Benzyl Alcohol → 2-Benzyloxy-nicotinic acid

HRID 1354865Notes

Reaction equation

HRID 1354865 reaction equation
Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.O>[CH2:13]([O:20][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1

Participants

7

Reactant 4

HCID 244Benzyl AlcoholHCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 762582-Chloronicotinic acid

Product 1

HCID 7626622-Benzyloxy-nicotinic acidYield 64.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

2-Chloro-nicotinic acid (421) (3 g, 19.04 mmol) was dissolved in anhydrous THF (50 mL) and chilled to 0° C. on an ice bath. NaH (50 mmol, 60% suspension in mineral oil) was added portion wise to the solution over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 30 minutes. Benzyl-alcohol (422) (2.27 g, 21 mmol) was added drop wise over a period of 10 minutes. The ice bath was removed and the mixture was warmed to room temperature over a period of 2 h. The mixture was refluxed for 16 h. LC-MS and TLC (Rf: 0.4–0.5 compared to Rf: 0.1 for compound 421 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The mixture was diluted with water (300 mL) and the pH was adjusted to ˜6 by the addition of HCl (aqueous, 1M) and the product was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure to give a yellow oil. Recrystallization from EtOAc/hexane gave the desired product (423) as a white powder (2.8 g, 12.2 mmol, 64% yield). LC-MS (ESI): (exact mass: 229.07) m/e=230.2 [M+1]+ (100%), 459.3 [2M+1]+ (90%).

Workup

  1. customThe ice bath was removed
  2. temperaturethe mixture was warmed to room temperature over a period of 2 h
  3. temperatureThe mixture was refluxed for 16 h
  4. customreaction at this point
  5. extractionthe product was extracted with EtOAc (3×200 mL)
  6. washThe combined organic layers were washed with brine (100 mL) via extraction
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated under reduced pressure
  9. customto give a yellow oil
  10. customRecrystallization from EtOAc/hexane

Sources & evidence

ORD record
ord-1a0fc7aa5d4e40cb971574c29237f8f7
Source dataset
uspto-grants-2007_05
Patent number
US07223759B2

Reaction notes

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