Hydrochloric Acid → 2-Methyl-6-(trifluoromethyl)nicotinic acid

HRID 2300031Notes

Reaction equation

HRID 2300031 reaction equation
[CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C(OCC)(=O)C>[CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 168937Lithium hydroxide, monohydrateHCID 2779428Methyl 2-methyl-6-(trifluoromethyl)nicotinate

Product 1

HCID 27756832-Methyl-6-(trifluoromethyl)nicotinic acidYield 90.9%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

6.68 g (0.0305 mol) of methyl 2-methyl-6-trifluoromethyinicotinate (prepared as described in Heterocycles, 46, 129 (1997)) are dissolved in 250 ml of methanovwater (3:1 mixture), and 1.92 g (0.046 mol) of lithium hydroxide hydrate are added a little at a time at 22° C. After 4 hours at 22° C, the reaction mixture is poured into ethyl acetate and 2N hydrochloric acid, the organic phase is washed three times with water, dried with sodium sulfate and evaporated and the residue is triturated with a little hexane. Filtration gives 5.69 g (90% of theory) of the expected 2-methyl-6-trifluoromethyinicotinic acid of m.p. 147-149° C. The 2-methyl6trifluoromethyinicotinic acid obtained (2.0 g, 0.0098 mol) is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added, and the mixture is heated under reflux for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-methyl-6-trifluoromethyinicotinoyl chloride) is taken up in 30 ml of methylene chloride. At 0° C., 2.7 ml (0.0196 mol) of triethylamine and 0.12 g (0.00098 mol) of dimethylaminopyridine are added. 1.49 g (0.0108 mol) of bicyclo[3.2.1]octane-2,4-dione, dissolved in 20 ml of methylene chloride, are then added dropwise. After 3 hours at 22° C., the reaction mixture is extracted with 2 N hydrochloric acid. The methylene chloride phase is separated off, washed with water and subsequently extracted with 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. This gives 3.18 g (100% of theory) of 4-oxobicyclo[3.2.1]oct-2-en-2-yl 2-methyl-6-trifluoromethyinicotinate as an oil, which can be processed further without purification.

Workup

  1. additionare added a little at a time at 22° C
  2. washthe organic phase is washed three times with water
  3. dry with materialdried with sodium sulfate
  4. customevaporated
  5. customthe residue is triturated with a little hexane
  6. filtrationFiltration

Sources & evidence

ORD record
ord-4ccb863c04b24d8680c1a92c3e122078
Source dataset
uspto-grants-2002_12
Patent number
US06498125B2

Reaction notes

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