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H. Yamagishi et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
d6) d 1.50 (s, 9H), 2.50 (s, 3H), 5.84 (s, 2H), 7.40–7.52 (m, 5H), 8.00
(dd, J = 6.3 Hz, 1H), 8.23 (dd, J = 6.3, 1.4 Hz, 1H), 9.30 (d, J = 1.1 Hz,
1H), 9.57 (s, 1H); MS (ESI) m/z 299 [MꢁBr]+.
1.74 (m, 1H), 1.78–1.89 (m, 1H), 2.31–2.43 (m, 1H), 2.82–2.92
(m, 1H), 3.07–3.17 (m, 1H), 3.20–3.27 (m, 1H), 3.40–3.49 (m,
1H), 4.32–4.39 (m, 1H), 4.68–4.78 (m, 1H), 6.58–6.64 (m, 1H),
7.46–7.49 (m, 1H), 7.94 (s, 1H), 10.78 (br s, 1H), 11.65 (br s, 1H);
MS (ESI) m/z 272 [M+H]+.
5.1.37. tert-Butyl ( )-cis-[1-benzyl-4-methylpiperidin-3-yl]
carbamate (14)
5.1.42. ( )-cis-3-[4-Methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-
d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]-3-
oxopropanenitrile (19)
To a solution of 13 (1.20 g, 3.16 mmol) in EtOH (48 mL) was
added PtO2 (Adam’s catalyst) (36 mg, 0.16 mmol), followed by cat-
alytic reduction at 40 °C under 3 atm of hydrogen gas for 4 h. The
reaction mixture was separated by filtration through a Celite pad
and the filtrate was concentrated under reduced pressure. The
obtained residue was neutralized with a saturated NaHCO3 aque-
ous solution, and the mixture was then extracted with CHCl3.
The organic layer was dried over MgSO4 and then filtered and con-
centrated in vacuo. The obtained residue was purified by column
chromatography on silica gel silica gel (hexane/EtOAc = 90:10 to
87:13) to obtain the product (664 mg, 69%) as a colorless oil. 1H
NMR (DMSO-d6) d 0.80 (d, J = 6.7 Hz, 3H), 1.30–1.36 (m, 1H), 1.37
(s, 9H), 1.42–1.55 (m, 1H), 1.56–1.68 (m, 1H), 1.92–2.10 (m, 2H),
2.53–2.70 (m, 2H), 3.38–3.49 (m, 2H), 3.51–3.59 (m, 1H), 6.12–
6.23 (m, 1H), 7.20–7.26 (m, 1H), 7.27–7.33 (m, 4H); MS (ESI) m/z
305 [M+H]+.
Compound 19 was prepared from 18 in 66% yield as a white
solid by a method similar to that described for 11. 1H NMR
(DMSO-d6) d 0.96 (d, J = 7.2 Hz, 3/2H), 0.97 (d, J = 7.2 Hz, 3/2H),
1.63–4.65 (m, 10H), 6.51–6.55 (m, 1H), 7.43 (dd, J = 2.4, 3.6 Hz,
1/2H), 7.46 (dd, J = 2.4, 3.6 Hz, 1/2H), 7.906 (s, 1/2H), 7.911 (s,
1/2H), 10.86 (br s, 1H), 11.57 (br s, 1/2H), 11.62 (br s, 1/2H); MS
(ESI) m/z 339 [M+H]+; Anal. Calcd for C17H18N6O2ꢀ0.1H2O: C,
60.62; H, 5.39; N, 24.71. Found: C, 59.64; H, 5.27; N, 24.33.
5.1.43. Ethyl 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
pyrrolo[2,3-b]pyridine-5-carboxylate (20)
To a solution of 4 (2.00 g, 8.90 mmol) in DMF (30 mL) was
added NaH (60% dispersion in mineral oil, 427 mg, 10.7 mmol) at
0 °C and the mixture was stirred at the same temperature for 1 h.
To the solution was added SEMCl (1.72 mL, 9.79 mmol) and the
resulting solution was allowed to stir for 30 min at room temper-
ature. The mixture was quenched with saturated NaHCO3 aqueous
solution, extracted with EtOAc, washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by col-
umn chromatography on silica gel (hexane/AcOEt = 100:0 to
90:10) to give the product (3.07 g, 97%) as colorless oil. 1H NMR
5.1.38. ( )-cis-1-Benzyl-4-methylpiperidin-3-amine (15)
To a solution of 14 (2.00 g, 6.57 mmol) in CH2Cl2 (5.0 mL) was
added TFA (5.0 mL) and the mixture was stirred at the same tem-
perature for 30 min. The mixture was evaporated in vacuo and the
residue was quenched with saturated NaHCO3 aqueous solution,
extracted with CHCl3, dried over Na2SO4, and evaporated in vacuo
to give the product (1.31 g, 98%). 1H NMR (DMSO-d6) d 0.85 (d,
J = 6.8 Hz, 3H), 1.29–1.47 (m, 2H), 1.47–1.58 (m, 1H), 1.91–2.01
(m, 1H), 2.05–2.14 (m, 1H), 2.43–2.53 (m, 1H), 2.54–2.66 (m,
2H), 2.66–2.71 (m, 1H), 3.33 (br s, 2H), 3.37–3.47 (m, 1H), 7.20–
7.26 (m, 1H), 7.27–7.34 (m, 4H); MS (ESI) m/z 205 [M+H]+.
(DMSO-d6)
d
ꢁ0.10 (s, 9H), 0.82 (t, J = 8.1 Hz, 2H), 1.36 (t,
J = 7.2 Hz, 3H), 3.52 (t, J = 8.0 Hz, 2H), 4.36 (q, J = 7.0 Hz, 2H), 5.67
(s, 2H), 6.75 (d, J = 3.7 Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H), 8.75 (s,
1H); MS (ESI) m/z 355 [M+H]+.
5.1.44. Ethyl ( )-cis-4-{[1-benzyl-4-methylpiperidin-3-yl] amino}-
1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-
5-carboxylate (21)
5.1.39. ( )-cis-Ethyl 4-{[1-benzyl-4-methylpiperidin-3-yl]amino}-
1H-pyrrolo[2,3-b]pyridine-5-carboxylate (16)
A mixture of 20 (1.05 g, 2.96 mmol), 15 (725 mg, 3.55 mmol),
and DIPEA (1.55 mL, 8.88 mmol) in NMP (3.0 mL) was heated at
180 °C for 2 h. After cooling to room temperature, the reaction mix-
ture was quenched with water, extracted with EtOAc, washed with
bine, dried over Na2SO4, and evaporated in vacuo. The crude mix-
ture was purified by column chromatography on silica gel
(hexane/AcOEt = 95:5 to 85:15) to give the product (1.51 g, 98%).
1H NMR (DMSO-d6) d ꢁ0.11 (s, 9H), 0.79 (t, J = 8.2 Hz, 2H), 0.86
(d, J = 6.7 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H), 1.50–1.63 (m, 2H),
1.81–1.94 (m, 1H), 2.08–2.17 (m, 1H), 2.23–2.31 (m, 1H), 2.72–
2.88 (m, 2H), 3.38–3.60 (m, 4H), 4.28–4.45 (m, 3H), 5.51 (s, 2H),
6.72 (d, J = 3.9 Hz, 1H), 7.11–7.23 (m, 3H), 7.28 (d, J = 3.6 Hz, 1H),
7.30–7.35 (m, 2H), 8.61 (s, 1H), 9.36 (d, J = 9.9 Hz, 1H); MS (ESI)
m/z 523 [M+H]+.
Compound 16 was prepared from 4 in 95% yield as a white solid
by a method similar to that described for 5c. 1H NMR (DMSO-d6) d
0.87 (d, J = 6.8 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H), 1.52–4.43 (m, 12H),
6.62 (dd, J = 2.0, 3.6 Hz, 1H), 7.09 (dd, J = 2.8, 3.6 Hz, 1H), 7.13–7.35
(m, 5H), 8.56 (s, 1H), 9.33 (d, J = 9.6 Hz, 1H), 11.59 (br s, 1H); MS
(ESI) m/z 393 [M+H]+.
5.1.40. ( )-cis-1-[1-Benzyl-4-methylpiperidin-3-yl]-3,6-dihydro-
imidazo [4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (17)
Compound 17 was prepared from 16 in 57% yield as a white
solid by a method similar to that described for 6a. 1H NMR
(DMSO-d6) d 0.94 (d, J = 7.1 Hz, 3H), 1.58–1.66 (m, 1H), 2.01–2.13
(m, 1H), 2.25–2.35 (m, 1H), 2.36–2.44 (m, 1H), 2.62–2.70 (m,
1H), 2.83–2.91 (m, 1H), 3.48–3.68 (m, 3H), 4.54–4.61 (m, 1H),
6.43–6.47 (m, 1H), 7.19–7.26 (m, 1H), 7.28–7.37 (m, 4H), 7.42–
7.47 (m, 1H), 7.58 (s, 1H), 10.77 (br s, 1H), 11.60 (br s, 1H); MS
(ESI) m/z 362 [M+H]+.
5.1.45. ( )-cis-1-[1-Benzyl-4-methylpiperidin-3-yl]-6-{[2-(trime-
thylsilyl)ethoxy]methyl}-3,6-dihydroimidazo[4,5-d]pyrrolo [2,3-
b]pyridin-2(1H)-one (22)
Compound 22 was prepared from 21 in 89% yield by a method
similar to that described for 6e. 1H NMR (DMSO-d6) d ꢁ0.10 (s, 9H),
0.86 (t, J = 8.0 Hz, 2H), 0.93 (d, J = 7.0 Hz, 3H), 1.57–1.65 (m, 1H),
2.02–2.15 (m, 1H), 2.25–2.43 (m, 2H), 2.61–2.69 (m, 1H), 2.84–
2.93 (m, 1H), 3.47–3.55 (m, 3H), 3.59–3.64 (m, 2H), 4.54–4.61
(m, 1H), 5.60 (s, 2H), 6.55 (d, J = 3.7 Hz, 1H), 7.19–7.26 (m, 1H),
7.28–7.37 (m, 4H), 7.63 (d, J = 3.7 Hz, 1H), 7.94 (s, 1H), 10.86 (br
s, 1H); MS (ESI) m/z 492 [M+H]+.
5.1.41. ( )-cis-1-[4-Methylpiperidin-3-yl]-3,6-dihydroimidazo
[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (18)
To a solution of 17 (8.10 g, 22.4 mmol) in EtOH (486 mL) was
added 20% Pd(OH)2 on carbon (6.29 g, 4.48 mmol) at room temper-
ature under nitrogen. Hydrogen gas was purged and stirred for
2 days at 30 °C under 4 atm. The mixture was filtered through a
Celite pad. The filtrate was evaporated in vacuo to give the crude
product (6.00 g, 99%). The crude residue was used without further
purification. 1H NMR (DMSO-d6) d 0.85 (d, J = 7.0 Hz, 3H), 1.56–