462
Chem. Pharm. Bull.
Vol. 68, No. 5 (2020)
d6) δ: 1.19–1.43 (2H, m), 1.34 (3H, t, J=7.0Hz), 1.64–1.85 piperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]-
(3H, m), 1.98–2.17 (2H, m), 2.20 (3H, s), 2.25–2.36 (2H, m), piperazin-1-yl}methyl)benzonitrile Succinate (26a) To a
2.39–2.45 (2H, m), 2.41 (4H, s), 2.79–2.96 (2H, m), 3.03–3.21 solution of 4-[(4-{5-[(4-methoxypiperidin-4-yl)methoxy]-3-
(2H, m), 3.54–3.69 (6H, m), 3.91 (2H, d, J=6.0Hz), 4.33 (2H, methylpyridine-2-carbonyl}piperazin-1-yl)methyl]benzonitrile
q, J=6.9Hz), 7.32 (1H, d, J=2.7Hz), 7.52 (2H, d, J=8.4 Hz), (24; 370mg, 0.79mmol) in CH2Cl2 (6.0mL) were added 6-eth-
7.79 (2H, d, J=8.4Hz), 8.06 (1H, d, J=2.7Hz), 8.16 (1H, d, oxypyridine-3-carbaldehyde (29; 120mg, 0.79mmol), acetic
J=1.3Hz), 8.21 (1H, d, J=1.3Hz), 12.10 (2H, brs); MS m/z: acid (5.0µL, 87µmol) and NaBH(OAc)3 (450mg, 2.1mmol).
570 (M+H)+; ESI-MS m/z: 570.3185 (M+H)+ (Calcd for After stirring at room temperature for 4h, the mixture was
C32H40O3N7: 570.3187).
diluted with saturated NaHCO3 aqueous solution and extracted
5-{[1-(tert-Butoxycarbonyl)-4-methoxypiperidin-4-yl]- with CHCl3. The organic layer was dried over MgSO4 and
methoxy}-3-methylpyridine-2-carboxylic Acid (22) To a concentrated in vacuo. The residue was purified by column
mixture of methyl 5-hydroxy-3-methylpyridine-2-carboxylate chromatography on silica gel (CHCl3/MeOH). To a solution
(18; 960mg, 5.7mmol), tert-butyl 4-(hydroxymethyl)-4-me- of the residue (370mg, 0.62mmol) in MeOH was added suc-
thoxypiperidine-1-carboxylate (37; 1.4g, 5.7mmol) and tolu- cinic acid (72mg, 0.61mmol). The mixture was concentrated
ene (20mL) was added cyanomethylenetributylphosphorane in vacuo. To the residue was added heptane, and the pre-
(2.2mL, 8.3mmol). The mixture was stirred at 100°C over- cipitated solid was collected by filtration to obtain the product
1
night under an argon atmosphere. After cooling to room tem- (340mg, 61%). H-NMR (DMSO-d6) δ: 1.30 (3H, t, J=7.1 Hz),
perature, the mixture was concentrated in vacuo. The residue 1.50–1.70 (2H, m), 1.73–1.87 (2H, m), 2.14–2.63 (8H, m), 2.21
was purified by column chromatography on silica gel (hexane/ (3H, s), 2.41 (4H, s), 3.05–3.16 (2H, m), 3.15 (3H, s), 3.44 (2H,
EtOAc). To a solution of the residue in MeOH (20mL) was s), 3.54–3.72 (2H, m), 3.59 (2H, s), 4.00 (2H, s), 4.28 (2H, q,
added 1.0mol/L NaOH aqueous solution (20mL, 20mmol). J=7.1Hz), 6.75 (1H, d, J=8.6Hz), 7.37 (1H, d, J=2.2 Hz),
The mixture was stirred at 60°C for 1h. After cooling to room 7.52 (2H, d, J=8.2Hz), 7.61 (1H, dd, J=2.4, 8.6Hz), 7.79
temperature, the mixture was washed with Et2O and the aque- (2H, d, J=8.2Hz), 8.03 (1H, d, J=2.2Hz), 8.10 (1H, d,
ous layer was acidified with 10% citric acid aqueous solution. J=2.4Hz), 12.22 (2H, brs); MS m/z: 599 (M+H)+; ESI-MS
The mixture was extracted with CHCl3, and the organic layer m/z: 599.3348 (M+H)+ (Calcd for C34H43O4N6: 599.3340).
was dried over MgSO4 and concentrated in vacuo. To the
4-({4-[5-({1-[(6-Ethoxypyridin-3-yl)methyl]-4-fluoropi-
residue was added Et2O, and the precipitated solid was col- peridin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piper-
1
lected by filtration to obtain the product (2.0g, 91%). H-NMR azin-1-yl}methyl)benzonitrile Succinate (27a) Compound
(DMSO-d6) δ: 1.40 (9H, s), 1.45–1.60 (2H, m), 1.73–1.88 (2H, 27a was prepared from 25 in 68% yield using a similar ap-
m), 2.51 (3H, s), 2.85–3.16 (2H, m), 3.19 (3H, s), 3.61–3.82 proach to that described for 26a. 1H-NMR (DMSO-d6) δ:
(2H, m), 4.11 (2H, s), 7.42 (1H, d, J=2.4Hz), 8.20 (1H, d, 1.30 (3H, t, J=7.1Hz), 1.55–2.06 (4H, m), 2.14–2.48 (6H, m),
J=2.4Hz), 12.60 (1H, brs); MS m/z: 381 (M+H)+.
2.21 (3H, s), 2.42 (4H, s), 2.58–2.74 (2H, m), 3.03–3.18 (2H,
5-{[1-(tert-Butoxycarbonyl)-4-fluoropiperidin-4-yl]- m), 3.46 (2H, s), 3.59 (2H, s), 3.60–3.70 (2H, m), 4.15 (2H, d,
methoxy}-3-methylpyridine-2-carboxylic Acid (23) Com- J=20.5Hz), 4.28 (2H, q, J=7.1Hz), 6.75 (1H, d, J=8.5 Hz),
pound 23 was prepared from 18 and tert-butyl 4-fluoro-4- 7.37 (1H, d, J=2.2Hz), 7.52 (2H, d, J=8.4Hz), 7.62 (1H,
(hydroxymethyl)piperidine-1-carboxylate18) in 54% yield using dd, J=2.4, 8.5Hz), 7.79 (2H, d, J=8.4Hz), 8.03 (1H, d,
1
a similar approach to that described for 22. H-NMR (DMSO- J=2.2Hz), 8.11 (1H, d, J=2.4Hz), 12.17 (2H, brs); MS m/z:
d6) δ: 1.41 (9H, s), 1.55–1.82 (2H, m), 1.83–2.01 (2H, m), 2.51 587 (M+H)+; ESI-MS m/z: 587.3137 (M+H)+ (Calcd for
(3H, s), 2.89–3.18 (2H, m), 3.73–3.93 (2H, m), 4.27 (2H, d, C33H40O3N6F: 587.3140).
J=21.2Hz), 7.42 (1H, d, J=2.4Hz), 8.21 (1H, d, J=2.4 Hz),
4-({4-[5-({1-[(5-Ethoxypyrazin-2-yl)methyl]-4-methoxypi-
peridin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piper-
12.64 (1H, brs); MS m/z: 369 (M+H)+.
4-[(4-{5-[(4-Methoxypiperidin-4-yl)methoxy]-3-meth- azin-1-yl}methyl)benzonitrile Succinate (26b) Compound
ylpyridine-2-carbonyl}piperazin-1-yl)methyl]benzonitrile 26b was prepared from 24 and 35b in 65% yield using a simi-
1
(24) Compound 24 was prepared from 22 in quantita- lar approach to that described for 21c. H-NMR (DMSO-d6)
tive yield using a similar approach to that described for 20. δ: 1.34 (3H, t, J=7.1Hz), 1.53–1.72 (2H, m), 1.72–1.88 (2H,
1H-NMR (DMSO-d6) δ: 1.41–1.62 (2H, m), 1.64–1.83 (2H, m), m), 2.21 (3H, s), 2.25–2.47 (6H, m), 2.41 (4H, s), 2.53–2.65
2.22 (3H, s), 2.26–2.36 (2H, m), 2.37–2.48 (2H, m), 2.63–2.81 (2H, m), 3.05–3.18 (2H, m), 3.15 (3H, s), 3.59 (4H, s), 3.61–3.69
(4H, m), 3.06–3.18 (2H, m), 3.16 (3H, s), 3.60 (2H, s), 3.60–3.70 (2H, m), 4.01 (2H, s), 4.33 (2H, q, J=7.1Hz), 7.37 (1H, d,
(2H, m), 4.00 (2H, s), 7.37 (1H, d, J=2.4Hz), 7.52 (2H, d, J=2.4Hz), 7.52 (2H, d, J=8.4Hz), 7.79 (2H, d, J=8.4 Hz),
J=8.4Hz), 7.80 (2H, d, J=8.4Hz), 8.11 (1H, d, J=2.4 Hz); 8.10 (1H, d, J=2.4Hz), 8.17 (1H, d, J=1.3Hz), 8.21 (1H, d,
MS m/z: 464 (M+H)+.
J=1.3Hz), 12.22 (2H, brs); MS m/z: 600 (M+H)+; ESI-MS
4-[(4-{5-[(4-Fluoropiperidin-4-yl)methoxy]-3-methylpyr- m/z: 600.3292 (M+H)+ (Calcd for C33H42O4N7: 600.3293).
idine-2-carbonyl}piperazin-1-yl)methyl]benzonitrile (25) 4-({4-[5-({1-[(5-Ethoxypyrazin-2-yl)methyl]-4-fluoro-
Compound 25 was prepared from 23 in quantitative yield piperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]-
1
using a similar approach to that described for 20. H-NMR piperazin-1-yl}methyl)benzonitrile Succinate (27b) To
(DMSO-d6) δ: 1.52–1.90 (4H, m), 2.21 (3H, s), 2.26–2.35 (2H,
a
solution of 4-[(4-{5-[(4-fluoropiperidin-4-yl)methoxy]-3-
m), 2.37–2.48 (2H, m), 2.63–2.87 (4H, m), 3.05–3.19 (2H, methylpyridine-2-carbonyl}piperazin-1-yl)methyl]benzonitrile
m), 3.60 (2H, s), 3.61–3.69 (2H, m), 4.14 (2H, d, J=21.0 Hz), (25; 2.0g, 4.4mmol) in MeCN (20mL) were added DIPEA
7.38 (1H, d, J=2.4Hz), 7.52 (2H, d, J=8.4Hz), 7.79 (2H, d, (2.7mL, 16mmol) and 2-(chloromethyl)-5-ethoxypyrazine
J=8.4Hz), 8.12 (1H, d, J=2.4Hz); MS m/z: 452 (M+H)+.
(35b; 960mg, 5.5mmol) in MeCN (5.0mL). After stirring at
4-({4-[5-({1-[(6-Ethoxypyridin-3-yl)methyl]-4-methoxy- 50°C for 18h, the mixture was concentrated in vacuo. The