References and Notes
1 Current Address: Pfizer Global Research & Development, 10770
Science Center Drive, San Diego, CA 92121, USA.
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11b Roehrscheid F, Rapp J, and Papenfuhs T. inventors; EP 647614.
;
Chem. Abstr 1995, 122, 290454
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.
For similar reactions with halo
nicotinic acid esters:
14a
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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
