Article
tert-Butyl 2-Benzyl-5-cyano-6-(2,2-dimethylpropyl)-4-(4-methy-
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 3 845
J = 7.5 Hz), 2.87 (2H, s), 3.68 (2H, s), 7.13 (2H, d, J = 8.0 Hz),
7.21 (2H, d, J = 8.0 Hz).
lphenyl)pyridine-3-carboxylate (24i). Compound 24i was prepared
in a manner similar to that described for 24a. 1H NMR (300 MHz,
CDCl3) δ: 1.00 (9H, s), 1.13 (9H, s), 1.24 (9H, s), 2.40 (3H, s), 2.76
(2H, d, J = 7.2 Hz), 2.99 (2H, s), 4.26 (2H, s), 7.12-7.40 (9H, m).
Methyl 5-(Aminomethyl)-2-methyl-4-(4-methylphenyl)-6-pro-
pylpyridine-3-carboxylate (25a). A mixture of 24a (22 g, 71.3
mmol), Raney-Ni (22 mL), 25% NH3 solution (22 mL), THF
(100 mL) and MeOH (100 mL) was stirred at room temperature
for 5 h in a sealed tube under a hydrogen atmosphere at 0.5 MPa.
The reaction mixture was filtered, and the filtrate was concen-
trated under reduced pressure. The residue was partitioned
between AcOEt and 10% aqueous potassium carbonate solu-
tion. The organic layer was washed with brine, dried over anhy-
drous MgSO4 and concentrated under reduced pressure. The
residue was purified by NH silica gel column chromatography
tert-Butyl 5-(Aminomethyl)-2-benzyl-6-(2,2-dimethylpropyl)-
4-(4-methylphenyl)pyridine-3-carboxylate (25i). Compound 25i
was prepared in a manner similar to that described for 25a
in 15% yield as a white powder (2 steps from compound 23i).
1H NMR (300 MHz, CDCl3) δ: 0.96 (9H, s), 1.07 (9H, s), 2.39
(3H, s), 2.85 (2H, s), 3.67 (2H, s), 4.18 (2H, s), 7.11-7.32 (9H, m).
Methyl 5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-
(4-methylphenyl)-6-propylpyridine-3-carboxylate (26a). Com-
pound 25a (13 g, 41.6 mmol) was dissolved in THF (100 mL),
and to the mixture was added (Boc)2O (9.8 g, 45 mmol). After
stirring at room temperature for 3 h, the mixture was concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/AcOEt = 50/50) to give
26a (12 g, 70%) as a pale yellow powder. 1H NMR (300 MHz,
CDCl3) δ: 1.03 (3H, t, J = 7.4 Hz), 1.39 (9H, s), 1.72-1.79
(2H, m), 2.38 (3H, s), 2.53 (3H, s), 2.84-2.90 (2H, m), 3.49
(3H, s), 4.15 (2H, d, J = 5.1 Hz), 4.25 (1H, s), 7.05 (2H, d, J =
8.1 Hz), 7.20 (2H, d, J = 8.1 Hz).
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(AcOEt) to afford 25a (15 g, 67%) as pale yellow crystals. H
NMR (300 MHz, CDCl3) δ: 1.02 (3H, t, J = 7.3 Hz), 1.64-1.85
(2H, m), 2.37 (3H, s), 2.53 (3H, s), 2.93-3.05 (2H, m), 3.47
(3H, s), 3.82 (2H, d, J = 5.5 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.31
(2H, d, J = 8.1 Hz), 8.38 (3H, s).
Methyl 5-(Aminomethyl)-6-butyl-2-methyl-4-(4-methylphenyl)-
pyridine-3-carboxylate (25b). Compound 25b was prepared in a
manner similar to that described for 25a in 68% yield as a
colorless oil. 1H NMR (300 MHz, CDCl3) δ: 0.95 (3H, t, J =
7.3 Hz), 1.35-1.54 (2H, m), 1.61-1.81 (2H, m), 2.37 (3H, s),
2.53 (3H, s), 2.94-3.09 (2H, m), 3.47 (3H, s), 3.82 (2H, d, J =
5.5 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 8.38
(3H, s).
Methyl 5-{[(tert-Butoxycarbonyl)amino]methyl}-6-butyl-2-
methyl-4-(4-methylphenyl)pyridine-3-carboxylate (26b). Com-
pound 26b was prepared in a manner similar to that described
1
for 26a in 60% yield as a white powder. H NMR (300 MHz,
CDCl3) δ: 0.95 (3H, t, J = 7.2 Hz), 1.39 (9H, s), 1.41-1.52
(2H, m), 1.63-1.77 (2H, m), 2.38 (3H, s), 2.53 (3H, s), 2.83-2.94
(2H, m), 3.49 (3H, s), 4.14 (2H, d, J = 4.9 Hz), 4.25 (1H, brs),
7.05 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz).
Methyl 5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-
(4-methylphenyl)-6-(2-methylpropyl)pyridine-3-carboxylate (26c).
Compound 26c was prepared in a manner similar to that
Methyl 5-(Aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-
methylpropyl)pyridine-3-carboxylate (25c). Compound 25c was
prepared in a manner similar to that described for 25a in 95%
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described for 26a in 93% yield as a white powder. H NMR
1
(300 MHz, CDCl3) δ: 0.97 (6H, d, J = 6.8 Hz), 1.39 (9H, s),
2.10-2.30 (1H, m), 2.39 (3H, s), 2.54 (3H, s), 2.78 (2H, d, J =
7.2 Hz), 3.50 (3H, s), 4.15 (2H, d, J = 4.9 Hz), 4.24 (1H, t, J =
4.9 Hz), 7.06 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.9 Hz).
5-(Aminomethyl)-2-methyl-4-(4-methylphenyl)-6-propylpyri-
dine-3-carboxylic Acid Dihydrochloride (27a). To a solution of
26a (2 g, 4.8 mmol) in MeOH (10 mL) and THF (10 mL) was
added 1 M NaOH solution (10 mL). The mixture was stirred at
room temperature for 3 days. The reaction mixture was neu-
tralized with 0.5 M HCl and extracted with AcOEt. The organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give a white powder.
The obtained white powder was dissolved in 1,4-dioxane (4 mL)
and added to 4 M HCl in 1,4-dioxane (4 mL, 16 mmol). The
mixture was stirred at room temperature for 2 h. The reaction
mixture was concentrated under reduced pressure and crystal-
lized from diisopropyl ether to give 27a (1.7 g, 80%) as a white
powder. 1H NMR (300 MHz, DMSO-d6) δ: 1.02 (3H, t, J = 7.4
Hz), 1.69-1.82 (2H, m), 2.37 (3H, s), 2.62 (3H, s), 3.01-3.07
(2H, m), 3.82 (2H, d, J = 5.3 Hz), 7.24 (2H, d, J = 8.1 Hz), 7.31
(2H, d, J = 8.1 Hz), 8.41 (3H, s). LC/MS m/z 299.2 (M þ H).
HPLC purity 98.07% (220 nm), 100% (254 nm). ESI-HRMS
calcd for C18H22N2O2 m/z 299.1754 (M þ H), found 299.1742
(M þ H).
yield as a white powder. H NMR (300 MHz, CDCl3) δ: 0.98
(6H, d, J = 6.6 Hz), 1.39 (2H, brs), 2.15-2.30 (1H, m), 2.39 (3H,
s), 2.53 (3H, s), 2.80 (2H, d, J = 7.2 Hz), 3.50 (3H, s), 3.66 (2H,
s), 7.11 (2H, d, J = 8.0 Hz), 7.21 (2H, d, J = 8.0 Hz). LC/MS m/z
327 (M þ H). Mp: 56.7-56.8 ꢀC.
tert-Butyl 5-(Aminomethyl)-6-(2,2-dimethylpropyl)-2-methyl-
4-(4-methylphenyl)pyridine-3-carboxylate (25d). Compound 25d
was prepared in a manner similar to that described for 25a in
92% yield as a white powder. 1H NMR (300 MHz, CDCl3) δ:
1.02 (9H, s), 1.19 (9H, s), 2.40 (3H, s), 2.54 (3H, s), 2.86 (2H, s),
3.68 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.22 (2H, d, J = 7.9 Hz).
tert-Butyl 5-(Aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-
methylphenyl)pyridine-3-carboxylate (25e). Compound 25e was
prepared in a manner similar to that described for 25a in 74%
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yield as a white powder. H NMR (300 MHz, CDCl3) δ: 0.98
(3H, t, J = 7.3 Hz), 1.02 (9H, s), 1.14 (2H, brs), 1.14 (9H, s),
1.73-1.86 (2H, m), 2.39 (3H, s), 2.72-2.77 (2H, m), 2.87 (2H, s),
3.68 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).
tert-Butyl 5-(Aminomethyl)-6-(2,2-dimethylpropyl)-4-(4-methy-
lphenyl)-2-propylpyridine-3-carboxylate (25f). Compound 25f
was prepared in a manner similar to that described for 25a in
74% yield as a white powder. 1H NMR (300 MHz, CDCl3) δ:
0.98 (3H, t, J = 7.3 Hz), 1.02 (9H, s), 1.14 (2H, brs), 1.14 (9H, s),
1.73-1.86 (2H, m), 2.39 (3H, s), 2.72-2.77 (2H, m), 2.87 (2H, s),
3.68 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).
tert-Butyl 5-(Aminomethyl)-6-(2,2-dimethylpropyl)-2-(1-methyl-
ethyl)-4-(4-methylphenyl)pyridine-3-carboxylate (25g). Compound
25g was prepared in a manner similar to that described for 25a in
51% yield as a white powder. 1H NMR (300 MHz, CDCl3) δ: 1.04
(9H, s), 1.18 (9H, s), 1.30 (6H, d, J = 6.9 Hz), 1.32 (2H, brs), 2.39
(3H, s), 2.85 (2H, s), 3.04-3.13 (1H, m), 3.66 (2H, s), 7.13 (2H, d,
J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz).
5-(Aminomethyl)-6-butyl-2-methyl-4-(4-methylphenyl)pyridine-
3-carboxylic Acid Dihydrochloride (27b). Compound 27b was
prepared in a manner similar to that described for 27a in 66%
yield as a white powder. 1H NMR (300 MHz, DMSO-d6) δ: 0.95
(3H, t, J = 7.4 Hz), 1.39-1.49 (2H, m), 1.65-1.75 (2H, m), 2.37
(3H, s), 2.61 (3H, s), 3.03-3.08 (2H, m), 3.81 (2H, d, J = 5.3
Hz), 7.24 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 8.40
(3H, s). LC/MS m/z 313.2 (M þ H). HPLC purity 100% (220
nm), 100% (254 nm). ESI-HRMS calcd for C19H24N2O2 m/z
313.1911 (M þ H), found 313.1896 (M þ H).
tert-Butyl 5-(Aminomethyl)-6-(2,2-dimethylpropyl)-4-(4-methy-
lphenyl)-2-(2-methylpropyl)pyridine-3-carboxylate (25h). Com-
pound 25h was prepared in a manner similar to that described
5-(Aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methyl-
propyl)pyridine-3-carboxylic Acid Dihydrochloride (27c). Com-
pound 27c was prepared in a manner similar to that described
1
for 25a in 89% yield as a white powder. H NMR (300 MHz,
CDCl3) δ: 0.93 (6H, d, J = 6.6 Hz), 1.02 (9H, s), 1.17 (9H,
s), 1.24 (2H, brs), 2.22-2.31 (1H, m), 2.39 (3H, s), 2.66 (2H, d,
1
for 27a in 57% yield as a white powder. H NMR (300 MHz,