2′-C-Methyl Analogues of Adenosine Receptor Agonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1713
evaporated to dryness, and the crude residue was purified by
flash chromatography on silica gel (n-hexanes-EtOAc, 88:12)
to provide 3 as a white solid (3.77 g, 83% yield): mp 128-130
°C. TLC (n-hexanes-EtOAc, 80:20): Rf ) 0.28. 1H NMR
(DMSO-d6): δ 1.60 (s, 3H, CH3), 4.85 (m, 3H, H-4′, H-5′), 6.08
(d, J ) 4.9 Hz, 1H, H-3′), 6.95 (s, 1H, H-1′), 7.4-7.73 (2m, 9H,
Ph), 7.90-8.10 (m, 6H, Ph), 8.90 (s, 1H, H-2), 9.02 (s, 1H, H-8).
Anal. (C32H25ClN4O7) C, H, N.
6-Ch lor o-9H-(2-C-m eth yl-â-D-r ibofu r a n osyl)p u r in e (4)
a n d 9H-(2-C-Meth yl-â-d -r ibofu r a n osyl)a d en in e (5). Com-
pound 3 (2 g, 3.26 mmol) was treated with methanolic
ammonia (40 mL, saturated at 0 °C) and stirred at room
temperature for 7 h in a pressure bottle. The solvent was
evaporated to dryness, and the solid residue was purified by
flash chromatogaphy on silica gel (CHCl3-MeOH, 97:3) to yield
4 as a white solid (72%): mp 200-202 °C dec. TLC (CHCl3-
MeOH, 90:10): Rf ) 0.41. 1H NMR (DMSO-d6): δ 0.80 (s, 3H,
CH3), 3.76 (dd, J ) 3.0, 4.9 Hz, 1H, H-5′), 3.85 (dd, J ) 1.9,
4.8 Hz, 1H, H-5′), 4.0 (t, J ) 2.3 Hz, 1H, H-4′), 4.07 (d, J ) 6.7
Hz, 1H, H-3′), 5.3 (d, J ) 6.4 Hz, 2H, OH), 5.43 (s, 1H, OH),
6.1 (s, 1H, H-1′), 8.83 (s, 1H, H-2), 9.10 (s, 1H, H-8). Anal.
(C11H13ClN4O4) C, H, N.
3.05 (q, J ) 6.0 Hz, 1H, CH2Ph), 3.7 (2m, 1H, H-5′), 3.82, 3.88
(2m, 1H, H-5′), 3.92 (pseudo t, 1H, H-4′), 4.08 (m, 1H, H-3′),
4.58 (br s, 1H, CHCH3), 5.22 (2d, t, 3H, OH), 5.95 (s, 1H, H-1′),
7.2 (m, 5H, Ph), 7.71 (d, J ) 9.1 Hz, 1H, NH), 8.2 (s, 1H, H-2),
8.48 (s, 1H, H-8). Anal. (C20H25N5O4) C, H, N.
2,6-Dich lor o-9H-(2-C-m eth yl-2,3,5-tr i-O-ben zoyl-â-D-r i-
bofu r a n osyl)p u r in e (11). The title compound was prepared
from 2,6-dichloropurine (10) (300 mg, 1.59 mmol) as described
for 3 (reaction time 1.5 h). The residue obtained was treated
with MeOH to give 11 as a white solid (870 mg, 92%): mp
125-127 °C. TLC (n-hexanes-EtOAc, 85:15): Rf ) 0.15. 1H
NMR (DMSO-d6): δ 1.6 (s, 3H, CH3), 4.82 (br s, 3H, H-4′, H-5′),
5.9 (br s, 1H, H-3′), 6.83 (s, 1H, H-1′), 7.37 (t, J ) 7.5, 2H,
Ph), 7.55, 7.68 (2m, 7H, Ph), 7.86 (d, J ) 7.4, 2H, Ph), 8.02-
8.15 (dd, J ) 7.2, 15.9 Hz, 4H, Ph), 9.0 (s, 1H, H-8). Anal.
(C32H24Cl2N4O7) C, H, N.
2-Ch lor o-9H-(2-C-m eth yl-â-D-r ibofu r an osyl)aden in e (12).
Compound 12 was obtained as described for 5 (white solid,
35%): mp 130-132 °C dec. TLC (CHCl3-MeOH, 90:10): Rf
) 0.25. 1H NMR (DMSO-d6): δ 0.82 (s, 3H, CH3), 3.72 (2m,
1H, H-5′), 3.82, 3.88 (2m, 1H, H-5′), 3.93 (pseudo t, 1H, H-4′),
4.04 (pseudo t, 1H, H-3′), 5.18 (d, t, 2H, OH), 5.3 (s, 1H, OH),
5.85 (s, 1H, H-1′), 7.82 (br s, 2H, NH2), 8.50 (s, 1H, H-8). Anal.
(C11H14ClN5O4) C, H, N.
Evaporation of the following fraction afforded 8% of 5 as a
white solid: mp >230 °C (lit.19 mp 257-258 °C). TLC (CHCl3-
MeOH, 85:15): Rf ) 0.26. 1H NMR (DMSO-d6): δ 0.77 (s, 3H,
CH3), 3.72 (m, 1H, H-5′), 3.82 (m, 1H, H-5′), 3.93 (br s, 1H,
H-4′), 4.05 (pseudo t, 1H, H-3′), 5.20 (s, t, d, 3H, OH), 5.95 (s,
1H, H-1′), 7.3 (br s, 2H, NH2), 8.15 (s, 1H, H-2), 8.48 (s, 1H,
H-8).
N6-Cyclop en tyl-2-ch lor o-9H-(2-C-m eth yl-â-D-r ibofu r a -
n osyl)a d en in e (13). The title compound was prepared from
11 (0.46 mmol) in anhydrous MeOH (10 mL) and cyclopenty-
lamine (5.9 mmol) as described for 6 (reaction time 4 h), as a
white solid (35%): mp 128-132 °C dec. TLC (CHCl3-MeOH,
95:5): Rf ) 0.34. 1H NMR (DMSO-d6): δ 0.8 (s, 3H, CH3),
1.5-1.8 (m, 6H, cyclopentyl), 1.95 (m, 2H, cyclopentyl), 3.69
(2m, 1H, H-5′), 3.82, 3.88 (2m, 1H, H-5′), 3.95 (pseudo t, 1H,
H-4′), 4.05 (m, 1H, H-3′), 4.42 (m, 1H, NHCH), 5.2 (d, t, 2H,
OH), 5.4 (br s, 1H, OH), 5.85 (s, 1H, H-1′), 8.32 (d, J ) 7.2 Hz,
1H, NH), 8.52 (s, 1H, H-8). Anal. (C16H22ClN5O4) C, H, N.
6-Ch lor o-9H-(2-C-m et h yl-2,3-O-isop r op ylid en e-â-D-r i-
bofu r a n osyl)p u r in e (14). A mixture of 4 (370 mg, 1.23
mmol), triethyl orthoformate (0.82 mL, 4.92 mmol), and
p-toluenesulfonic acid monohydrate (220 mg, 1.16 mmol) in
anhydrous acetone (12 mL) was stirred at room temperature
for 3 h under nitrogen atmosphere. Evaporation of the
reaction mixture gave a foam which was purified by flash
chromatography on silica gel eluting with CHCl3. Compound
14 was yielded as a white solid (69%): mp 115-118 °C. TLC
(CHCl3): Rf ) 0.15. 1H NMR (DMSO-d6): δ 1.15 (s, 3H, CH3),
1.38 (s, 3H, CH3), 1.6 (s, 3H, CH3), 3.76 (t, J ) 4.5 Hz, 2H,
H-5′), 4.3 (m, 1H, H-4′), 4.65 (s, 1H, H-3′), 6.38 (s, 1H, H-1′),
8.83 (s, 1H, H-2), 8.95 (s, 1H, H-8). Anal. (C14H17ClN4O4) C,
H, N.
1′-Deoxy-1′-(6-ch lor o-9H -p u r in -9-yl)-2′-C-m et h yl-2′,3′-
O-isop r op yl-id en e-â-D-r ibofu r on ic Acid (15). To a stirred
solution of 14 (280 mg, 0.82 mmol) in acetone (5 mL) was added
a solution of chromium trioxide (2 M) in aqueous H2SO4 (3 M,
0.8 mL) dropwise. After 2 h at room temperature, the dark
mixture was filtered through Celite washing with EtOAc (2 ×
10 mL). The filtrates were washed with 0.5 M Na2S2O5 (5 mL)
and water (3 × 5 mL) and then extracted with 0.5 M NaOH
solution (10 mL). The extract was washed with EtOAc (10
mL) and acidified with concentrated HCl. Evaporation of the
acidic solution gave a white solid residue which was washed
with MeOH repeatedly and then filtered. The filtrate was
evaporated in vacuo, and the residue was chromatographed
on a silica gel column (CHCl3-MeOH, 60:40) to give 15 as a
white solid (90%): mp >240 °C dec. TLC (CHCl3-MeOH, 80:
20): Rf ) 0.26. 1H NMR (DMSO-d6): δ 0.98 (s, 3H, CH3), 1.38
(s, 3H, CH3), 1.6 (s, 3H, CH3), 4.5 (s, 1H, H-3′), 4.67 (s, 1H,
H-4′), 6.45 (s, 1H, H-1′), 8.8 (s, 1H, H-2), 10.15 (s, 1H, H-8).
Anal. (C14H15ClN4O5) C, H, N.
N 6-Cyclop e n t yl-9H -(2-C-m e t h yl-â-D-r ib ofu r a n osyl)-
a d en in e (6). A mixture of 4 (80 mg, 0.26 mmol) in anhydrous
EtOH (2 mL) and cyclopentylamine (0.15 mL, 1.54 mmol)
under a nitrogen atmosphere was heated under reflux for 5
h. The mixture was concentrated in vacuo, and the residue
was chromatographed on a silica gel column (CHCl3-MeOH,
95:5) to give 6 as a white solid (55 mg, 60%): mp 118-120 °C
dec. TLC (CHCl3-MeOH, 90:10): Rf ) 0.56. 1H NMR
(DMSO-d6): δ 0.78 (s, 3H, CH3), 1.53-1.80 (m, 6H, cyclopen-
tyl), 1.95 (m, 2H, cyclopentyl), 3.69 (2m, 1H, H-5′), 3.82, 3.88
(2m, 1H, H-5′), 3.94 (pseudo t, 1H, H-4′), 4.06 (dd, J ) 7.0, 8.9
Hz, 1H, H-3′), 4.58 (br s, 1H, NHCH), 5.26 (2d, t, 3H, OH),
5.98 (s, 1H, H-1′), 7.73 (d, J ) 7.7 Hz, 1H, NH), 8.2 (s, 1H,
H-2), 8.48 (s, 1H, H-8). Anal. (C16H23N5O4) C, H, N.
N6-(3-Iod oben zyl)-9H-(2-C-m eth yl-â-D-r ibofu r a n osyl)-
a d en in e (7). A stirred solution of 4 (100 mg, 0.32 mmol) in
anhydrous EtOH (4 mL) was treated with 3-iodobenzylamine
hydrochloride (96 mg, 0.34 mmol) and triethylamine (0.14 mL,
0.102 mmol), and the mixture was heated at 80 °C for 12 h
under nitrogen atmosphere. After cooling to room tempera-
ture, the solvent was evaporated to dryness, and the solid
residue was purified by chromatography on a silica gel column
(CHCl3-MeOH, 98:2) to yield 7 as a white solid (142 mg,
90%): mp 183-185 °C. TLC (CHCl3-MeOH, 95:5): Rf ) 0.12.
1H NMR (DMSO-d6): δ 0.80 (s, 3H, CH3), 3.71 (2m, 1H, H-5′),
3.83, 3.90 (2m, 1H, H-5′), 3.95 (pseudo t, 1H, H-4′), 4.05 (pseudo
t, 1H, H-3′), 4.66 (br s, 2H, NHCH2), 5.2 (2d, t, 3H, OH), 5.98
(s, 1H, H-1′), 7.1 (t, J ) 7.8 Hz, 1H, Ph), 7.38, 7.58 (2d, J )
7.8 Hz, 2H, Ph), 7.75 (s, 1H, Ph), 8.2 (s, 1H, H-2), 8.44 (br s,
1H, NH), 8.5 (s, 1H, H-8). Anal. (C18H20IN5O4) C, H, N.
N6-[(R)-P h en ylisop r op yl]-9H-(2-C-m eth yl-â-D-r ibofu r a -
n osyl)a d en in e (8). Compound 8 was obtained from 4 (0.2
mmol) with d-amphetamine as described for 6, as a white solid
(60%): mp 125-130 °C dec. TLC (CHCl3-MeOH, 95:5): Rf
) 0.29. 1H NMR (DMSO-d6): δ 0.78 (s, 3H, CH3), 1.2 (d, J )
6.2 Hz, 3H, CHCH3), 2.75 (dd, J ) 6.9, 13.6 Hz, 1H, CH2Ph),
3.05 (dd, J ) 7.0, 13.5 Hz, 1H, CH2Ph), 3.7 (2m, 1H, H-5′),
3.82, 3.88 (2m, 1H, H-5′), 3.93 (pseudo t, 1H, H-4′), 4.07 (pseudo
t, 1H, H-3′), 4.58 (br s, 1H, CHCH3), 5.22 (s, d, t, 3H, OH),
5.95 (s, 1H, H-1′), 7.2 (2m, 5H, Ph), 7.71 (d, J ) 9.1 Hz, 1H,
NH), 8.2 (s, 1H, H-2), 8.48 (s, 1H, H-8). Anal. (C20H25N5O4)
C, H, N.
Eth yl-1′-Deoxy-1′-(6-ch lor o-9H-p u r in -9-yl)-2′-C-m eth yl-
2′,3′-O-isop r op ylid en e-â-D-r ib ofu r a n u r oa t e (16). To a
solution of 15 (250 mg, 0.7 mmol) in anhydrous EtOH (30 mL)
at 0 °C was added dropwise 0.25 mL of SOCl2, and the solution
was stirred overnight under nitrogen atmosphere. After
evaporation in vacuo, the residue was purified by chromatog-
raphy on a silica gel column (CHCl3-MeOH, 97:3). The
appropriate fractions were collected and concentrated to yield
16 as a white solid (78%): mp 110-113 °C; TLC (CHCl3-
N6-[(S)-P h en ylisop r op yl]-9H-(2-C-m eth yl-â-D-r ibofu r a -
n osyl)a d en in e (9). Compound 9 was obtained from 4 (0.2
mmol) with l-amphetamine as described above, as a white solid
(60%): mp 125-130 °C dec. TLC (CHCl3-MeOH, 90:10): Rf
) 0.5. 1H NMR (DMSO-d6): δ 0.78 (s, 3H, CH3), 1.2 (d, J )
6.2 Hz, 3H, CHCH3), 2.75 (dd, J ) 6.9, 13.6 Hz, 1H, CH2Ph),