Benzyl Bromide → Benzyl 6-aminopyridine-3-carboxylate

HRID 1011500Notes

Reaction equation

HRID 1011500 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 7498Benzyl BromideHCID 11430Potassium CarbonateHCID 184966-Aminonicotinic acid

Product 1

HCID 45790947Benzyl 6-aminopyridine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred suspension of 6-aminonicotinic acid (100 g, 0.72 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in N,N-dimethylformamide (700 mL) with brisk mechanical stirring was added potassium carbonate (150 g, 1.08 mol) and the reaction was stirred for 10 min before the portionwise addition of benzyl bromide (95 mL, 0.80 mol). The reaction was stirred at room temperature overnight, then the solids were filtered off and washed thoroughly with ethyl acetate, and the solvent was removed under vacuum. The filter cake was dissolved in water and extracted with ethyl acetate. The residue after evaporation of N,N-dimethylformamide was combined with the ethyl acetate extracts (total volume 2 L of ethyl acetate) and the combined organic extracts washed with brine (5×500 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was refluxed with 1:1 diethyl ether:hexane for 30 min then the solids filtered off (warm), washed with diethyl ether:hexane (1:1), and dried. This solid was precipitated from hot toluene (hot filtration required to remove dibenzylated material) and dried to afford (I-28a) (107.2 g, 65%) as an off-white solid; 1H NMR (DMSO-d6): δ 8.50 (1H), 7.82 (1H), 7.34-7.29 (5H), 6.84 (2H), 6.43 (1H), 5.23 (2H); m/z 229.4 (M+H)+.

Workup

  1. stirringThe reaction was stirred at room temperature overnight
  2. filtrationthe solids were filtered off
  3. washwashed thoroughly with ethyl acetate
  4. customthe solvent was removed under vacuum
  5. dissolutionThe filter cake was dissolved in water
  6. extractionextracted with ethyl acetate
  7. customThe residue after evaporation of N,N-dimethylformamide
  8. washthe combined organic extracts washed with brine (5×500 mL)
  9. dry with materialdried (MgSO4)
  10. customthe solvent removed under reduced pressure
  11. temperatureThe crude product was refluxed with 1:1 diethyl ether
  12. filtrationthe solids filtered off
  13. temperature(warm)
  14. washwashed with diethyl ether:hexane (1:1)
  15. customdried
  16. customThis solid was precipitated from hot toluene (hot filtration required to remove dibenzylated material)
  17. customdried
  18. customto afford (I-28a) (107.2 g, 65%) as an off-white solid

Sources & evidence

ORD record
ord-c18cd5c5e0fd4a228f708ca2c88b38db
Source dataset
uspto-grants-2011_07
Patent number
US07977367B2

Reaction notes

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