T. Ohashi et al. / Bioorg. Med. Chem. 23 (2015) 4777–4791
4789
59%) as a brown powder. To a solution of obtained product
(250 mg, 0.828 mmol) in THF (3 mL) were added pyridine
(0.5 mL), and the mixture was stirred at room temperature for
overnight. The mixture was acidified with 1 N HCl aq, and diluted
with water. The precipitate was collected by filtration using water
to give the title compound (99.6 mg, 99%) as a pale yellow powder.
1H NMR (DMSO-d6) d 1.29 (3H, t, J = 7.4 Hz), 2.89 (2H, q, J = 7.4 Hz),
4.01 (3H, s), 5.10 (2H, q, J = 8.9 Hz), 7.45–7.72 (3H, m), 7.96–8.10
(2H, m), 10.82 (1H, s), 13.47 (1H, br s).
(100
at 0 °C, and the mixture was stirred at 0 °C for 2.5 h. Benzoyl chlo-
ride (53 L, 0.457 mmol) was added, and the mixture was stirred at
0 °C for 1 h. Further benzoyl chloride (53 L, 0.457 mmol) and pyr-
idine (55 L, 0.680 mmol) were added, the mixture was stirred at
lL, 1.24 mmol) and benzoyl chloride (106 lL, 0.913 mmol)
l
l
l
0 °C for 1 h. The mixture was quenched with aqueous NaHCO3
solution, and the mixture was extracted with AcOEt. The organic
layer was dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexane/AcOEt = 19/1 to 1/1) to give the title compound (312 mg,
5.40. 2-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-7-methyl-4-
oxo-5-(2,2,2-trifluoroethoxy)-4,7-dihydro-3H-pyrrolo[2,3-d]pyr
imidine-6-carboxamide (2a)
93%) as an orange oil. 1H NMR (DMSO-d6)
d
1.22 (3H, t,
To a mixture of 3a (1.0 g, 3.1 mmol), 2-(4-aminopiperidin-1-yl)-
2-oxoethanol hydrochloride (732 mg, 3.7 mmol) and HOBt
(635 mg, 4.7 mmol) in DMF (15 mL) were added EDC (900 mg,
4.7 mmol) and Et3N (1.2 mL, 8.5 mmol) at 0 °C, and the mixture
was stirred at room temperature for 4.5 h. The reaction mixture
was diluted with saturated NaHCO3 aq, and the precipitated solid
was collected by filtration. The solid was washed with water, and
dried in vacuo to give the title compound (1.1 g, 79%) as a white
powder. 1H NMR (DMSO-d6) d 1.13–1.52 (5H, m), 1.76–1.98 (2H,
m), 2.63 (2H, q, J = 7.5 Hz), 2.75–2.95 (1H, m), 3.00–3.19 (1H, m),
3.61–3.75 (1H, m), 3.83 (3H, s), 3.93–4.17 (3H, m), 4.17–4.34
(1H, m), 4.53 (1H, t, J = 5.5 Hz), 5.20 (2H, q, J = 9.1 Hz), 7.43 (1H,
d, J = 7.7 Hz), 12.10 (1H, s).
J = 7.5 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.73 (2H, q, J = 7.5 Hz), 4.33
(2H, q, J = 7.1 Hz), 5.55 (2H, s), 7.28–7.47 (3H, m), 7.47–7.71 (5H,
m), 7.95–8.09 (2H, m), 10.76 (1H, s).
5.37. Ethyl 5-ethyl-6-[(phenylcarbonyl)amino]-3-{[(trifluorome
thyl)sulfonyl]oxy}pyrazine-2-carboxylate (6f)
To a solution of 36 (310 mg, 0.765 mmol) in EtOH (5 mL) was
added 10% Pd-C (32.7 mg), and the mixture was stirred at room
temperature for 3 h under H2 atmosphere. The catalyst was
removed by filtration through Celite pad, and the filtrate was con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/AcOEt = 9/1 to 1/4) to give ethyl 5-
ethyl-3-hydroxy-6-[(phenylcarbonyl)amino]pyrazine-2-carboxy-
late (185 mg, 77%) as a pale yellow powder. To a solution of the
compound obtained above (183 mg, 0.580 mmol) in pyridine
The following compounds 2b–f were prepared in a same man-
ner similar to that described for 2a.
5.41. 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-5-
(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-1H-
pyrrolo[2,3-b]pyridine-2-carboxamide (2b)
(2 mL) was added dropwise Tf2O (147
lL, 0.871 mmol) at 0 °C,
and the mixture was stirred at 0 °C for 1 h. Further Tf2O (30
lL,
0.178 mmol) was added, and the mixture was stirred at 0 °C for
1 h. The mixture was diluted with water (15 mL), and the mixture
was extracted three times with AcOEt (15 mL). The extracts were
combined, washed with water (20 mL) and brine (10 mL), dried
over MgSO4 and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexane/AcOEt = 49/1 to
1/1) to give the title compound (244 mg, 94%) as yellow oil. 1H
NMR (DMSO-d6) d 1.21 (3H, t, J = 7.3 Hz), 1.34 (3H, t, J = 7.1 Hz),
2.83 (2H, q, J = 7.3 Hz), 4.43 (2H, q, J = 7.1 Hz), 7.49–7.74 (3H, m),
7.99–8.10 (2H, m), 11.42 (1H, s).
Yield 47%, white crystals. Mp 150 °C (recrystallized from
hexane/AcOEt) 1H NMR (DMSO-d6) d 1.22 (3H, t, J = 7.4 Hz), 1.28–
1.58 (2H, m), 1.82–2.02 (2H, m), 2.70 (2H, q, J = 7.2 Hz), 2.78–
2.94 (1H, m), 3.02–3.21 (1H, m), 3.60–3.78 (1H, m), 3.93 (3H, s),
4.00–4.19 (3H, m), 4.20–4.36 (1H, m), 4.53 (1H, t, J = 5.4 Hz), 4.63
(2H, s), 4.91 (2H, q, J = 8.9 Hz), 7.52–7.64 (2H, m), 7.64–7.74 (1H,
m), 7.79 (1H, d, J = 7.7 Hz), 8.03 (1H, s), 8.11 (2H, d, J = 7.4 Hz).
Anal. Calcd for C28H31N4O5F3: C, 59.99; H, 5.57; N, 9.99. Found: C,
59.75; H, 5.51; N, 9.81. LC–MS: m/z = 561 (MH+).
5.38. Ethyl 3-ethyl-7-hydroxy-5-methyl-2-[(phenylcarbonyl)-
amino]-5H-pyrrolo[2,3-b]pyrazine-6-carboxylate (4f)
5.42. 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-5-
[(phenylcarbonyl)amino]-3-(2,2,2-trifluoroethoxy)-1H-pyrrolo-
[2,3-b]pyridine-2-carboxamide (2c)
In the same manner as in the preparation of 4b, the title com-
pound (159 mg, 80%) was obtained as a pale yellow powder from
6f (242 mg, 0.541 mmol). 1H NMR (DMSO-d6) d 1.28 (3H, t,
J = 7.6 Hz), 1.35 (3H, t, J = 7.2 Hz), 2.88 (2H, q, J = 7.6 Hz), 3.95
(3H, s), 4.37 (2H, q, J = 7.2 Hz), 7.45–7.72 (3H, m), 7.94–8.12 (2H,
m), 9.91 (1H, br s), 10.72 (1H, s).
Yield 53%, white crystals. Mp 200 °C (recrystallized from
hexane/AcOEt). 1H NMR (DMSO-d6) d 1.24 (3H, t, J = 7.5 Hz),
1.32–1.55 (2H, m), 1.84–1.99 (2H, m), 2.79–2.92 (1H, m), 2.86
(2H, q, J = 7.5 Hz), 3.02–3.19 (1H, m), 3.63–3.78 (1H, m), 3.94
(3H, s), 4.00–4.18 (1H, m), 4.10 (2H, t, J = 5.7 Hz), 4.21–4.37 (1H,
m), 4.53 (1H, t, J = 5.5 Hz), 4.94 (2H, q, J = 8.8 Hz), 7.46–7.71 (3H,
m), 7.86 (1H, d, J = 7.6 Hz), 8.03 (2H, d, J = 6.8 Hz), 8.13 (1H, s),
10.11 (1H, s). Anal. Calcd for C27H30N5O5F3: C,57.75; H,5.38;
N,12.47. Found: C, 58.03; H,5.47; N,12.44. LC–MS: m/z = 562 (MH+).
5.39. 3-Ethyl-5-methyl-2-[(phenylcarbonyl)amino]-7-(2,2,2-tri-
fluoroethoxy)-5H-pyrrolo[2,3-b]pyrazine-6-carboxylic acid (3f)
To a solution of 4f (59.2 mg, 0.161 mmol) in DMF were added
Cs2CO3 (72.0 mg, 0.220 mmol) and 2,2,2-trifluoroethyl trifluo-
romethanesulfonate (28 lL, 0.166 mmol) at 0 °C, and the mixture
5.43. 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-5-
[(phenylcarbonyl)amino]-3-(2,2,2-trifluoroethoxy)-1H-indole-2
-carboxamide (2d)
was stirred at 0 °C for 2 h. The mixture was diluted with water,
and the precipitate was collected by filtration. The collection was
dissolved in hexane/AcOEt, and purified by silica gel column chro-
matography (hexane/AcOEt = 49/1 to 2/1) to give ethyl 3-ethyl-
5-methyl-2-[(phenylcarbonyl)amino]-7-(2,2,2-trifluoroethoxy)-5H
-pyrrolo[2,3-b]pyrazine-6-carboxylate (53.2 mg, 74%) as a pale yel-
low powder. To a solution of obtained compound above (107 mg,
0.238 mmol) in THF (1 mL)/EtOH (2 mL) was added 1 M NaOH aq
Yield 82%, white crystals. Mp 227 °C (recrystallized from
hexane/AcOEt). 1H NMR (DMSO-d6) d 1.20 (3H, t, J = 7.5 Hz),
1.30–1.50 (2H, m), 1.91 (2H, d, J = 9.9 Hz), 2.72 (2H, q, J = 7.5 Hz),
2.82 (1H, t, J = 11.9 Hz), 3.10 (1H, t, J = 11.9 Hz), 3.71 (1H, d,
J = 12.9 Hz), 3.89 (3H, s), 4.04–4.12 (3H, m), 4.30 (1H, d,
J = 13.8 Hz), 4.54 (1H, t, J = 5.4 Hz), 4.85 (2H, q, J = 8.9 Hz), 7.44