Ethyl Acetate → 5-(4-Trifluoromethoxy-phenyl)-nicotinic acid methyl ester

HRID 220022Notes

Reaction equation

HRID 220022 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 522689Potassium FluorideHCID 699336Methyl 5-bromopyridine-3-carboxylateHCID 27343864-(Trifluoromethoxy)phenylboronic acid

Product 1

HCID 580025915-(4-Trifluoromethoxy-phenyl)-nicotinic acid methyl ester

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalyst3×HCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

A solution of 26 g (121 mmol) of methyl 5-bromonicotinate in toluene (220 ml) was admixed under argon at RT with 2.8 g (2.4 mmol) of tetrakis(triphenylphosphine)palladium, and then a solution of 30 g (146 mmol) of 4-trifluoromethoxyphenylboronic acid in ethanol (58 ml) was added. After adding 14 g (243 mmol) of potassium fluoride in water (58 ml), the mixture was stirred under reflux overnight, a further 0.70 g (0.61 mmol) of tetrakis(triphenylphosphine)palladium was added, and the mixture was stirred under reflux for a further 24 h. After adding another 1.4 g (1.2 mmol) of tetrakis(triphenylphosphine)palladium, the mixture was stirred under reflux for 20 h, and the reaction solution was admixed with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, cyclohexane/dichloromethane 1:1→dichloromethane). Yield: 31 g (86% of theory)

Workup

  1. temperatureunder reflux overnight
  2. stirringthe mixture was stirred
  3. temperatureunder reflux for a further 24 h
  4. stirringthe mixture was stirred
  5. temperatureunder reflux for 20 h
  6. washwashed with water and saturated aqueous sodium chloride solution
  7. dry with materialThe organic phase was dried over magnesium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by means of column chromatography (silica gel, cyclohexane/dichloromethane 1:1→dichloromethane)

Sources & evidence

ORD record
ord-ff750b873a2b49ee8d7cb45d858c96a4
Source dataset
uspto-grants-2012_06
Patent number
US08202862B2

Reaction notes

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