J. Korhonen et al. / Bioorg. Med. Chem. 22 (2014) 6694–6705
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5.1.17. (3H-[1,2,3]Triazol[4,5-b]pyridin-3-yl)(4-(3-
phenoxybenzyl)-piperazin-1-yl)-methanone (7e)
with a gradient of EtOAc/hexane, to give slightly yellow solid
(442 mg, yield 78%). 1H NMR (500 MHz, CDCl3):
2.52 (t,
d
A solution of 6 (300 mg, 0.907 mmol), 1H-[1,2,3]-triazolo[4,5-
b]pyridine (73 mg, 0.608 mmol), DMAP (4.87 mg, 0.040 mmol),
and DIPEA (0.211 mL, 1.233 mmol) in anhydrous THF (7.7 mL)
was stirred overnight at RT. The reaction was diluted by addition
of EtOAc (23 mL) and water (12 mL). The organic phase was
washed twice with saturated NaCl solution, and dried over Na2SO4.
The solvents were evaporated to dryness and the residue was puri-
fied by column chromatography on silica gel eluting with a gradi-
ent of EtOAc/petroleum ether to give waxy solid (125 mg, yield
33%). 1H NMR (500 MHz, CDCl3): d 2.65 (t, J = 5.0 Hz, 4H), 3.58 (s,
2H), 3.90 (br s, 2H), 4.03 (br s, 2H), 6.92 (dd, J = 7.7, 2.0 Hz, 1H),
7.00–7.06 (m, 3H), 7.08 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H),
7.30 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.4 Hz, 2H), 7.6 (dd, J = 8.2,
4.4 Hz, 1H), 8.38 (dd, J = 8.5, 1.6 Hz, 1H), 8.81 (dd, J = 4.4, 1.6 Hz,
1H). ESI-MS (m/z) 414.8 (M+). Anal. Calcd for C23H23N6O2: C
66.65, H 5.35, N 20.28. Found: C 65.65, H 5.39, N 18.94.
J = 1.0 Hz, 4H), 3.54 (s, 2H), 3.60 (br s, 2H), 3.69 (br s, 2H), 6.98
(d, J = 8.2 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 7.11 (t, J = 7.60 Hz, 1H),
7.29 (m, 4H), 7.34 (t, J = 7.9 Hz, 2H), 8.25 (d, J = 8.8 Hz, 2H). ESI-
MS (m/z) 434.0 (M+). Anal. Calcd for C24H23N3O5: C 66.50, H 5.35,
N 9.69. Found: C 65.99, H 5.37, N 9.48.
5.1.21. (1H-Benzo[d][1,2,3]triazol-1-yl)(4-(4-phenoxybenzyl)-
piperazin-1-yl)-methanone hydrochloride (9b)
To a solution of bis(1H-benzo[d][1,2,3]triazol-1-yl)methanone21
(240 mg, 0.908 mmol) in THF (20 mL) was added 8 (350 mg,
1.304 mmol) and the mixture was heated in a microwave oven
(130 °C) for 2.5 h. The reaction mixture was evaporated to dryness
and the residue was chromatographed over a silica gel column using
gradient solvent system of MeOH–CH2Cl2 (2:98–0:100) to give free
amine of 9b as an oil. It was converted to its HCl salt by dissolving it
in EtOAc and adding dropwise solution of 2.5 M HCl in EtOAc until
the solution was acidic. Excess of HCl was removed by bubbling
with nitrogen gas. EtOAc was evaporated, and the precipitated
product was washed three times with hexane to afford 9b hydro-
chloride as a white crystalline solid (162 mg, 43%). 1H NMR
(500 MHz, CDCl3): d 2.64 (br s, 4H), 3.57 (s, 2H), 3.94 (br s, 4H),
6.98 (d, J = 8.5 Hz, 2H), 7.00–7.05 (m, 2H), 7.10 (t, J = 7.6 Hz, 1H),
7.30 (d, J = 8.5 Hz, 2H), 7.34 (td, J = 8.5, 0.9 Hz, 2H), 7.45 (td, J = 7.9,
0.8 Hz, 1H), 7.60 (td, J = 8.2, 0.9 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H),
8.09 (d, J = 8.2 Hz, 1H). ESI-MS (m/z) 414.1 (M+). Anal. Calcd for
5.1.18. 1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(3-
phenoxybenzyl)piperazine-1-carboxylate (7f, JW642)
To
a
stirring mixture of hexafluoroisopropanol (80
ll,
0.760 mmol), DIPEA (260
l
l, 1.49 mmol) in CH2Cl2 (4 mL) was
added triphosgene (66 mg, 0.220 mmol) at 0 °C. After stirring for
30 min at 0 °C the mixture was allowed to warm up to RT and stir-
red for 2 h. Compound 6 (191 mg, 0.712 mmol) dissolved in 4 mL of
CH2Cl2 was added to the mixture at 0 °C and stirred overnight. Sol-
vents were concentrated in vacuo and the residue was purified by
silica gel column chromatography eluting with a gradient of hex-
ane–EtOAc (from 99:1 to 85:15) to give 7f as syrup (97 mg,
28%).1H NMR (500 MHz, CDCl3) d 2.44 (m, 4H), 3.51 (s, 2H), 3.54
(m, 4H), 5.74 (sep, J = 6.3 Hz, 1H) 6.90 (ddd, J = 8.2, 2.7, 0.9 Hz,
1H), 6.98–7.02 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 7.10 (tt, J = 7.4,
1.1 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.34 (dd, J = 8.6, 7.4 Hz, 2H).
ESI-MS (m/z) 462.19 (M+). Anal. Calcd for C21H20F6N2O3: C 54.55,
H 4.36, N 6.06. Found: C 55.08, H 4.10, N 6.02.
C23H24ClN5O2: C 64.07, H 5.38, N 15.57. Found: C 64.25, H 5.38, N 15.78.
5.1.22. (1H-imidazol-1-yl)(4-(4-phenoxy-benzyl)-piperazin-1-
yl)-methanone hydrochloride 9c
A mixture of 8 (300 mg, 1.12 mmol) and 1,10-carbonyldiimidaz-
ole (CDI, 199 ll, 1.23 mmol) in THF (15 mL) was heated first 1 h at
80 °C, then 1 h at 90 °C, and 1 h at 110 °C under microwave irradi-
ation. Since the reaction was not completed, additional CDI
(100 mg, 6.17 mmol) was added and microwave heating was con-
tinued for 1 h at 120 °C. The reaction mixture was evaporated to
dryness and the residue was purified by silica gel column chroma-
tography eluting with a gradient of MeOH–CH2Cl2 (from 99:1 to
90:10) to give 9c as oily substance which was converted to its
HCl salt as described for 9b. The precipitated product was washed
three times with hexane to afford 9b hydrochloride as a white
crystalline solid (39 mg, 9%). 1H NMR (500 MHz, CD3OD): d 3.36
(br s, 4H), 3.91 (br s, 4H), 4.33 (s, 2H), 7.01–7.09 (m, 4H) 7.16–
7.22 (m, 2H), 7.40 (td, J = 7.3, 1.0 Hz, 2H), 7.51–7.59 (m, 3H), 8.30
(s, 1H). ESI-MS (m/z) 363.1 (M+). Anal. Calcd for C21H23ClN4O2 ꢂ
0.4H2O: C 62.11, H 5.91, N 13.80. Found: C 61.79, H 5.79, N 13.40.
5.1.19. (1H-Imidazol-1-yl)(4-(3-phenoxybenzyl)piperazin-1-
yl)methanone (7g)
To
a solution of 6 (150 mg, 0.555 mmol), DIPEA (190 ll,
1.1 mmol) in THF (4 mL) at 0 °C was added dropwise 1,10-carbonyl-
diimidazole (CDI, 1 equiv, 85 mg, 0.555 mmol) over 10 min. After
addition the mixture was allowed to warm up to RT and stirred over-
night. The organic layer was washed with water, dried over anhy-
drous MgSO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography eluting with a gradient of
EtOAc–MeOH (from 99:1 to 90:10) to give 7g as oily substance
(94 mg, 47%). 1H NMR (500 MHz, CDCl3) d 2.52 (m, 4H), 3.53 (s,
2H), 3.61 (m, 4H), 6.91 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H), 6.98–7.02 (m,
3H), 7.04 (d, J = 7.6 Hz, 1H), 7.09 (dd, J = 1.5, 1.1 Hz, 1H), 7.29 (tt,
J = 7.3, 1.1 Hz, 1H), 7.18 (t, J = 1.4 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H),
7.34 (dd, J = 8.6, 7.4 Hz, 2H), 7.86 (dd, J = 1.2, 1.0 Hz, 1H). ESI-MS
(m/z) 463.16 (MH+). Anal. Calcd for C21H22N4O2: C 69.59, H 6.12, N
15.46. Found: C 69.01, H 6.15, N 15.54.
5.1.23. 1-Benzyl 4-ethyl piperidine-1,4-dicarboxylate (14)
Benzyl chloroformate (11.9 g, 70.0 mmol) was added dropwise
to a solution of ethyl isonipecotate (13) (10.0 g, 63.6 mmol) and
Et3N (11.5 ml, 83.0 mmol) in CHCl3 (140 mL) at 0 °C. After addition,
the reaction mixture was stirred at 0 °C for 1 h, then allowed to
warm up to room temperature and stirred overnight. The reaction
mixture was washed brine, with 2 M HCl, and again with brine. The
solution was dried over magnesium sulfate and concentrated in
vacuo. The residue (6.10 g, 66% yield) was used without further
purification. 1H NMR (CDCl3, 500 MHz): d l.26 (3H, t, J = 7.1 Hz),
1.66 (2H, dq, J = 11.6, 3.4 Hz), 1.84–1.95 (2H, m), 2.46 (1H, tt,
J = 11.0, 4.0 Hz), 2.93 (2H, t, J = 10.4 Hz), 4.14 (2H, q, J = 7.1 Hz),
4.02–4.17 (2H, m), 5.13 (2H, s), 7.28–7.39 (5H, m).
5.1.20. 4-Nitrophenyl-4-(4-phenoxy-benzyl)-piperazine-1-
carboxylate (9a)
To a solution of 1-(4-phenoxybenzyl)-piperazine (8)20 (350 mg,
1.304 mmol) in anhydrous CH2Cl2 (2.7 mL) was added DIPEA
(1.75 mL, 10.0 mmol) and 4-nitrophenyl chloroformate (342 mg,
1.70 mmol), and solution was stirred at RT for 15 h. The reaction
was quenched with 2 M NaOH (2 mL) and the layers separated.
The aqueous layer was extracted with EtOAc and the combined
organics were washed with 2 M NaOH (3ꢂ) and brine, and dried
over Na2SO4. The solvents were evaporated to dryness, and residue
was purified by flash chromatography on silica gel, eluting first
5.1.24. 4-Nitrophenyl-4-(bis(benzo[d][1,3]dioxol-5-
yl)methyl)piperidine-1-carboxylate (11a)
To a solution of 10a20 (250 mg, 0.737 mmol) in anhydrous
CH2Cl2 (20 mL) was added Et3N (0.534 mL, 3.83 mmol) and