March 2012
Preparation of 2-, 4-, 5-, and 6-Aminonicotinic Acid tert-Butyl Esters
445
due was diluted with petroleum ether, filtered, dried over anhy-
drous sodium sulfate, and concentrated to give 19.9 g (73%) of
1a as a light yellow solid (purity 97.87% by HPLC).
tert-Butyl 4-aminonicotinate (1c). This compound was pre-
pared in a similar manner from 3c (2.54 g, 12.1 mmol) and
Raney nickel 2400 active catalyst suspension (6 mL, 50% in
water) in 40 mL of 2-propanol. It was obtained as a white solid,
1
1.93 g (82%), m.p. 129–131ꢀC. IR 3409, 1689, 1621 cmꢁ1. H
REFERENCES AND NOTES
NMR (deuteriochloroform): d 1.59 (s, 9 H) 6.20 (br. S, 2 H)
6.48 (d, J ¼ 5.85 Hz, 1 H) 8.16 (d, J ¼ 5.85 Hz, 1 H) 8.84 (s, 1
H).; 13C NMR (deuteriochloroform): d 28.23, 81.51, 109.10,
110.63, 151.77, 153.25, 154.91, 166.95. ms: m/z 195 (MþHþ).
Anal. Calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42.
Found: C, 61.91; H, 7.44; N, 14.32.
[1] (a) Simons, L. J.; Caprathe, B. W.; Callahan, M.; Graham,
J. M.; Kimura, T.; Lai, Y.; LeVine, H.; Lipinski, W.; Sakkab, A. T.;
Tasaki, Y.; Walker, L. C.; Yasunaga, T.; Ye, Y.; Zhuang, N.; Augelli-
Szafran, C. E. Bioorg Med Chem Lett 2009, 19, 654; (b) Singh, S.;
Soni, L. K.; Gupta, M. K.; Prabhakar, Y. S.; Kaskhedikar, S. G. Eur J
Med Chem 2008, 43, 1071.
tert-Butyl 5-aminonicotinate (1d). Cuprous iodide (438 mg,
2.3 mmol), trans-4-hydroxy-L-proline (590 mg, 4.5 mmol), and
2d (2.89 g, 11.2 mmol) were stirred with 20 mL of dimethyl
sulfoxide in a screw cap pressure tube. Concentrated ammo-
nium hydroxide (12 mL, 180 mmol) was added, and the tube
was closed and the homogeneous blue solution was heated at
80ꢀC overnight. The mixture was then cooled, diluted with
100 mL of saturated ammonium chloride solution and
extracted with 30 mL of 1,1,1-trichloroethane [16]. The aque-
ous phase was separated and extracted with another 30 mL
portion of 1,1,1-trichloroethane. The combined extracts were
dried and concentrated to afford 1.85 g (85%) of 1d as a white
[2] (a) Sugasawa, K.; Kawaguchi, K.; Nomura, T.; Matsumoto,
S.; Shin, T.; Azami, H.; Abe, T.; Suga, A.; Seo, R.; Tanahashi, M.;
Watanabe, T. WO 2009/054468 (2009); Chem Abstr 2009, 150,
494851; (b) Ghisalberti, C. WO 2006/087393 (2009); Chem Abstr
2009, 145, 263246.
[3] (a) Hopper, A. T.; Caroon, J. M.; Chin, E.; Dunn, R.; Laba-
die, S. S.; Li, J.; Schumacher, R. A.; Talamas, F. X. WO 2010/003084
(2010); Chem Abstr 2010, 152, 119684; (b) Boovanahalli, S. K.; Jin,
X.; Jin, Y.; Kim, J. H.; Dat, N. T.; Hong, Y.-S.; Lee, J. H.; Jung, S.-
H.; Lee, K.; Lee, J. J. Bioorg Med Chem Lett 2007, 17, 6305.
[4] (a) Watterson, S. H.; Xiao, Z.; Dodd, D. S.; Tortolani, D.
R.; Vaccaro, W.; Potin, D.; Launay, M.; Stetsko, D. K.; Skala, S.;
Davis, P. M.; Lee, D.; Yang, X.; McIntyre, K. W.; Balimane, P.; Patel,
K.; Yang, Z.; Marathe, P.; Kadiyala, P.; Tebben, A. J.; Sheriff, S.;
Chang, C. Y. Y.; Ziemba, T.; Zhang, H.; Chen, B.-C.; DelMonte, A.
J.; Aranibar, N.; McKinnon, M.; Barrish, J. C.; Suchard, S. J.; Murali
Dhar, T. G. J Med Chem 2010, 53, 3814; (b) Wei, P.; Shi, M.; Bar-
num, S.; Cho, H.; Carlson, T.; Fraser, J. D. Diabetologia 2009, 52,
2142; (c) Morishita, K.-I.; Yakushiji, N.; Ohsawa, F.; Takamatsu, K.;
Matsuura, N.; Makishima, M.; Kawahata, M.; Yamaguchi, K.; Tai, A.;
Sasaki, K.; Kakuta, H. Bioorg Med Chem Lett 2009, 19, 1001; (d)
Takamatsu, K.; Takano, A.; Yakushiji, N.; Morohashi, K.; Morishita,
K.; Matsuura, N.; Makishima, M.; Tai, A.; Sasaki, K.; Kakuta, H.
ChemMedChem 2008, 3, 780.
solid, m.p. 107–108ꢀC. IR 3370, 3208, 2978, 1704 cmꢁ1 1H
.
NMR (deuteriochloroform): d 1.59 (s, 9 H) 3.82 (br. s., 2 H)
7.51 (dd, J ¼ 2.93, 1.76 Hz, 1 H) 8.21 (d, J ¼ 2.73 Hz, 1 H)
8.57 (d, J ¼ 1.76 Hz, 1 H); 13C NMR (deuteriochloroform): d
28.14, 81.73, 121.72, 127.88, 140.49, 140.99, 142.09, 164.75.
ms: m/z 195 (MþHþ).
Anal. Calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42.
Found: N, 61.59; H, 7.15, N, 14.21.
Telescoped large-scale preparation of 1a. A mixture of 6-
chloronicotinic acid (50 g, 0.32 mol) and (4-dimethylamino)-
pyridine (3.3 g, 0.027 mol) in 150 mL of anhydrous tetrahydro-
furan was stirred and heated to reflux, while a solution of di-
tert-butyl dicarbonate (172 g, 0.79 mol) in 150 mL of dry tetra-
hydrofuran was added dropwise from an addition funnel over
1.5 h. The resulting mixture was heated at reflux for an addi-
tional 2 h and then cooled to room temperature. The reaction
mixture was concentrated and partitioned between methyl t-
butyl ether (500 mL) and water (500 mL). The layers were sep-
arated, and the organic layer was washed with water, saturated
ammonium chloride solution (200 mL), and brine and dried.
Concentration afforded crude 2a (95 g) as a yellow solid, which
was used for the next step without further purification.
[5] Benbow, J. W.; Lou, J.; Pfefferkorn, J. A.; Tu, M. M. WO
2010/013161 2010; Chem Abstr 2010, 152, 238781.
[6] (a) Suzuki, K.; Nunokawa, Y.; Ogou, N. WO 2002/076918
(2002); Chem Abstr 2002, 137, 279214; (b) Van Scott, E. J.; Yu, R.
J. US 4141977 (1979); Chem Abstr 1979, 90, 174689.
[7] Dudash, J.; Rybczynski, P.; Urbanski, M.; Xiang, A.; Zeck,
R.; Zhang, X.; Zhang, Y. WO 2007/053503 (2007); Chem Abstr 2007,
146, 481914.
[8] Venkatachalam; T. K.; Huang, H.; Yu, G.; Uckun, F. M.
Synth Commun 2004, 34, 1489.
[9] Taylor; E. C.; Fletcher, S. R.; Sabb, A. L. Synth Commun
1984, 14, 921.
To a solution of 2a (95 g, 0.32 mol) in tert-butanol (100
mL) was added hydrazine hydrate (186 g, 180 mL, 3.2 mol)
dropwise from addition funnel with stirring. Heating was con-
tinued while the reaction was monitored by TLC on aliquots
that had been removed and quenched into water and methyl
tert-butyl ether. After 3 h, 2a had been consumed by TLC
analysis. The mixture was cooled and concentrated, then
diluted with methyl tert-butyl ether (200 mL) and washed with
water, saturated ammonium chloride, and dried. Concentration
afforded 3a (78 g) as a white solid, which was used for the
next step without further purification.
[10] Kim, S.; Lee, J. I.; Kim, Y. C. J Org Chem 1985, 50, 560.
[11] Aminolysis of 2 by ammonia with or without catalysis by
copper afforded 1 in yields of <10%.
The reduction could be carried out with or without an additional
reducing agent, such as hydrogen or hydrazine hydrate, being present.
In addition, the latter two may be telescoped into a one pot procedure
on large scale.
[13] Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J Org Chem
2009, 74, 4542.
[14] Hoffmann-Emery, F.; Hilpert, H.; Scalone, M.; Waldmeier,
P. J Org Chem 2006, 71, 2000.
A solution of 3a (29.5 g, 0.14 mol) and Raney nickel 2400
active catalyst suspension (about 20 mL) in 300 mL of metha-
nol was hydrogenated under 50 psi of hydrogen at room tem-
perature for 24 h in a 500-mL Parr reaction bottle. The reaction
mixture was filtered through Celite and concentrated. The resi-
[15] The yield is lower in this case due to the presence of a con-
siderable amount of 4-hydroxynicotinic acid in the starting 4-chloroni-
cotinic acid.
[16] Martin, D.; Weise, A.; Niclas, H. J. Angew Chem Int Ed
Eng 1967, 6, 318.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet