Potassium Hydroxide → 6-Chloro-4-(trifluoromethyl)nicotinic acid

HRID 2300026Notes

Reaction equation

HRID 2300026 reaction equation
[OH-].[K+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1>O1CCOCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:16])[F:17])[C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1

Participants

4

Reactant 2

HCID 14797Potassium HydroxideHCID 2775340Methyl 6-chloro-4-(trifluoromethyl)nicotinate

Product 1

HCID 27833826-Chloro-4-(trifluoromethyl)nicotinic acid

Reagents, catalysts & solvents 1

HCID 218864351,4-Dioxane--water (1/1)Solvent

Procedure

9.6 g (0.047 mol) of methyl 4-trifluoromethylpyridin-3-ylcarboxylate, dissolved in 50 ml of dichloromethane, are treated with 30% hydrogen peroxide/urea adduct and 17 ml of trifluoroacetic anhydride. The reaction solution is stirred at temperature of 20° C. for 20 hours and then washed once each with dilute sodium hydroxide solution and half-saturated sodium chloride solution. The product obtained is 3-methoxycarbonyl4-trifluoromethyl-3-pyridine N-oxide; 1H NMR (CDCl3, ppm): 8.55, s, 1H; 8.31, d, 1H; 7.6, d, 1H; 3.98, s, 3H. 4.85 g (0.022 mol) of the above product are then added to a mixture of 5 ml of phosphorus oxychloride and 4.3 ml of ethyidiisopropylamine in 15 ml of 1,2dichloroethane, and the mixture is heated to a temperature of 60° C. After about 2 hours, another 2 ml of phosphorus oxychloride and 2.8 ml of ethyidiisopropylamine are added, and the mixture is stirred at this temperature for 20 hours. The reaction mixture is subsequently added to ice-water, adjusted to pH 3 using 30% NaOH and then extracted with dich ioromethane. Filtration through a little silica gel gives an approximately 5:1 product mixture of the two 6-chloro- and 2-chloro-4-trifluoromethylpyridin-3-yl methyl esters, which can be separated by HPLC into the pure components. Thus, pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the main product; 1H NMR (CDCl3, ppm): 8.91, s, 1H; 7.68, s, 1H; 3.98, s, 3H, and pure methyl 2-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is obtained as the byproduct; 1H NMR (CDCl3, ppm): 8.64, d, 1H; 7.52, d, 1H; 4.01, s, 3H. In the presence of 0.073 g of potassium hydroxide, 0.22 g of pure methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate are hydrolysed at room temperature in a 1:1 mixture of 6 ml of dioxane/water. Recrystallization gives the pure 6-chloro-4-trifluoromethyinicotinic acid: m.p. 115-117° C.; 1H NMR (CDCl3, ppm): 9.12, s, 1H; 7.24, s, 1H.

Workup

  1. customRecrystallization

Sources & evidence

ORD record
ord-610361c0c53f49ffa611e30525193d65
Source dataset
uspto-grants-2002_12
Patent number
US06498125B2

Reaction notes

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