3-Bromopyridine → Benzoic acid, 4-(hydroxy-3-pyridinylmethyl)-, methyl ester

HRID 1458427Notes

Reaction equation

HRID 1458427 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:14].[Li]C1C=CC=CN=1>CCOCC>[OH:14][CH:13]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1

Participants

6

Reactant 4

HCID 122863-BromopyridineHCID 15294Methyl 4-FormylbenzoateHCID 178418339ButyllithiumHCID 178506720HCID 178506720, compound

Product 1

HCID 10776613Benzoic acid, 4-(hydroxy-3-pyridinylmethyl)-, methyl esterYield 64.4%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a cooled solution (-78° C.) of 10.6 mL (0.11 mol) of 3-bromopyridine in 1.2 L of anhydrous Et2O was added dropwise 93.8 mL (0.15 mol) of 1.6M n-BuLi in hexanes over 1 h period. The turbid yellow solution was stirred at -78° C. for 25 min, and then 24.62 g (0.15 mol) of methyl 4-formylbenzoate in 300 mL of Et2O was cannulated to the lithiopyridine solution. The mixture was continually stirred at -78° C. for 2 h and at room temperature for 2 more h. The reaction was quenched with 400 mL of brine and 200 mL of H2O. The organic layer was separated and the aqueous layer was extracted with 3×1.0 L of CH2Cl2. To the combined organic layer was added 200 mL of MeOH to dissolve the product which precipitated out. This was then dried over MgSO4 and concentrated. The crude product was crystallized from MeOH to afford 17.24 g (64%) of a white solid: mp 151° C.; 1H NMR (CDCl3) δ8.62 (br s, 1H), 8.51 (br s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.30 (br s, 1H), 5.93 (s, 1H), 3.90 (s, 3H), 2.92 (br s, 1H); FDMS 244 (M+1). Anal. (C14H13NO3.0.16C2H4O) C, H, N.

Workup

  1. stirringThe mixture was continually stirred at -78° C. for 2 h and at room temperature for 2 more h
  2. customThe reaction was quenched with 400 mL of brine and 200 mL of H2O
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with 3×1.0 L of CH2Cl2
  5. additionTo the combined organic layer was added 200 mL of MeOH
  6. dissolutionto dissolve the product which
  7. customprecipitated out
  8. dry with materialThis was then dried over MgSO4
  9. concentrationconcentrated
  10. customThe crude product was crystallized from MeOH

Sources & evidence

ORD record
ord-e832b9837fd74908917994092ad61ba5
Source dataset
uspto-grants-1998_12
Patent number
US05849922

Reaction notes

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