence

ORD record
ord-eae5182607904023b0c13c80d6d3a7d3
Source dataset
uspto-grants-1994_11
Patent number
US05364943

Reaction notes

Loading…