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C. Lambertucci et al. / European Journal of Medicinal Chemistry 65 (2013) 41e50
4.3.2. 6-Chloro-9-(5-iodo-2-isopropyl-4-methoxybenzyl)-9H-purin-
2-amine (18) and 6-chloro-7-(5-iodo-2-isopropyl-4-methoxybenzyl)-
7H-purin-2-amine (20)
evaporated and the resulting residue was extracted with EtOAc. The
combined organics were washed with water, dried over anhydrous
Na2SO4, concentrated and the crude was crystallized from MeCN to
give 24 as white solid. Yield 76%; mp 238e240 ꢁC. 1H NMR (DMSO-
Compounds 18 and 20 were obtained from 15 after flash chro-
matography eluting with CH2Cl2eMeCN (98:2, v/v) as white solids.
d6):
d
1.09 (d, 6H, J ¼ 6.8 Hz, CH(CH3)2), 2.86 (s, 3H, NHCH3), 3.20
18: Yield 52%; mp 120e122 ꢁC. 1H NMR (DMSO-d6):
d
1.08 (d, 6H,
(sept, 1H, J ¼ 7.2 Hz, CH(CH3)2), 3.81 (s, 3H, OCH3), 5.10 (s, 2H,
NCH2), 5.85 (s, 2H, NH2), 6.88 (s,1H, HePh), 7.21 (s,1H, NHCH3), 7.37
(s, 1H, HePh), 7.50 (s, 1H, H-8); ESI-MS: positive mode m/z 453.0
([M þ H]þ), 475.0 ([M þ Na]þ).
J ¼ 6.8 Hz, CH(CH3)2), 3.20 (sept, 1H, J ¼ 6.8 Hz, CH(CH3)2), 3.82 (s,
3H, OCH3), 5.20 (s, 2H, NCH2), 6.89 (s, 1H, HePh), 6.95 (s, 2H, NH2),
7.47 (s, 1H, HePh), 7.99 (s, 1H, H-8); and CH2Cl2eMeCN (96:04, v/v).
20: Yield 12%; mp 140e142 ꢁC. 1H NMR (DMSO-d6):
d 1.18 (d, 6H,
J ¼ 6.8 Hz, CH(CH3)2), 3.10 (sept, 1H, J ¼ 6.8 Hz, CH(CH3)2), 3.83 (s,
3H, OCH3), 5.52 (s, 2H, NCH2), 6.71 (brs, 2H, NH2), 6.88 (s, 1H, He
Ph), 6.94 (s, 1H, HePh), 8.27 (s, 1H, H-8).
4.4.5. N6-Cyclopentyl-9-(5-iodo-2-isopropyl-4-methoxybenzyl)-9H-
purine-2,6-diamine (25)
A suspension of 18 (0.050 g, 0.10 mmol) and cyclopentylamine
(1.02 mL,10.40 mmol) in dry THF (2 mL) was stirred for 30 h at 60 ꢁC.
Then solvent was evaporated and the resulted residue was extracted
with EtOAc. The combined organics were washed with water, dried
over anhydrous Na2SO4, evaporated under vacuo and the crude was
chromatographed over flash silica gel column eluting with CHCl3e
MeCN (98:2, v/v) to give 25 as white solid. Yield 69%; mp 182e
4.4. General procedure for the preparation of compounds 21 and 22
Ammonia gas was condensed at ꢃ70 ꢁC in cooled steel vial then
starting material 17 or 18 was added and reaction mixture was
maintained at room temperature for 16 h. Volatiles were removed
and crude mixture was partitioned between EtOAC and H2O. Then
combined organics were washed with saturated solution of NH4Cl,
dried over Na2SO4 and concentrated under reduced pressure to
obtain crude product 21 or 22, respectively.
184 ꢁC. 1H NMR (DMSO-d6):
d
1.09 (d, 6H, J ¼ 6.8 Hz, CH(CH3)2), 1.50
(m, 4H, H-cyclopentyl), 1.68 (m, 2H, H-cyclopentyl), 1.88 (m, 2H, H-
cyclopentyl), 3.20 (sept,1H, J ¼ 6.8 Hz, CH(CH3)2), 3.81 (s, 3H, OCH3),
4.44 (m, 1H, NHCH), 5.10 (s, 2H, NCH2), 5.80 (brs, 2H, NH2), 6.88 (s,
1H, HePh), 7.06 (brs, 1H, NH), 7.38 (s, 1H, HePh), 7.51 (s, 1H, H-8);
ESI-MS: positive mode m/z 507.1 ([M þ H]þ), 529.0 ([M þ Na]þ).
4.4.1. 9-(2-Isopropyl-4,5-dimethoxybenzyl)-9H-purine-2,6-diamine
(21)
Compound 21 was obtained from 17 after crystallization from
4.5. General procedure for the preparation of compounds (26 and 27)
MeOH, as white solid. Yield 54%; mp 198e200 ꢁC. 1H NMR (DMSO-
d6):
d
1.03 (d, 6H, J ¼ 6.4 Hz, CH(CH3)2), 3.18 (sept, J ¼ 6.4 Hz, 1H,
Ammonia gas was condensed at ꢃ70 ꢁC in steel vial then starting
material 19 or 20 was added and reaction mixture maintained at
100 ꢁC for 16 h in well packed steel vial. Volatiles were removed and
the residue was partitioned between EtOAC and H2O; the combined
organics were washed with saturated solution of NH4Cl, dried over
the Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash column chromatography.
CH(CH3)2), 3.66 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 5.08 (s, 2H, NCH2),
5.78 (brs, 2H, NH2), 6.64 (brs, 2H, NH2), 6.84 (s, 1H, HePh), 6.89 (s,
1H, HePh), 7.46 (s, 1H, H-8); ESI-MS: positive mode m/z 343.1
([M þ H]þ), 365.1 ([M þ Na]þ).
4.4.2. 9-(5-Iodo-2-isopropyl-4-methoxybenzyl)-9H-purine-2,6-di
amine (22)
Compound 22 was obtained from 18 after flash silica gel column
chromatography eluting with CHCl3eMeOH (98:2e95:5, v/v) as
4.5.1. 7-(2-Isopropyl-4,5-dimethoxybenzyl)-7H-purine-2,6-diamine
(26)
white solids. Yield 40%; mp 230e232 ꢁC. 1H NMR (DMSO-d6):
d
1.14
Compound 26 was obtained from 19 after flash silica gel column
chromatography eluting with CHCl3eMeOH (98:2e92:8, v/v) as
(d, 6H, J ¼ 6.8 Hz, CH(CH3)2), 3.09 (sept, 1H, J ¼ 6.8 Hz, CH(CH3)2),
3.82 (s, 3H, OCH3), 5.46 (s, 2H, NCH2), 5.55 (s, 2H, NH2), 6.29 (s, 2H,
NH2), 6.91 (s, 1H, HePh), 7.65 (s, 1H, H-8), 7.08 (s, 1H, HePh); ESI-
MS: positive mode m/z 439.0 ([M þ H]þ), 461.0 ([M þ Na]þ),
477.0 ([M þ K]þ).
white solid. Yield 24%; mp 245e247 ꢁC. 1H NMR (DMSO-d6):
d 1.09
(d, 6H, J ¼ 6.8 Hz, CH(CH3)2), 3.03 (sept, 1H, J ¼ 6.8 Hz, CH(CH3)2),
3.57 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 5.42 (s, 1H, NCH2), 5.51 (brs,
2H, NH2), 6.32 (brs, 2H, NH2), 6.57 (s, 1H, HePh), 6.89 (s, 1H, HePh),
7.51 (s, 1H, H-8); ESI-MS: positive mode m/z 343.1 ([M þ H]þ), 685.3
([2M þ H]þ), 707.3 ([2M þ Na]þ).
4.4.3. 9-(5-Iodo-2-isopropyl-4-methoxybenzyl)-6-methoxy-9H-
purin-2-amine (23)
A suspension of 18 (50 mg, 0.10 mmol) and sodium methoxide
(53 mg, 0.98 mmol) in dry CH3OH (2 mL) was refluxed for 2 h. Then
solvent was evaporated and the resulted residue was extracted
with EtOAc and water. Combined organics were washed with
saturated NH4Cl solution, dried over anhydrous Na2SO4, and
evaporated to dryness. The crude was crystallized from MeCN to
give 23 as white solid. Yield 69%; mp 212e214 ꢁC. 1H NMR (DMSO-
4.5.2. 7-(5-Iodo-2-isopropyl-4-methoxybenzyl)-7H-purine-2,6-
diamine (27)
Compound 27 was obtained from 20 after flash silica gel column
chromatography eluting with CHCl3eMeOH (98:2e95:5, v/v) as
white solid. Yield 40%; mp 240e242 ꢁC. 1H NMR (DMSO-d6):
d 1.14
(d, 6H, J ¼ 6.8 Hz, CH(CH3)2), 3.09 (sept, 1H, J ¼ 6.8 Hz, CH(CH3)2),
3.82 (s, 3H, OCH3), 5.46 (s, 2H, NCH2), 5.55 (s, 2H, NH2), 6.29 (s, 2H,
NH2), 6.91 (s, 1H, HePh), 7.08 (s, 1H, HePh), 7.65 (s, 1H, H-8); ESI-
MS: positive mode m/z 439.0 ([M þ H]þ), 877.2 ([2M þ H]þ),
899.0 ([2M þ Na]þ), 915.0 ([2M þ K]þ).
d6):
d
1.08 (d, 6H, J ¼ 6.8 Hz, CH(CH3)2), 3.21 (sept, 1H, J ¼ 6.8 Hz,
CH(CH3)2), 3.81 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 5.17 (s, 2H, NCH2),
6.43 (s, 2H, NH2), 6.89 (s, 1H, HePh), 7.37 (s, 1H, HePh), 7.71 (s, 1H,
H-8); ESI-MS: positive mode m/z 454.0 ([M
þ
H]þ), 492.0
([M þ K]þ), 929.0 ([2M þ Na]þ).
4.6. General procedure for the preparation of compounds (28 and 29)
4.4.4. 9-(5-Iodo-2-isopropyl-4-methoxybenzyl)-N6-methyl-9H-
purine-2,6-diamine (24)
To a suspension of 18 (50 mg, 0.10 mmol) in dry THF (2 mL) was
added methylamine (1.5 mL, 33.80 mmol) at ꢃ20 ꢁC and reaction
mixture was left for 3 h at room temperature, then solvent was
To compound 17 or 19 (0.22 mmol), taken in steel vessel
at ꢃ70 ꢁC, methylamine (1.0 mL) was added. The reaction was left
for 1 day at room temperature, volatiles were then removed and the
crude mixture was purified by silica gel flash column chromatog-
raphy eluting with the suitable solvent.