R. Vardanyan et al. / Bioorg. Med. Chem. 17 (2009) 5044–5053
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5.1.6.2. [2-Methyl-1-(1-benzyl-piperidin-4-yl)-1H-indol-3-yl]-
acetic acid ethyl ester (8b). Light yellow liquid (79.3%). IR:
(0.00625 mol) is done without water. After stirring the mixture
for 30 min and filtering the potassium acetate, acetonitrile is evap-
orated under vacuo giving as a residue of the desired acids 9a,d.
m
(cmÀ1) = 1747 (C@O). 1H NMR (600 MHz, CDCl3) d 7.59 (m, 1H),
7.56 (m, 1H), 7.40 (m, 2H), 7.37 (m, 2H), 7.29 (m, 1H), 7.13 (m,
1H), 7.08 (m, 1H), 4.18 (m, 1H), 4.12 (q, 2H, J = 7.26 Hz), 3.90 (s,
2H), 3.69 (s, 2H), 3.62 (s, 2H), 3.10 (d, 2H, J = 11.16 Hz), 2.43 (s,
3H), 1.81 (m, 2H), 1.24 (t, 3H, J = 7.07 Hz). EI-MS: m/z 391. HRMS
calcd for C25H31N2O2: 391.2380 found (ESI, [M+H]+): 391.2385.
5.1.7.1. [2-Methyl-1-(1-methyl-piperidin-4-yl)-1H-indol-3-yl]-
acetic acid (9a). Crystalline solid (55.2%), mp 83–85 °C. IR:
m
(cmÀ1) = 1718 (C@O). 1H NMR (600 MHz, CDCl3) d 10.93 (br s,
1H), 7.53 (d, 1H, J = 7.28 Hz), 7.44 (d, 1H, J = 7.70 Hz), 6.97 (m,
2H), 4.08 (m, 1H), 3.60 (s, 2H), 3.11 (d, 2H, J = 11.16 Hz), 2.60 (m,
3H), 2.27 (s, 3H), 2.21 (t, 2H, J = 11.17 Hz), 2.02 (s, 1H), 1.96 (s,
1H), 1.91 (s, 1H), 1.57 (d, 2H, J = 11.53 Hz), 2.38 (3H, s). 13C NMR
5.1.6.3. [2-Methyl-1-(1-phenethyl-piperidin-4-yl)-1H-indol-3-yl]-
acetic acid ethyl ester (8c). Crystalline solid (85.6%). mp 93–
94 °C. IR:
m
(cmÀ1) = 1744 (C@O). 1H NMR (600 MHz, CDCl3) d
(125 MHz, MeOD) d 178.23, 176.56, 133.79, 129.47, 120.78,
7.47 (d, 1H, J = 8.65 Hz), 7.31 (m, 2H), 7.22 (m, 3H), 7.02 (d, 1H,
J = 2.51 Hz), 6.77 (dd, 1H, J = 8.65, 2.51 Hz), 4.11 (q, 2H,
J = 7.16 Hz), 3.85 (s, 3H), 3.65 (s, 2H), 3.20 (d, 2H, J = 10.77 Hz),
2.87 (m, 2H), 2.68 (m, 2H), 2.62 (m, 2H), 2.41 (s, 3H), 2.21 (t, 2H,
J = 11.23 Hz), 1.83 (m, 2H), 1.24 (t, 3H, J = 7.16 Hz). EI-MS: m/z
405. EI-MS: m/z 391. HRMS calcd for C26H33N2O2: 405.2537 found
(ESI, [M+H]+): 405.2543.
118.95, 118.58, 111.05, 107.27, 54.16, 50.68, 42.78, 32.32, 27.65,
21.41, 10.46. EI-MS: m/z 287. HRMS calcd for C17H23N2O2:
287.1754 found (ESI, [M+H]+): 287.1761.
5.1.7.2. [2-Methyl-1-(1-benzyl-piperidin-4-yl)-1H-indol-3-yl]-
acetic acid (9b). Crystalline solid (83.0%), mp 78–80 °C. IR:
m
(cmÀ1) = 1720 (C@O). 1H NMR (600 MHz, CDCl3) d 11.23 (br s,
1H), 7.39 (m, 7H), 6.99 (m, 1H), 6.91 (m, 1H), 4.02 (m, 1H), 3.89
(s, 2H), 3.61 (s, 2H), 3.17 (d, 2H, J = 10.99 Hz), 2.62 (m, 2H), 2.33
(m, 2H), 2.06 (s, 3H), 1.38 (d, 2H, J = 11.78 Hz). 13C NMR
5.1.6.4. [5-Methoxy-2-methyl-1-(1-methyl-piperidin-4-yl)-1H-
indol-3-yl]-acetic acid ethyl ester (8d). Light yellow liquid
(75.6%). IR:
m
(cmÀ1) = 1745 (C@O). 1H NMR (500 MHz, CDCl3) d
(125 MHz, MeOD) d 177.04, 175.42, 133.87, 131.21, 129.63,
7.43 (m, 1H), 6.99 (m, 1H), 6.72 (m, 1H), 4.09 (m+q 3H), 3.81 (s,
3H), 3.61 (s, 2H), 3.01 (d, 2H, J = 11.69 Hz), 2.59 (m, 2H,), 2.37 (s,
3H), 2.33 (s, 3H), 2.11 (m, 2H), 1.77 (m, 2H), 1.21 (m, 3H). EI-MS:
m/z 345. HRMS calcd for C20H29N2O3: 345.2173 found (ESI,
[M+H]+): 345.2166.
129.25, 129.13, 120.67, 118.92, 118.39, 111.00, 106.55, 60.60,
52.09, 51.29, 31.59, 27.53, 20.75, 10.43. EI-MS: m/z 363. HRMS
calcd for C23H27N2O2: 363.2067 found (ESI, [M+H]+): 363.2061.
5.1.7.3. [2-Methyl-1-(1-phenethyl-piperidin-4-yl)-1H-indol-3-
yl]-acetic acid (9c). Crystalline solid (80%), mp 83–85 °C. IR:
m
5.1.6.5. [5-Methoxy-2-methyl-1-(1-benzyl-piperidin-4-yl)-1H-
indol-3-yl]-acetic acid ethyl ester (8e). Light yellow liquid
(81.9%). IR:
7.48 (m, 1H), 7.37 (m, 4H), 7.28 (m, 1H), 7.04 (m, 1H), 6.79 (m,
1H), 4.13 (m+q, 3H), 3.86 (s, 3H), 3.66 (s, 2H), 3.60 (s, 2H), 3.07
(m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.15 (m, 2H), 1.79 (m, 2H),
1.25 (t, 3H, J = 6.98 Hz). EI-MS: m/z 421. HRMS calcd for
C26H33N2O3: 421.2486 found (ESI, [M+H]+): 421.2493.
(cmÀ1) = 1717 (C@O). 1H NMR (600 MHz, CDCl3) d 10.77 (br s,
1H), 8.97 (br s, 1H), 7.52 (m, 1H), 7.28 (m, 2H), 7.20 (m, 4H),
7.00 (m, 1H), 6.95 (m, 1H), 4.08 (m, 1H), 3.62 (s, 2H), 3.30 (d, 2H,
J = 10.78 Hz), 2.95 (m, 2H,), 2.91 (m, 2H), 2.62 (d, 2H, J = 9.26 Hz),
2.38 (m, 2H), 2.05 (s, 3H), 1.39 (m, 2H). 13C NMR (125 MHz, MeOD)
d 178.02, 137.55, 133.79, 129.45, 128.88, 128.84, 127.02, 120.80,
118.94, 118.59, 58.18, 52.47, 51.32, 32.38, 31.00, 27.82, 21.30,
10.59. EI-MS: m/z 377. HRMS calcd for C24H29N2O2: 377.2224
found (ESI, [M+H]+): 377.2219.
m
(cmÀ1) = 1747 (C@O). 1H NMR (600 MHz, CDCl3) d
5.1.6.6. [5-Methoxy-2-methyl-1-(1-phenethyl-piperidin-4-yl)-
1H-indol-3-yl]-acetic acid ethyl ester (8f). Light yellow liquid
(87.4%). IR:
5.1.7.4. [5-Methoxy-2-methyl-1-(1-methyl-piperidin-4-yl)-1H-
indol-3-yl]-acetic acid (9d). Crystalline solid (59.2%), mp 58–
m
(cmÀ1) = 1745 (C@O). 1H NMR (600 MHz, CDCl3) d
7.47 (d, 1H, J = 8.65 Hz), 7.31 (m, 2H), 7.22 (m, 3H), 7.02 (d, 1H,
J = 2.51 Hz), 6.77 (dd, 1H, J = 8.65, 2.51 Hz), 4.11 (q, 2H,
J = 7.16 Hz), 3.85 (s, 3H), 3.65 (s, 2H), 3.20 (d, 2H, J = 10.77 Hz),
2.87 (m, 2H), 2.68 (m, 2H), 2.62 (m, 2H), 2.41 (s, 3H), 2.21 (t, 2H,
J = 11.23 Hz), 1.83 (m, 2H), 1.24 (t, 3H, J = 7.16 Hz). EI-MS: m/z
435. HRMS calcd for C25H31N2O3: 407.2329 found (ESI, [M+H]+):
407.2323.
60 °C. IR: m
(cmÀ1) = 1721 (C@O). 1H NMR (500 MHz, CDCl3) d
11.45 (br s, 1H), 7.43 (m, 1H), 6.99 (m, 1H), 6.72 (m, 1H), 4.09
(m, 1H), 3.81 (s, 3H), 3.61 (s, 2H), 3.01 (d, 2H, J = 11.69 Hz), 2.59
(m, 2H), 2.37 (s, 3H), 2.33 (s, 3H), 2.11 (m, 2H), 1.77 (m, 2H). 13C
NMR (125 MHz, MeOD) d 178.32, 154.03, 134.55, 128.62, 112.25,
110.66, 107.11, 101.30, 55.04, 54.18, 50.30, 43.05, 32.24, 28.31,
10.48. EI-MS: m/z 317. HRMS calcd for C18H25N2O3: 317.1860
found (ESI, [M+H]+): 317.1856.
5.1.7. General method for the synthesis of [2-methyl-1-(1-
methyl-piperidin-4-yl)-1H-indol-3-yl]-acetic acids (9a–f)
(a) 0.005 mol of one of the N-[(1-substitutedl-piperidin-4-yl)-
phenyl-hydrazono]-pentanoic acids ethyl ethers 7a–f dissolved in
8 mL of ethanol was added with cooling (ice) to a stirred solution
of 0.00625 mol KOH in 4 mL of ethanol. The solution was left at
room temperature for 48 h. Ethanol was removed in vacuo.
Remaining residue was washed several times with boiling ether.
5.1.7.5. [5-Methoxy-2-methyl-1-(1-benzyl-piperidin-4-yl)-1H-
indol-3-yl]-acetic acid (9e). Crystalline solid (82%), mp 135–
137 °C. IR:
m
(cmÀ1)=1718 (C@O). 1H NMR (600 MHz, CDCl3) d
10.88 (br s, 1H), 7.48 (m, 1H), 7.37 (m, 4H), 7.28 (m, 1H), 7.04
(m, 1H), 6.79 (m, 1H), 4.13 (m, 1H), 3.86 (s, 3H), 3.66 (s, 2H),
3.60 (s, 2H), 3.07 (m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.15 (m,
2H), 1.79 (m, 2H). 13C NMR (125 MHz, MeOD) d 179.14, 153.83,
134.37, 133.46, 130.64, 130.16, 129.99, 128.82, 128.76, 111.79,
109.98, 107.11, 101.08, 61.46, 55.32, 52.60, 52.28, 32.97, 28.69,
10.52. EI-MS: m/z 393. HRMS calcd for C24H29N2O3: 393.2173
found (ESI, [M+H]+): 393.2167.
A
new portion of ether was added and on cooling (ice)
0.00625 mol (0.375 mL) of acetic acid in 1 mL of water was added.
Ether layer was separated and remaining part was extracted with
CHCl3 and dried (MgSO4). The solvent was removed in vacuo. The
product does not need further purification. Yields are between
55% and 84%.
5.1.7.6. [5-Methoxy-2-methyl-1-(1-phenethyl-piperidin-4-yl)-
(b) For cases 9a,d the work up during acidification of potassium
salts differs. To the remaining residue after ethanol evaporation
was added 10 mL acetonitrile, and neutralization with acetic acid
1H-indol-3-yl]-acetic acid (9f). Crystalline solid (84.3%), mp 98–
100 °C. IR:
11.26 (br s, 1H), 7.42 (s, 1H), 7.29 (m, 2H), 7.21 (m, 4H), 6.99 (d,
m
(cmÀ1) = 1720 (C@O). 1H NMR (600 MHz, CDCl3) d