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B.Y. Kim et al. / European Journal of Medicinal Chemistry 39 (2004) 433–447
6.1.39. Preparation of 5-(4-{2-[methyl-(4-phenylaminopy-
ridin-2-yl)amino]ethoxy}-benzylidene)thiazolidine-2,4-
dione (11d)
Yield: 1.19 g, 62%. m.p.: 160–161 °C. IR (KBr) mmax
cm–1: 3350, 1748, 1720, 1234. 1H-NMR (400 MHz, DMSO-
d6) d: 3.02 (s, 3H), 3.95 (m, 2H), 4.22 (m, 2H), 6.03 (s, 1H),
6.28 (m, 1H), 6.98 (m, 2H), 7.11 (m, 2H), 7.28 (m, 1H), 7.45
(m, 4H), 7.80 (s, 1H) 7.93 (m, 1H).
CDCl3) d: 3.08 (s, 3H), 3.11 (m, 1H), 3.44 (m, 1H), 3.96 (m,
2H), 4.16 (m, 2H), 4.52 (m, 1H), 6.08 (s, 1H), 6.18 (m, 1H),
6.83 (m, 2H), 7.12 (m, 4H), 7.21 (m, 1H), 7.42 (m, 2H), 8.04
(d, J = 3.0 Hz, 1H). 13C-NMR (100 MHz, CDCl3) d: 36.6,
37.5, 49.0, 53.4, 65.8, 93.7, 101.9, 114.7, 120.6, 125.2,
129.1, 130.6, 130.8, 149.7, 154.6, 157.8, 160.4, 165.7, 172.1,
176.1. MS (ESI) m/z (M+1) 450.
6.1.44. Preparation of 5-(4-{2-[methyl-(4-phenylaminopy-
ridin-2-yl)amino]ethoxy}benzyl)-thiazolidine-2,4-dione
(12d)
6.1.40. Preparation of 5-(4-{2-[methyl-(4-phenylthiopyri-
din-2-yl)amino]ethoxy}benzylidene)-thiazolidine-2,4-dione
(11e)
Yield: 710 mg, 71%. m.p.: 160–163 °C. IR (KBr) mmax
cm–1: 1745, 1730, 1625, 1235. 1H-NMR (400 MHz, CDCl3)
d: 3.02 (s, 3H), 3.15 (m, 1H), 3.45 (m, 1H), 3.95 (m, 2H),
4.22 (m, 2H), 4.51 (m, 1H), 6.23 (s, 1H), 6.28 (m, 1H), 6.85
(m, 2H), 7.10 (m, 4H), 7.21 (m, 1H), 7.40 (m, 2H), 8.05 (m,
1H). 13C-NMR (100 MHz, CDCl3) d: 35.0, 41.5, 49.2 57.6,
58.9, 71.5, 95.0, 99.1, 115.0, 118.4, 128.0, 132.4, 147.6,
150.1, 156.3, 157.2, 162.1, 165.3 171.5, 176.9. MS (ESI) m/z
(M+1) 449.
Yield: 1.50 g, 71%. m.p.: 152–154 °C. IR (KBr) mmax
1
cm–1: 3163, 3052, 2937, 1745, 1697. H-NMR (400 MHz,
DMSO-d6) d: 3.02 (s, 3H), 3.93 (m, 2H), 4.18 (m, 2H), 6.53
(s, 1H), 6.58 (m, 1H), 6.98 (d, J = 8.4 Hz, 2H), 7.40 (m, 4H),
7.52 (d, J = 8.4 Hz, 2H), 7.73 (s, 1H), 7.93 (m, 1H).
6.1.41. Preparation of 5-(4-{2-[methyl-(4-methoxypyridin-
2-yl)amino]ethoxy}-benzyl)thiazolidine-2,4-dione (12a)
General procedure: To a stirred solution of 11a (0.92 g,
2.1 mmol) in MeOH (50 ml) was added Pd(OH)2 on carbon
(0.9 g) under hydrogen atmosphere at room temperature for
48 h. The mixture was filtered using celite and washed with
MeOH. The filtrate was condensed by evaporation under
reduced pressure. The concentrate thus obtained was purified
by column chromatography on SiO2 with dichloromethane-
methanol (20:1, v/v) as eluent to give the title compound 12a
as a yellowish solid (700 mg, 76% yield). m.p.: 148–150 °C.
6.1.45. Preparation of 5-(4-{2-[methyl-(4-phenylthiopyri-
din-2-yl)amino]ethoxy}-benzyl)thiazolidine-2,4-dione (12e)
Yield: 1.22 g, 85%. m.p.: 162–165 °C. IR (KBr) mmax
cm–1: 2924, 1752, 1698, 1577, 1511. 1H-NMR (400 MHz,
CDCl3) d: 3.02 (s, 3H), 3.10 (m, 1H), 3.42 (m, 1H), 3.89 (m,
2H), 4.05 (m, 2H), 4.47 (m, 1H), 6.22 (s, 1H), 6.25 (d,
J = 5.4 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz,
2H), 7.38 (m, 3H), 7.52 (m, 2H), 7.91 (d, J = 5.4 Hz, 1H).
1
IR (CHCl3) mmax cm–1: 2920, 1750, 1690, 1600. H-NMR
13C-NMR (100 MHz, CDCl3) d
: 37.7, 37.9, 49.6, 53.6,
(400 MHz, CDCl3) d: 3.11 (m, 4H), 3.41 (m, 1H), 3.80 (s,
3H), 3.96 (m, 2H), 4.13 (m, 2H), 4.48 (m, 1H), 5.96 (d,
J = 2 Hz, 1H), 6.21 (m, 1H), 6.83 (d, J = 8.58 Hz, 2H), 7.12
(d, J = 8.56 Hz, 2H), 7.99 (d, J = 5.82 Hz, 1H). 13C-NMR
(100 MHz, CDCl3) d: 37.6, 38.0, 49.7, 53.6, 66.4, 69.6, 92.3,
99.8, 114.7, 127.4, 130.4, 148.5, 158.3, 160.1, 165.6, 171.2,
175.0. MS (ESI) m/z (M+1) 388.
66.2, 103.0, 110.2, 114.7, 127.6, 129.0, 129.5, 130.4, 130.7,
134.6, 147.5, 150.3, 170.2, 174.0. MS (ESI) m/z (M+1)
466.
6.1.46. Preparation of (6-chloropurin-9-yl)acetic acid
methyl ester (14)
General procedure: A stirred suspension sodium hy-
The following compounds 12b–e were synthesized by a
similar procedure to that described for the preparation of 12a.
dride (60% in mineral oil, 1.03 g, 25.88 mmol) in DMF
(50 ml) was added 6-chloro-9H-purine (2.0 g, 12.94 mmol)
under N2 atmosphere at room temperature for 2 h, after
which methyl bromoacetate (2.45 ml, 25.88 mmol) and
tert-butylammonium iodide (1.23 g, 2.58 mmol) were
added to the mixture at the same temperature. The reaction
mixture was then stirred at room temperature for 6 h, and
quenched with aqueous NH4Cl solution (25 ml). The reac-
tion mixture was poured into water (50 ml), and extracted
with EtOAc (100 ml). The organic layer was washed with
brine, and dried over MgSO4, after which the organic layer
was condensed by evaporation under reduced pressure. To
leave a yellowish oil which was purified by column chro-
matography on SiO2 with CH2Cl2/MeOH (30:1, v/v) to
give the title compound 14. (2.06 g, 72.8% yield). IR
(CHCl3) mmax cm–1: 2875, 1745, 1712, 1584. 1H-NMR
(400 MHz, CDCl3) d: 3.84 (s, 3H), 5.09 (s, 2H), 8.26 (s, 1H),
8.78 (s, 1H).
6.1.42. Preparation of 5-(4-{2-[methyl-(4-isopropoxypyri-
din-2-yl)amino]ethoxy}-benzyl)thiazolidine-2,4-dione (12b)
Yield: 680 mg, 58%. m.p.: 140–141 °C. IR (KBr) mmax
cm–1: 2976, 2929, 1753, 1699, 1603, 1510, 1246. 1H-NMR
(400 MHz, CDCl3) d: 1.33 (d, J = 6.03 Hz, 6H), 3.10 (m, 4H),
3.34 (m, 1H), 3.88 (m, 3H), 4.08 (m, 1H), 4.44 (m, 1H), 4.59
(m, 1H), 5.94 (d, J = 211 Hz, 1H), 6.17 (m, 1H), 6.80 (d,
J = 8.50 Hz, 2H), 7.11 (d, J = 8.51 Hz, 2H), 7.94 (m, 1H).
13C-NMR (100 MHz, CDCl3) d: 21.9, 37.5, 38.1, 49.9, 53.7,
66.3, 69.6, 92.1, 100.7, 114.6, 127.5, 130.5, 148.4, 158.3,
159.9, 165.6, 171.1, 175.0. MS (ESI) m/z (M+1) 416.
6.1.43. Preparation of 5-(4-{2-[methyl-(4-phenoxypyridin-
2-yl)amino]ethoxy}-benzyl)thiazolidine-2,4-dione (12c)
Yield: 690 mg, 67%. m.p.: 158–159 °C. IR (KBr) mmax
1
cm–1: 2925,1749, 1698, 1587, 1247. H-NMR (400 MHz,