6-Trifluoromethyl-2-pyridinecarboxylic acid

White powder

Preparation C4: 2-bromo-6-(trifluoromethyl)-pyridine (100 mg, 0.44 mmol, 1 eq.) was dissolved in diethyl ether at room temperature under nitrogen then cooled to -70° C. Added 1.6M n-Butyllithium in hexanes (0.28 mL, 0.44 mmol, 1 eq.) dropwise via an addition funnel. Diethyl ether (4.32 L) and hexanes (5.40 L) were added to the reaction vessel under N2 atmosphere, and cooled to -75 C. to -65 C. Dropwise addition of n-Butyl lithium (3.78 L in 1.6 M hexane) under N2 atmosphere at below -65 C. was followed by dropwise addition of dimethyl amino ethanol (327.45 g, 3.67 mol) and after 10 min. dropwise addition of 2-trifluoromethyl pyridine (360 g, 2.45 mol). The reaction was stirred under N2 while maintaining the temperature below -65 C. for about 2.0-2.5 hrs. The reaction mixture was poured over crushed dry ice under N2, then brought to a temperature of 0 to 50 C. while stirring (approx. 1.0 to 1.5 h) followed by the addition of water (1.8 L). The reaction mixture was stirred for 5-10 mins and allowed to warm to 5-10 C. 6N HCl (900 mL) was added dropwise until the mixture reached pH 1.0 to 2.0, then the mixture was stirred for 10-20 min. at 5-10 C. The reaction mixture was diluted with ethyl acetate at 25-35 C., then washed with brine solution. The reaction was concentrated and rinsed with n-heptane and then dried to yield 6-trifluoromethyl-pyridine-2-carboxylic acid.Example 2, Step 1: Preparation of 6-trifluoromethyl-pyridine-2-carboxylic acid Diethyl ether (4.32 L) and hexanes (5.40 L) were added to the reaction vessel under N2 atmosphere, and cooled to -75 C. to -65 C. Dropwise addition of n-Butyl lithium (3.78 L in 1.6 M hexane) under N2 atmosphere at below -65 C. was followed by dropwise addition of dimethyl amino ethanol (327.45 g, 3.67 mol) and after 10 min. dropwise addition of 2-trifluoromethyl pyridine (360 g, 2.45 mol). The reaction was stirred under N2 while maintaining the temperature below -65 C. for about 2.0-2.5 hrs. The reaction mixture was poured over crushed dry ice under N2, then brought to a temperature of 0 to 5 C. while stirring (approx. 1.0 to 1.5 h) followed by the addition of water (1.8 L). The reaction mixture was stirred for 5-10 mins and allowed to warm to 5-10 C. 6N HCl (900 mL) was added dropwise until the mixture reached pH 1.0 to 2.0, then the mixture was stirred for 10-20 min. at 5-10 C. The reaction mixture was diluted with ethyl acetate at 25-35 C., then washed with brine solution. The reaction was concentrated and rinsed with n-heptane and then dried to yield 6-trifluoromethyl-pyridine-2-carboxylic acid.Preparation C4: Synthesis of 6-(trifluoromethyl)picolinic Acid Preparation C4, Step 1: 2-bromo-6-(trifluoromethyl)-pyridine (100 mg, 0.44 mmol, 1 eq.) was dissolved in diethyl ether at room temperature under nitrogen then cooled to -70 C. Added 1.6M n-Butyllithium in hexanes (0.28 mL, 0.44 mmol, 1 eq.) dropwise via an addition funnel. Stirred at -40 C. for 15 minutes then cooled to -70 C. and bubbled in CO2 gas for 10 minutes. Allowed to warm to room temperature. Added water then rinsed 3 times with diethyl ether. The aqueous pH was adjusted to=3 with conc. HCl. Extracted the acidic aqueous layer 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 6-(trifluoromethyl)picolinic acid (30 mg) as a white solid. Yield=35%. LCMS detects (M+H)+=192.06.

Molecular Weight:191.11
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:191.01941286
Monoisotopic Mass:191.01941286
Topological Polar Surface Area:50.2
Heavy Atom Count:13
Complexity:204
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes