5
138 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 14
Methyl Ester of 6-(Benzylamino)-5-cyano-2-methylnicotinic
de los Rı ´o s et al.
(1.2-2.2 equiv) were added. The reaction mixture was heated
under reflux (27-49 h). After the reaction was complete (TLC
analysis), the mixture was allowed to cool to room temperature
Acid (5). Following the general method for the synthesis of
benzyl-protected aminopyridine derivatives, reaction of 3 (506 mg,
2
(
.40 mmol) and benzylamine (309 mg, 2.88 mmol) in MeOH
7 mL), after 7 days, yielded compound 5 (648 mg, 96%) as a white
solid. IR (KBr) ν 3354, 3034, 2957, 2223, 1719, 1599, 1580, 1454,
2
and a mixture of THF/H O (2:1) was added. An aqueous
solution of 10% NaOH was added dropwise to the mixture
until the aqueous solution was basic (pH 9). After being stirred
for 30 min, the mixture was extracted three times with dichloro-
methane. The organic layer was washed with brine, dried over
anhydrous sodium sulfate, filtered, and the solvent was evapo-
rated. The resultant solid was purified by silica gel flash chro-
matography using methanol/dichloromethane mixtures as
eluent to provide pure compounds.
-1 1
1435, 1325, 1262, 1237, 1210, 1149, 1090, 780, 693 cm ; H NMR
(
CDCl , 300 MHz) δ 8.28 (s, 1 H, H4), 7.35 (m, 5H, Ph), 5.75 (br,
3
1
H, NH), 4.79 (d, J = 8.7 Hz, 2 H, CH ), 3.86 (s, 3 H, OCH
2
3
), 2.77
13
[
s, 3 H, CH (C2)]; C NMR (DMSO-d
3
6
, 75.4 MHz) δ 165.1, 164.9
0
0
(
(
(
CO, C6), 157.8 (C2), 145.2 (C4), 139.5 (C1 ), 128.4 (C3 ), 127.7
0
0
C2 ), 127.0 (C4 ), 116.1 (C3), 112.8 (CN), 88.1 (C5), 52.0
CO CH ), 44.2 (CH N), 25.7 [CH
(C2)]. MS (API-ESþ) m/z:
Methyl Ester of 5-Amino-2-methyl-7,8-dihydro-6H-cyclopenta-
2
3
þ
2
3
þ
[
b][1,8]naphthyridine-3-carboxylic Acid (9). This compound was
obtained following the general method for the Friedl €a nder
reaction. To a stirred suspension of AlCl (93 mg, 0.70 mmol)
[
M þ 1] 282.3, 296.3; [M þ Na] 304.3, 318.3.
Ethyl Ester of 6-(benzylamino)-5-cyano-2-methylnicotinic
Acid (6). Following the general method for the synthesis of
benzyl-protected aminopyridine derivatives, reaction of 4 (225
mg, 1.00 mmol) and benzylamine (129 mg, 1.20 mmol) in MeOH
3
in dry 1,2-dichloroethane (5 mL) were added methyl 6-amino-5-
cyano-2-methyl-3-pyridinecarboxylate 7 (95 mg, 0.50 mmol)
and cyclopentanone (59 mg, 0.70 mmol). Upon the TLC anal-
(
2 mL), after 4 days, yielded compound 6 (203 mg, 69%) as a
white solid. IR (KBr) ν 3350, 3062, 3032, 2985, 2926, 2903, 2225,
3
ysis, 33 mg of AlCl (0.25 mmol) and 21 mg of cyclopentanone
1
1
716, 1600, 1582, 1454, 1403, 1368, 1327, 1258, 1234, 1148, 1109,
091, 1033, 779, 742, 714, 693, 615 cm ; H NMR (CDCl , 300
3
(0.25 mmol) were added after 28 h of reflux. The reaction was
complete at 49 h of total time, yielding compound 9 (63 mg,
60%) as a yellow solid: mp 255-258 ꢀC; IR (KBr) ν 3317, 3188,
-
1 1
MHz) δ 8.29 (s, 1 H, H4), 7.35 (m, 5H, Ph), 5.72 (br, 1 H, NH),
.79 (d, J = 8.4 Hz, 2 H, CH ), 4.32 (q, J = 7.2 Hz, 2 H, CO
CH CH ), 2.77 [s, 3 H, CH (C2)], 1.37 (t, 3 H, J = 7.2 Hz,
2
7
7
951, 2844, 1724, 1645, 1601, 1549, 1431, 1358, 1259, 1114, 802,
4
2
2
-
-
1 1
77 cm ; H NMR (DMSO-d , 200 MHz) δ 9.14 (s, 1 H, H4),
6
2
3
3
1
3
.03 (br, 2 H, NH
2
), 3.89 (s, 3 H, CH
3
O), 3.37 (m, 2 H, H8), 2.91
C
CO
(
(
2
CH
2
CH
3
3
); C NMR (CDCl , 75.4 MHz) δ 166.5, 165.3
1
3
0
0
(
m, 2 H, H6), 2.79 [s, 3 H, CH
3
C(2)], 2.10 (m, 2 H, H7);
CO, C6), 158.2 (C2), 144.9 (C4), 138.3 (C1 ), 129.2 (C3 ), 128.4
0
0
C2 ), 128.2 (C4 ), 116.6 (C3), 114.7 (CN), 89.1 (C5), 61.3
6
NMR (DMSO-d , 50.2 MHz) δ 171.8 (CO), 166.5 (C8a), 158.9
(
(
(
C2), 157.0 (C9a), 148.1 (C4), 135.8 (C5), 119.5 (C3), 114.1
C5a), 109.0 (C4a), 52.1 (CH O), 35.1 (C8), 27.5 [CH C(2)], 25.3
(
CH
CO CH CH ), 45.7 (CH N), 26.4 [CH (C2)], 14.7 (CO CH -
2
2
3
2
3
2
2
þ
þ
). MS (API-ESþ) m/z: [M þ 1] 296.0; [M þ Na] 318.0.
3
3
3
þ
C6), 21.8 (C7). MS (API-ESþ) m/z: 258.1 [(M þ 1) , 100],
Anal. (C H N O ) C, H, N.
2
17
17
3
2
45.1, 205.1, 157.1. Anal. (C H N O ) C, H, N.
14 15
General Method for the Synthesis of Aminopyridine Deriva-
tives. Trifluoromethanesulfonic acid (10-13 equiv) was added
dropwise to a solution of the corresponding benzyl-protected
3
2
Methyl 5-Amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naph-
thyridine-3-carboxylate (10). This compound was obtained fol-
lowing the general method for the Friedl €a nder reaction. To a
6
-aminopyridine in anhydrous dichloromethane (8 mL/mmol)
under argon at 0 ꢀC. The mixture was then refluxed for 2-3 h,
cooled and diluted in water, basified to pH 10 with 10% NaOH,
and extracted with dichloromethane. The organic phase was
dried over anhydrous sodium sulfate, evaporated, and purified
by flash chromatography using hexane and ethyl acetate mix-
tures as eluent to give pure compounds.
3
stirred suspension of AlCl (83 mg, 0.62 mmol) in dry 1,2-
dichloroethane (5 mL) were added methyl 6-amino-5-cyano-2-
methyl-3-pyridinecarboxylate 7 (85 mg, 0.44 mmol) and cyclo-
hexanone (61 mg, 0.62 mmol). Upon the TLC analysis, an
amount of 30 mg of AlCl
reflux. Then 30 mg of AlCl
3
(0.22 mmol) was added after 6 h of
(0.22 mmol) and 22 mg of
3
Methyl Ester of 6-Amino-5-cyano-2-methylnicotinic Acid (7).
Following the general method for the synthesis of aminopyr-
idine derivatives, reaction of 5 (69 mg, 0.25 mmol) and trifluor-
omethanesulfonic acid (482 mg, 3.22 mmol) in dichloromethane
cyclohexanone (0.22 mmol) were added after 21 h of reflux.
The reaction was complete at 30 h of total time, yielding
compound 10 (85 mg, 70%) as a yellow solid: mp >300 ꢀC
(dark at 185 ꢀC); IR (KBr) ν 3338, 3229, 2941, 2862, 1716, 1620,
1601, 1568, 1543, 1437, 1361, 1284, 1246, 1116, 1070, 802, 779
(
2 mL) after 3 h yielded compound 7 (47 mg, 98%) as a yellow
-
1 1
solid. IR (KBr) ν 3387, 3334, 3144, 2224, 1719, 1667, 1598, 1550,
cm ; H NMR (CDCl
2H, NH ), 3.94 (s, 3H, CH
CH C(2)], 2.59 (m, 2H, H6), 1.93 (m, 4H, H7, H8); C NMR
(DMSO-d , 75.4 MHz) δ 166.4 (CO), 161.9 (C9a), 159.6 (C2),
154.1 (C10a), 150.9 (C5), 136.0 (C4), 119.7 (C3), 109.9 (C5a),
3
, 200 MHz) δ 8.82 (s, 1H, H4), 5.19 (bs,
-
1 1
439, 1340, 1292, 1265, 1170, 1072, 780 cm ; H NMR (CDCl
1
3
,
2
3
O), 3.07 (m, 2H, H9), 2.95 [s, 3H,
1
3
3
00 MHz) δ 8.31 (s, 1 H, H4), 5.55 (br, 2 H, NH ), 3.87 (s, 3 H,
2
3
þ
OCH ), 2.73 [s, 3 H, CH (C2)]. MS (API-ESþ) m/z: [M þ 1]
6
3
3
þ
1
92.2; [M þ Na] 214.0.
Ethyl Ester of 6-Amino-5-cyano-2-methylnicotinic Acid (8).
108.3 (C4a), 52.1 (CH
22.1, 22.0 (C7, C8). MS (API-ESþ) m/z: 272 [(M þ 1) , 100], 248
3
O), 33.4 (C9), 25.2 [CH C(2)], 23.3 (C6),
3
þ
Following the general method for the synthesis of aminopyr-
idine derivatives, reaction of 6 (1.000 g, 3.39 mmol) and tri-
fluoromethanesulfonic acid (5.080 g, 33.88 mmol) in dichloro-
methane (27 mL) after 2.5 h yielded compound 8 (679 mg, 98%)
as a yellow solid. IR (KBr) ν 3390, 3333, 3140, 2973, 2226, 1719,
(12), 205 (13). Anal. (C H N O ) C, H, N.
2
1
5
17
3
Methyl 5-Amino-2-methyl-7,8,9,10-tetrahydro-6H-cyclohepta-
[b][1,8]naphthyridine-3-carboxylate (11). This compound was
obtained following the general method for the Friedl €a nder
1
7
5
672, 1599, 1549, 1400, 1369, 1338, 1291, 1265, 1172, 1069, 943,
3
reaction. To a stirred suspension of AlCl (93 mg, 0.70 mmol)
-
1 1
79, 556 cm ; H NMR (CDCl
3
, 200 MHz) δ 8.32 (s, 1 H, H4),
CH CH ), 2.74
in dry 1,2-dichloroethane (5 mL) were added methyl 6-amino-5-
cyano-2-methyl-3-pyridinecarboxylate 7 (95 mg, 0.50 mmol)
and cycloheptanone (78 mg, 0.70 mmol). Upon the TLC anal-
.50 (br, 2 H, NH ), 4.33 (q, J = 7.0 Hz, 2 H, CO
2
2
2
3
1
3
[s, 3 H, CH (C2)], 1.38 (t, 3 H, J = 7.0 Hz, CO CH CH );
2
NMR (CDCl
1
C
3
2
3
3
, 75.4 MHz) δ 166.5, 165.0 (CO, C6), 159.7 (C2),
CH
3
ysis, 33 mg of AlCl (0.25 mmol) and 28 mg of cycloheptanone
45.1 (C4), 116.3, 116.2 (C3, CN), 88.9 (C5), 61.5 (CO
2
2
-
(0.25 mmol) were added after 19h of reflux. The reaction was
complete at 27 h of total time, yielding compound 11 (95 mg,
67%) as a yellow solid: mp 227-233 ꢀC; IR (KBr) ν 3330, 3199,
2918, 2850, 1720, 1651, 1601, 1579, 1543, 1429, 1361, 1346, 1257,
CH ), 25.9 [CH (C2)], 14.7 (CO CH CH ). MS (API-ESþ) m/z:
3
3
2
2
3
þ
[
M þ 1] 206.0. Anal. (C H N O ) C, H, N.
1
0
11
3
2
General Method of Friedl €a nder Reaction for the Synthesis of
1,8]Naphthyridine Derivatives. Aluminum chloride (1.2-2.2
-
1 1
[
1105, 1082, 810, 779 cm ; H NMR (CDCl
3
, 200 MHz) δ 8.77
equiv) was suspended in dry 1,2-dichloroethane (10 mL/mmol)
under argon. The corresponding alkyl 6-amino-5-cyano-2-
methyl-3-pyridinecarboxylate (1 equiv) and the cycloalkanone
(s, 1H, H4), 5.03 (bs, 2H, NH ), 3.96 (s, 3H, CH O), 3.19 (m,
2
3
2H, H10), 2.96 [s, 3H, CH C(2)], 2.75 (m, 2H, H6), 1.98-1.46
3
13
6
(m, 6H, H7, H8, H9); C NMR (DMSO-d , 75.4 MHz)