2
572 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 13
Wang et al.
(
2s, 2H, H-2, H-6), 5.96 (d, J ) 4.5 Hz, 1H, H-1′), 5.48 (br, 1H,
filtered, and the filtrate was concentrated. Crystallization from
OH), 5.20 (br, 1H, OH), 4.34 (m, 1H), 4.26 (m, 1H), 3.94 (m,
1
(
water/methanol gave 90 mg (72%) of 15a as a colorless solid:
1
H, H-4′), 3.84 (m, 1H), 1.28 (d, J ) 6.3 Hz, 3H, Me). Anal.
) C, H, N.
-Cya n o-7-(5(R)-C-m et h yl-â-D-r ib ofu r a n osyl)p yr r olo-
2,3-d ]-4-p yr im id on e (13b) was prepared from 11b by the
H NMR (DMSO-d
6
) δ 10.42 (br, 2H, NH
2
), 8.63 (br, 3H, H-6,
C
12
H
12
N
4
O
4
NH
2
), 8.14 (s, 1H, H-2), 5.98 (d, J ) 7.2 Hz, 1H, H-1′), 5.18-
5
5.54 (m, br, 3H, 3OH), 4.35 (t, J ) 5.1 Hz, 1H), 4.17 (m, 1H),
3.70-3.84 (m, 2H), 1.07 (d, J ) 6.3 Hz, 3H, Me).
[
same procedure as described for 13a . Yield: 68%. Colorless
solid (recrystallized from water): mp 236-237 °C; H NMR
7-(5(S)-C-Met h yl-â-D-r ib ofu r a n osyl)p yr r olo[2,3-d ]-4-
p yr im id on e-5-ca r boxa m id in e h yd r och lor id e (15c) was
prepared from 14c by the same procedure as described for 15b.
Yield: 60%. Colorless solid (water/methanol): 1H NMR (DMSO-
1
(
6
DMSO-d ) δ 12.51 (s, br, 1H, NH), 8.34, 8.08 (2s, 2H, H-2,
H-6), 5.98 (d, J ) 6.6 Hz, 1H, H-1′), 5.41 (d, J ) 6.3 Hz, 1H),
5
4
.19 (d, J ) 3.9 Hz, 1H, OH), 5.11 (d, J ) 4.5 Hz, 1H, OH),
.31 (dd, J ) 10.8, 5.4 Hz, 1H), 4.14 (m, 1H), 3.80 (m, 1H,
d
6
2 2
) δ 10.10 (s, 2H, NH ), 8.78 (br, 2H, NH ), 8.75 (s, 1H, H-6),
8.25 (s, 1H, H-2), 6.07 (d, J ) 5.7 Hz, 1H, H-1′), 5.53 (d, J )
6.0 Hz,1H, OH), 5.25 (d, J ) 5.1 Hz, 1H, OH), 4.82 (d, J ) 5.7
Hz, 1H, OH), 4.26 (dd, J ) 10.4, 5.7 Hz, 1H), 4.09 (m, 1H),
H-5′), 3.68 (m, 1H), 1.07 (d, J ) 6.3 Hz, 3H, 5′-Me). Anal.
(C
13
H
14
N
4
O
5
) C, H, N.
-Cya n o-7-(5(S)-C-m et h yl-â-D-r ib ofu r a n osyl)p yr r olo-
2,3-d ]-4-p yr im id on e (13c) was prepared from 11c by the
5
3.72-3.83 (m, 2H), 1.12 (d, J ) 6.3 Hz, 3H, Me). Anal. (C13
18
H -
[
ClN ‚H O) C, H, N.
5
O
5
2
same procedure as described for 13a . Yield: 70%. Colorless
5-Am in om eth yl-7-(â-D-r ibofu r a n osyl)p yr r olo[2,3-d ]-4-
p yr im id on e (16e). A mixture of 5-cyano-7-(â-D-ribofuranosyl)-
pyrrolo[2,3-d]-4-pyrimidone27 (120 mg, 0.41 mmol) and 20%
palladium hydroxide (Aldrich, 120 mg) in water (100 mL) was
shaken in a hydrogenation apparatus (50 psi hydrogen) at
room temperature for 15 h. Catalysts were filtered, and solvent
was evaporated. Recrystallization from water yielded 80 mg
1
solid: H NMR (DMSO-d
6
) δ 12.5 (s, br, 1H, NH), 8.38, 8.08
(
2s, 2H, H-2, H-6), 6.01 (d, J ) 5.1 Hz, 1H, H-1′), 5.47 (br, 1H,
OH), 5.15 (br, 1H, OH), 5.07 (d, J ) 5.4 Hz, 1H, OH), 4.24 (m,
1
6
H), 4.06 (m, 1H), 3.73-3.86 (m, 2H, H-4′, H-5′), 1.13 (d, J )
.3 Hz, 3H, 5′-Me).
7
-(5-Deoxy-â-D-r ibofu r a n osyl)p yr r olo[2,3-d ]-4-p yr im i-
d on e-5-ca r boxa m id oxim e (14a ). A mixture of 13a (300 mg,
.09 mmol), hydroxylamine hydrochloride (226 mg, 3.26 mmol),
1
(65%) of 16e as a colorless solid: mp >250 °C (dec); H NMR
1
6
(DMSO-d ) δ 7.89 (s, 1H, H-2), 7.15 (s, 1H, H-6), 5.95 (d, J )
and potassium carbonate (225 mg, 1.63 mmol) in ethanol (40
mL) was refluxed under argon overnight. The precipitate was
filtered and washed with warm ethanol. The filtrate was
concentrated, and the residue was chromatographed on silica
6.6 Hz, 1H, H-1′), 5.0-5.5 (br, 3H, 3OH), 4.28 (t, J ) 5.7 Hz,
1H), 4.03 (t, J ) 3.0 Hz, 1H), 3.84 (dd, J ) 7.2, 3.6 Hz, 1H),
3.71 (s, 2H, CH ), 3.45-3.60 (m, 2H, H5′).
2
5-Cya n o-7-(â-D-a r a b in ofu r a n osyl)p yr r olo[2,3-d ]-4-p y-
2
8
(
MeOH/CHCl
3
, 1:3) to give 270 mg (87%) of 14a as a colorless
r im id on e (17a ) was prepared from arabinotoyocamycin by
the same procedure as described for 13a . Yield: 79%. Slightly
1
solid (recrystallizaed from methanol): H NMR (DMSO-d
1
6
) δ
2.4 (br, 1H, NH), 9.16 (br, 1H, NOH), 8.01, 7.45 (2s, 2H, H-2,
brownish solid (recrystallized from water): mp 314 °C (dec);
1
H-6), 6.75 (s, br, 2H, NH
2
), 6.00 (d, J ) 5.1 Hz, 1H, H-1′), 5.40
6
H NMR (DMSO-d ) δ 12.46 (br, 1H, NH), 8.14 (s, 1H, H-2),
(
br, 1H, OH), 5.18 (br, 1H, OH), 4.32 (m, 1H), 3.93 (m, 1H,
H-4′), 3.78 (m, 1H), 1.27 (d, J ) 6.6 Hz, 3H, Me).
-(5(R)-C-Met h yl-â-D-r ib ofu r a n osyl)p yr r olo[2,3-d ]-4-
p yr im id on e-5-ca r boxa m id oxim e (14b) was prepared from
3b by the same procedure as described for 14a . Yield: 83%.
8.05 (d, J ) 2.4 hz, 1H, H-6), 6.33 (d, J ) 5.4 Hz, 1H, H-1′),
5.56 (d, J ) 6.0 Hz, 1H, OH), 5.54 (d, J ) 5.4 Hz, 1H, OH),
5.15 (t, J ) 5.4 Hz, 1H, OH), 4.13 (dd, J ) 10.5, 5.1 Hz, 1H),
4.04 (dd, J ) 9.6, 5.1 Hz, 1H), 3.77 (dd, J ) 9.0, 5.1 Hz, 1H),
7
1
12 4 5
3.66 (m, 2H, H-5′). Anal. (C12H N O ) C, H, N.
1
Colorless solid (recrystallized from water): H NMR (DMSO-
) δ 12.45 (s, 1H, NH), 9.16 (s, 1H, NOH), 8.01, 7.67 (2s, 2H,
H-2, H-6), 6.75 (br, 2H, NH ), 6.03 (d, J ) 7.5 Hz, 1H, H-1′),
7-(â-D-Ar a bin ofu r a n osyl)p yr r olo[2,3-d ]-4-p yr im id on e-
5-ca r boxa m id oxim e (17b) was prepared from 17a by the
same procedure as described for 14a . Yield: 72%. Slightly
d
6
2
1
5
5
4
.31 (d, J ) 6.9 Hz, 1H, OH), 5.14 (d, J ) 4.2 Hz, 1H, OH),
brownish solid (recrystallized from water): H NMR (DMSO-
.04 (d, J ) 4.5 Hz, 1H, OH), 4.31 (dd, J ) 12.3, 6.9 Hz, 1H),
.10 (m, 1H), 3.66-3.80 (m, 2H), 1.07 (d, J ) 6.6 Hz, 3H, Me).
d
6
) δ 12.40 (br, 1H, NH), 9.10 (s, 1H, NOH), 7.99-7.62 (2s,
2H, H-2, H-6), 6.75 (br, 2H, NH ), 6.39 (d, J ) 4.2 Hz, 1H,
H-1′), 5.53 (br, 2H, 2OH), 5,07 (br, 1H, OH), 4.05 (m, 2H), 3.75
2
Anal. (C13
H
17
N
5
O
6
2
‚H O) C, H, N.
7
-(5(S)-C-Met h yl-â-D-r ib ofu r a n osyl)p yr r olo[2,3-d ]-4-
p yr im id on e-5-ca r boxa m id oxim e (14c) was prepared from
3c by the same procedure as described for 14a . Yield: 64%.
15 5 6
(dd, J ) 9.0, 4.8 Hz, 1H), 3.60 (m, 2H, H-5′). Anal. (C12H N O )
C, H, N.
7-(â-D-Ar a bin ofu r a n osyl)p yr r olo[2,3-d ]-4-p yr im id on e-
5-ca r boxa m id in e h yd r och lor id e (17c) was prepared from
17b by the same procedure as described for 15b. Yield: 58%.
1
1
Colorless solid (recrystallized from water): H NMR (DMSO-
) δ 12.43 (s, 1H, NH), 9.19 (s, 1H, NOH), 8.01, 7.80 (2s, 2H,
H-2, H-6), 6.75 (br, 2H, NH ), 6.08 (d, J ) 6.3 Hz, 1H, H-1′),
.33 (d, J ) 6.6 Hz, 1H, OH), 5.10 (d, J ) 4.5 Hz, 1H, OH),
.02 (d, J ) 4.8 Hz, 1H), 4.28 (q, J ) 10.4, 6.0 Hz, 1H), 4.03
d
6
2
Slightly brownish solid (recrystallized from water): mp 232-
1
5
5
234 °C (dec); H NMR (DMSO-d
6
) δ 13.05 (br, 1H, NH), 10.15
2 2
(br, 2H, NH ), 8.71 (s, 2H, NH ), 8.61 (s, 1H, H-6), 8.23 (s, 1H,
(
m, 1H), 3.72-3.84 (m, 2H), 1.08 (d, J ) 6.3 Hz, 3H, Me). Anal.
‚0.5H O) C, H, N.
-(5-Deoxy-â-D-r ibofu r a n osyl)p yr r olo[2,3-d ]-4-p yr im i-
H-2), 6.44 (d, J ) 4.8 Hz, 1H, H-1′), 5.62 (m, 2H, 2OH), 5,09
(C
13
H
17
N
5
O
6
2
(t, 1H, OH), 4.03-4.16 (m, 2H), 3.83 (m, 1H), 3.68 (m, 2H,
7
H-5′). Anal. (C12
H
16ClN
5
O
5
2
‚H O) C, H, N.
d on e-5-ca r boxa m id in e (15a ). A solution of 14a (120 mg, 0.43
mmol) in ammonia-saturated methanol (120 mL) was heated
in a steel bomb at 125 °C for 64 h. After removal of solvent,
the residue was chromatographed on silica (5% aqueous
ammonia (30%) in MeOH) to give a brownish solid, which was
dissolved in hot water and decolored with charcoal to give 71
7-(â-D-Ar a bin ofu r a n osyl)p yr r olo[2,3-d ]-4-p yr im id on e-
5-car boxam idr azon e h ydr och lor ide (17d). A solution of 17a
(300 mg) in methanol was slowly saturated with dry HCl at
10 °C for 2 h and then stood at ambient temperature for 6 h
and was concentrated to dryness. Crystallization from metha-
nol gave 272 mg (73%) of methyl 7-(â-D-arabinofuranosyl)-
pyrrolo[2,3-d]-4-pyrimidone-5-formimidate hydrochloride as a
colorless solid, which was converted to 17d by the same proce-
mg (56%) of 15a as a colorless solid: mp 257-259 °C (dec,
1
water/methanol); H NMR (DMSO-d
6
) δ 11.2 (br, 1H, NH), 8.82
2
7
(
br, 2H, NH
Hz, 1H, H-1′), 5.57 (br, 1H, OH), 5.22 (br, 1H, OH), 4.16 (t, J
4.2 Hz, 1H), 3.95 (m, H, H-4′), 3.84 (t, J ) 5.4 Hz, 1H), 1.31
d, J ) 6.0 Hz, 3H, Me).
-(5(R)-C-Met h yl-â-D-r ib ofu r a n osyl)p yr r olo[2,3-d ]-4-
2
), 8.17, 7.96 (2s, 2H, H-2, H-6), 6.03 (d, J ) 3.9
dure for preparation of 16d . Yield: 52%. Slightly brownish
solid (recrystallized from water): 1H NMR (DMSO-d
) δ 12.2
(br, NH), 9.31 (br, NH ), 8.47, 8.21 (2s, 2H, H-2, H-6), 6.43 (d,
J ) 5.1 Hz, 1H, H-1′), 4.70-5.80 (br, 5H, NH , 3OH), 4.13 (dd,
J ) 9.0, 4.5 Hz, 1H), 4.05 (m, 1H), 3.82 (dd, J ) 10.8, 6.3 Hz,
1H), 3.60-3.78 (m, 2H, H-5′). Anal. (C12 ‚HCl) C, H, N.
6
)
(
2
2
7
pyr im idon e-5-car boxam idin e h ydr och lor ide (15b). A mix-
ture of 14b (120 mg, 0.35 mmol), ammonium chloride (21 mg,
16 6 5
H N O
5-Am in om et h yl-7-(â-D-a r a b in ofu r a n osyl)p yr r olo[2,3-
d ]-4-p yr im id on e (17e) was prepared from 17a by the same
procedure as described for 16e. Yield: 74%. Colorless solid
0
(
.39 mmol), and Raney nickel (Aldrich, 200 mg, wet) in water
70 mL) was shaken in a hydrogenation apparatus (50 psi
hydrogen) at room temperature for 18 h. Catalysts were
1
(recrystallized from MeOH): mp 218-200 °C (dec); H NMR