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.

Key words

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

References and Notes

• 2a Hawes EM. Gorecki DKJ. J. Heterocycl. Chem.  1972,  9:  703 
• 2b Armarego WLF. J. Chem. Soc.  1962,  4094 
• 2c Ismail AG. Wibberley Denman G. J. Chem. Soc.  1967,  24:  2613 
• 2d Stukenbrock H. Mussmann R. Geese M. Ferandin Y. Lozach O. Lemcke T. Kegel S. Lomow A. Burk U. Dohrmann C. Meijer L. Austen M. Kunick C. J. Med. Chem.  2008,  51:  2196 
• 2e Wall MJ. Chen J. Meegalla S. Ballentine SK. Wilson KJ. DesJarlais RL. Schubert C. Chaikin MA. Crysler C. Petrounia IP. Donatelli RR. Yurkow EJ. Boczon L. Mazzulla M. Player MR. Patch RJ. Manthey CL. Molloy C. Tomczuk B. Illig CR. Bioorg. Med. Chem. Lett.  2008,  18:  2097 
• 2f Boerjesson L, Connolly S, Johansson H, Kristoffersson A, Linnanen T, Shamovsky I, and Skrinjar M. inventors; WO 2006-SE1012  20060904.  ; Chem. Abstr. 2007, 146, 337739
• 2g Nagase T, Sato N, Kanatani A, and Tokita S. inventors; US  2005182045.  ; Chem. Abstr. 2005, 143, 211923
• 3 Didiuk MT. Griffith DA. Benbow JW. Liu KC. Walker DP. Bi FC. Morris J. Guzman-Perez A. Gao H. Bechle BM. Kelley RM. Yang X. Dirico K. Ahmed S. Hungerford W. DiBrinno J. Zawistoski MP. Bagley SW. Li J. Zeng Y. Santucci S. Oliver R. Corbett M. Olson T. Chen C. Li M. Paralkar VM. Riccardi KA. Healy DR. Kalgutkar AS. Maurer TS. Nguyen HT. Frederick KS. Bioorg. Med. Chem. Lett.  2009,  19:  4555 
• 4a Vasil’ev LS. Surzhikov FE. Dorokhov VA. Russ. Chem. Bull. Int. Ed.  2004,  53:  2319 
• 4b An alternative and attractive synthesis of ethyl ester of 2-trifluoromethyl nicotinic acid via construction of the pyridine ring was reported after this work was completed: Kiss LE. Ferreira HS. Learmonth DA. Org. Lett.  2008,  10:  1835 
• 5 Gilman H. Jones RG. J. Am. Chem. Soc.  1943,  53:  2319 
• 6a Schlosser M. Marull M. Eur. J. Org. Chem.  2003,  1569 
• 6b Schlosser M. Angew Chem. Int. Ed.  2006,  45:  5432 
• 6c Schlosser M. Synlett  2007,  3096 
• For methods developed specifically for CF₃-group installation:
• 7a Jarvie JMS. Fitzgerald WE. Janz GJ. J. Am. Chem. Soc.  1956,  78:  978 
• 7b Clark JH. McClinton MA. Blade RJ. J. Chem. Soc., Chem. Commun.  1988,  638 
• 7c Paratian JM. Sibille S. Perichon J. J. Chem. Soc., Chem. Commun.  1992,  53 
• 7d Cottet F. Schlosser M. Eur. J. Org. Chem.  2002,  327 
• 7e Cottet F. Marull M. Mongin F. Espinosa D. Schlosser M. Synthesis  2004,  1619 
• 8 Li B. Buzon RA. Castaldi MJ. Org. Process Res. Dev.  2001,  5:  609 
• 9 Mongin F. Trécourt F. Quéguiner G. Tetrahedron Lett.  1999,  40:  5483 
• An N-oxide intermediate was used for the preparation of 4-dimethylamino nicotinic acid:
• 10a Tono-Oka S. Bull. Chem. Soc. Jpn.  1982,  55:  1531 
• 10b Yamada S. Misono T. Iwai Y. Masumizu A. Akiyama Y. J. Org. Chem.  2006,  71:  6872 
• 11a Xu H. Wolf C. Chem. Commun.  2009,  3035 
• 11b Roehrscheid F, Rapp J, and Papenfuhs T. inventors; EP  647614.  ; Chem. Abstr 1995, 122, 290454
• For similar reactions with halo nicotinic acid esters:
• 14a 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 
• 14b Collins I, Reader JC, Matthews TP, Cheung KM, Proisy N, Williams D, Hugh K, Sukhbinder S, Scanlon JE, Piton N, Addison GJ, and Cherry M. inventors; WO  2009044162.  ; Chem. Abstr. 2009, 150, 398578

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.