4-Chloro-2-(trifluoroMethyl)nicotinic acid

Preparation of 4-Chloro-2-(trifluoromethyl)nicotinic acid; To a stirred solution of 2, 2, 6, 6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a -78° C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at -78° C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at -78° C. for 20 minutes, followed by warming to -50° C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to -15° C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94percent) of the title compound as a tan solid: To a solution of Example 42b (22.1 g, 157.1 mmol) in THF (250 mL) was added nBuLi (84 mL, 209.4 mmol, 2.5 M in THF) at -70°C, followed, after 0.5 h, by the addition of asolution of Example 42a (10 g, 52.3 mmol) in THF (40 mL). The solution was stirred at -70°Cfor 20 mm, followed by warming to -50°C for 1 h. In a separate flask, C2C16 (37.2 g, 157.1mmol) was dissolved in THF (250 mL) and cooled to -15°C. The solution containing the lithiated pyridine was added to the C2C16 solution. After complete addition, the mixture was warmed to r.t. and stirred for 0.5 h. The reaction was quenched with water (250 mL), followed by removal of THF in vacuo. The aqueous residue was extracted with MTBE (250 mL). The aqueous layer was acidified with HC1 (1 M, 60 mL), extracted with EtOAc (250 mL*2). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42c, 10.4 g, yield 88percent) as a yellow solid. LCMS [M+1] = 225.9.’HNIVIR (400 MHz, DMSO-d6) 8.78 (d, J5.3 Hz, 1H), 8.04 (d, J 5.3 Hz, 1H).A mixture of To a solution of Example 42c (10.4 g, 46.1 mmol) in THF/MeOH (70 mL/70 mL) was added TMSCHN2 (69 mL, 138.3 mmol, 2.0 M in hexanes) at 0C. The mixture was stirred at r.t. for 4 h. The reaction was quenched with HOAc (40% in water) and extracted with EtOAc (200 mL * 2). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by doing silica gel chromatography (Petroleum Ether/EtOAc = 10/1) to give the desired product (Example 42d, 7.2 g, yield 65%) as a yellow oil. LCMS [M+1] = 239.9.

Molecular Weight:225.55
XLogP3:1.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:224.9804405
Monoisotopic Mass:224.9804405
Topological Polar Surface Area:50.2
Heavy Atom Count:14
Complexity:234
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes