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HETEROCYCLES, Vol. 78, No. 9, 2009
acid diethyl ester (10a). To a suspension of acid 9a (50 mg, 0.17 mmol) in DMF (5 mL) was added
N-methylmorpholine (20 µL, 0.18 mmol) followed by 2-chloro-4,6-dimethoxy-1,3,5–triazine (32 mg,
0.18 mmol), and the solution was stirred at 25 °C for 2 h. Another portion of N-methylmorpholine (20 µL,
0.18 mmol) was added to the solution followed by diethyl L-glutamate hydrochloride (44 mg, 0.18 mmol),
and the mixture was stirred at 25 °C for 4 h. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (silica gel/CH2Cl2: MeOH = 20: 1) to give 10a (73 mg ,
1
89%) as a white solid, mp 137~139 °C. MS (ESI): m/z 485 [M+H]+. H NMR (300 MHz, DMSO-d6) δ:
10.59 (s, 1H, 7-H), 10.13 (s, 1H, 3-H), 8.61 (d, 2H, J=6.9Hz, CONH, pyridine 2-H), 7.76 (dd, 1H, J=2.4,
8.4Hz, pyridine 4-H), 7.27 (d, 1H, J=8.4Hz, pyridine 5-H), 6.29 (d, 1H, 6-H), 5.99 (s, 2H, 2-NH2), 4.40
(m, 1H, glutamate α-CH), 4.08, 4.03 (2q, 4H, J=6.9Hz, 2CH2CH3), 2.96 (m, 2H, 5-CH2CH2), 2.84 (m, 2H,
5-CH2CH2), 2.42 (t, 2H, J=7.5Hz, glutamate γ-CH2), 2.04 (m, 2H, glutamate β-CH2), 1.16 (m, 6H,
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2CH2CH3). C NMR (75 MHz, DMSO-d6) δ: 173.3, 172.9, 167.7, 156.1, 155.2, 151.9, 151.1, 146.5,
132.3, 129.5, 128.4, 117.7, 116.2, 99.4, 61.6, 61.0, 53.1, 36.4, 31.3, 28.1, 26.8, 15.1. HRMS: Calcd for
C23H28N6O6: 484.2070; found: 484.2069.
N-{6-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]nicotinoyl}-L-glutamic
acid (2a). To a solution of 10a (50 mg, 0.10 mmol) in THF (5 mL) was added 1 N NaOH (2 mL). The
mixture was stirred at 25 °C for 3 h. The solvent was evaporated under reduced pressure, and the residual
solution was acidified with AcOH. The precipitate was collected by filtration, washed with H2O, EtOAc,
and Et2O, and dried under reduced pressure to give 2a (30 mg, 70%) as a green solid, mp 190~192 °C.
1
MS (ESI): m/z 429 [M+H]+. H NMR (300 MHz, DMSO-d6) δ: 10.58 (s, 1H, 7-H), 10.13 (s, 1H, 3-H),
8.58 (d, 1H, J=2.4Hz, pyridine 2-H), 8.41 (d, 1H, J=8.1Hz, CONH), 7.75 (dd, 1H, J=2.4, 8.4Hz, pyridine
4-H), 7.26 (d, 1H, J=8.4Hz, pyridine 5-H), 6.28 (d, 1H, 6-H), 5.98(s, 2H, 2-NH2), 4.35 (m, 1H, glutamate
α-CH), 2.94 (m, 2H, 5-CH2CH2), 2.83 (m, 2H, 5-CH2CH2), 2.32 (t, 2H, J=7.8Hz, glutamate γ-CH2), 1.96
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(m, 2H, glutamate β-CH2). C NMR (75 MHz, DMSO-d6) δ: 174.8, 174.2, 166.8, 160.0, 152.9, 146.7,
132.2, 128.9, 127.9, 118.3, 114.1, 99.4, 52.8, 36.8, 31.7, 28.7, 27.2. HRMS: Calcd for C19H20N6O6:
428.1444; found: 428.1450.
6-[4-Nitro-3-(2,4,6-triaminopyrimidin-5-yl)butyl]nicotinic acid methyl ester (8b). Prepared from 4
(0.56 g, 2.36 mmol) and pyrimidine-2,4,6-triamine 3b (0.36 g, 2.88 mmol) as described for the
preparation of 8a, obtained 8b (0.56 g, 66%) as a yellow solid, mp 89~91 °C. MS (ESI): m/z 362 [M+H]+.
1H NMR (300 MHz, DMSO-d6) δ: 8.86 (d, 1H, J=2.4Hz, pyridine 2-H), 7.83 (dd, 1H, J=2.4, 8.4Hz,
pyridine 4-H), 7.27 (d, 1H, J=8.4Hz, pyridine 5-H), 5.64 (br s, 4H, 4-NH2, 6-NH2), 5.36 (s, 2H, 2-NH2),
4.84 (d, 2H, J=7.5Hz, CH2NO2), 3.79 (s, 3H, CH3), 3.61 (m, 1H, 5-CHCH2CH2), 2.62, 2.48 (2m, 2H,
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5-CHCH2CH2), 2.00, 1.84 (2m, 2H, 5-CHCH2CH2). C NMR (75 MHz, DMSO-d6) δ: 166.9, 164.2,
161.6, 148.7, 129.9, 129.2, 127.9, 83.3, 77.6, 52.6, 34.7, 33.7, 31.6. HRMS: Calcd for C15H19N7O4: