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Synlett 2010(14): 2133-2135  
DOI: 10.1055/s-0030-1258481
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Bryan Li*, F. Christopher Bi, Richard A. Buzon, Ming Kang, Robert M. Oliver, John F. Sagal, Lacey Samp, Daniel P. Walker, Zhijun Zhang
Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
e-Mail: bryan.li@pfizer.com;
Further Information

Publication History

Received 3 February 2010
Publication Date:
09 July 2010 (online)

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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.

Key words

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

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1

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

12

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.

13

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.