A Practical Synthesis of 4-Amino-2-(Trifluoromethyl)nicotinic Acid

Abstract

A practical synthesis of 4-amino-2-(trifluoromethyl)-nicotinic acid is described. 2-(Trifluoromethyl)pyridine was lithiated using lithium 2,2,6,6-tetramethylpiperidide (LTMP) in the presence of 1,3-dimethyl-2-imidazolidinone (DMI) and followed by CO₂ quench to give the C-3 carboxylation product. Subsequent directed C-4 lithiation of carboxylation product afforded 4-iodo-2-(trifluoromethyl)nicotinic acid, which was coupled with tert-butyl carbamate under Pd-catalyzed conditions and followed by Boc deprotection to yield the title product in four steps and 50% overall yield.

pyridine - directed lithiation - trifluoromethyl - iodination - Boc-amide - amination

References and Notes

<A NAME="RS00410ST-1">1</A>

Current Address: Pfizer Global Research & Development, 10770 Science Center Drive, San Diego, CA 92121, USA.

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An N-oxide intermediate was used for the preparation of 4-dimethylamino nicotinic acid:

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<A NAME="RS00410ST-12">12</A>

4-Iodo-2-(trifluoromethyl)nicotinic acid (50 g, 158 mmol), Boc-amide (22.2 g, 189 mmol), and Cs₂CO₃ (103 g, 315 mmol) were combined in 2-methyl-2-butanol (500 mL) that was previously bubbled with dry nitrogen. The reaction flask was purged four times with nitrogen by applying vacuum to the flask then flushed with dry nitrogen. Xantphos (2.74 g, 4.73 mmol) and Pd₂(dba)₃ (2.89 g, 3.15 mmol) were added. The nitrogen purging sequence was repeated four times. The reaction was then heated to reflux (104-107 ˚C internal temperature) for 2 h. Upon confirmation of reaction completion by HPLC analysis, the reaction was cooled to r.t., and the solids (mostly Cs₂CO₃) were removed by filtration. The filter cake was rinsed with EtOAc. The filtrate was concentrated under reduced pressured to give a dark orange oil. To this was added CH₂Cl₂ (250 mL), the resulting mixture was stirred for 10 min, and a slurry was obtained. The solids were collected by filtration, rinsed with CH₂Cl₂ (25 mL), and dried to give 5b (40.6 g, 84%) as a white solid: mp 180-182 ˚C (EtOAc). ^¹H NMR (400 MHz, MeOH-d ₄): δ = 8.36 (d, 1 H, J = 4.0 Hz), 8.31 (d, 1 H, J = 4.0 Hz), 1.51 (s, 9 H). ^¹³C NMR (100 MHz, MeOH-d ₄): δ = 173.1, 170.4, 153.4, 149.0, 145.8, 144.6 (q, J = 33 Hz), 115.96, 82.7, 28.8. MS (ESI⁺): m/z = 307.0 [M + 1]⁺, 251
[M + 1 - t-Bu]⁺, 206.9 [M + 1 - Boc]⁺. Anal. Calcd for C₁₂H₁₃F₃N₂O₄˙H₂O: C, 44.45; H, 4.66; F, 17.58; N, 8.64. Found: C, 44.16; H, 4.77; F, 17.28; N, 8.56.

<A NAME="RS00410ST-13">13</A>

Compound 5b was dissolved in MeOH (150 mL), and HCl (gaseous, 5.75 g, 158 mmol) was bubbled into the solution. A white solid began to precipitate in 5 min. MeOH was removed under reduced pressure to give 1 as a white solid: mp 214-215 ˚C (MeOH, dec. observed). ^¹H NMR (400 MHz, MeOH-d ₄): δ = 7.85 (d, 1 H, J = 7.0 Hz), 6.90 (d, 1 H, J = 7.0 Hz). ^¹³C NMR (100 MHz, MeOH-d ₄): δ = 166.1, 157.8, 139.3, 136.2 (q, J = 37.5 Hz), 119.2 (q, J = 275.8 Hz), 116.8 (q, J = 2.0 Hz), 112.2. MS (ESI⁺): m/z = 207.2 [M + 1]⁺, 189.0 [M + 1 - H₂O]⁺. Anal. Calcd for C₇H₆ClF₃N₂O₂: C, 34.66; H, 2.49; Cl, 14.61; F, 23.50; N, 11.55. Found: C, 34.52; H, 2.55; Cl, 14.48; F, 23.36; N, 11.37.

For similar reactions with halo nicotinic acid esters:

<A NAME="RS00410ST-14A">14a</A> Spicer JA. Rewcastle GW. Kaufman MD. Black SL. Plummer MS. Denny WA. Quin J. Shahripour AB. Barrett SD. Whitehead CE. Milbank JBJ. Ohren JF. Gowan RC. Omer C. Camp HS. Esmaeil N. Moore K. Sebolt-Leopold JS. Pryzbranowski S. Merriman RL. Ortwine DF. Warmus JS. Flamme CM. Pavlovsky AG. Tecle H. J. Med. Chem.  2007,  50:  5090 

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