Synthesis of novel pyridazine nucleosides

Article abstract of DOI:10.1002/jhet.5570380523

This paper presents the synthesis of novel pyridazine nucleosides containing the dicyanomethylene group and pyrrolo[2,3-c]pyridazine nucleoside.

Full text of DOI:10.1002/jhet.5570380523

Sep-Oct 2001
Synthesis of Novel Pyridazine Nucleosides
1179
Sang-Gyeong Lee, Deok-Heon Kweon and Yong-Jin Yoon*
Department of Chemistry and Research Institute of Natural Sciences,
Gyeongsang National University, Chinju 660-701, Korea
Received October 18, 2000
This paper presents the synthesis of novel pyridazine nucleosides containing the dicyanomethylene group
and pyrrolo[2,3-c]pyridazine nucleoside.
J. Heterocyclic Chem., 38, 1179 (2001).
The synthesis and the biological activity of some pyri-
dazine nucleosides as the isosteric analogs of uridine have
been reported [1-6]. We also reported the synthesis of
some bicyclic pyridazine nucleosides [7] and pyridazine
acyclonucleosides [8,9].
In connection with our research program for the
synthesis of multicyclic N-nucleosides containing the
pyridazine ring, we need some pyridazine nucleosides
containing dicyanomethylene at the 3- or 4-position of the
pyridazine ring.
In the present paper, we would like to report the
synthesis of 3- or 4-dicyanomethylenepyridazin-6-one and
pyrrolo[2,3-c]pyridazin-3(2H)-one nucleosides from
chloropyridazin-6-ones or the corresponding nucleosides.
Reaction of 3 [5] with malononitrile in the presence of
sodium hydride in dimethyl sulfoxide at room temperature
gave 4 in low yield (Method A). Ribosylation of 2 [6] with
1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose was also
i) 1) Ammonium sulfate, hexanemethyldisilazane, 1-O-acetyl-2,3,5-tri-
O-benzoyl β-D-ribofuranose, SnCl , 1,2-dichloroethane, 2) sodium
4
bicarbonate, ethanol. ii) CH (CN) , NaH, DMSO. iii) NaOMe, MeOH,
2
2
+
Amberlite IRC-50H .
accomplished by the stannic chloride catalyzed procedure to
give 4 in 70% yield (Method B). Debenzoylation of 4 with
methanolic sodium methoxide furnished 5 in 91% yield.
The structures of 4 and 5 were established by ir, pmr and
elemental analyses. The infrared spectra of 4 and 5 showed
the absorption bands of two cyano groups at 2170 and 2210
-1
-1
cm , one amide carbonyl group at 1640 cm and one ester
-1
carbonyl group for 4 at 1725 cm . The pmr spectra of 4 and
5 also revealed the signals of two protons on the pyridazine
ring and protons for the sugar moiety, however the signal of
one proton for dicyanomethylene was not detected. This
may be due to broadening by nitrogen and tautomerization
of dicyanomethylenepyridazinone [10].
i) CH (CN) , tetrahydrofuran, NaH. ii) 1) Ammonium sulfate, hexa-
2
2
methyldisilazane, 1-O-acetyl-2,3,4-tri-O-benzoyl-β-D-ribofuranose
SnCl , 1,2-dichloroethane, 2) Sodium bicarbonate, ethanol.
4
iii) CH (CN) , NaH, DMSO. iv) 1) NaOMe, MeOH 2) Amberlite
2
2
+
IRC-50H .

1180
S.-G. Lee, D.-H. Kweon and Y.-J. Yoon
Vol. 38
Treatment of 8 [5] with malononitrile in the presence of
nucleosides 15 (90%), 16 (88%) and 18 (73%),
respectively. The structures of 15, 16 and 18 were
established by spectral and elemental analytical data. The
infrared spectrum of 18 showed the absorption bands of one
sodium hydride in dimethyl sulfoxide afforded 9 in 74%
yield. The position of dicyanomethylene group on the
pyridazine ring was determined by the further reactions of
9 [11]. Debenzoylation of 9 with methanolic sodium
methoxide gave compound 10 in 92% yield. The structures
of 9 and 10 were established by spectral and elemental
analytical data. The infrared spectrum of 10 showed the
absorption bands of two cyano groups (for 9: 2200, 2160
-1
cyano group at 2200 cm and one amide carbonyl group at
-1
1660 cm . The pmr spectrum of 18 also revealed the
signals of NH at δ 11.95 ppm and NH at δ 8.48 ppm.
2
-1
-1
cm , for 10: 2200, 2170 cm ) and carbonyl groups (for 9:
-1
-1
1700, 1620 cm , for 10: 1620 cm ). The pmr spectra of 9
and 10 showed the proton signals for the pyridazine ring
(at 3-position) and sugar moiety, however the proton signal
of dicyanomethylene was not detected.
On the other hand, reaction of 11 [5] with malononitrile
in the presence of sodium hydride in dimethyl sulfoxide
furnished 12 (5%), 13 (19%) and 14 (49%), respectively.
The structures of 12, 13, and 14 were assigned on the basis
of spectral and elemental analytical data. The infrared
spectra of 12 and 14 showed the absorption bands
-1
corresponding to the nitro group at 1550 and 1350 cm ,
whereas for 13 the absorption bands of the nitro group
were not detected. The position of the dicyanomethylene
group of 14, however, could not establish by the spectral
and elemental analytical data. Therefore, we carried out a
cyclization of 14 in order to establish the position of
dicyanomethylene group.
The reductive cyclization of 14 with stannous chloride
dihydrate/sodium borohydride (1:1 mole ratio) in ethyl
acetate furnished selectively 17 in 63% yield. The
conversion of 14 to 17 is corroborative evidence for the
structure of 14. Debenzoylation of 13, 14 and 17 with
methanolic sodium methoxide gave the corresponding
i) NaBH , SnCl •2H O, EtOAc, Reflux. ii) 1) NaOMe, MeOH,
2) Amberlite IRC-50H .
4
2
2
+

Sep-Oct 2001
Synthesis of Novel Pyridazine Nucleosides
1181
residue was used without further purification. The silylated
pyridazine and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose
(1.8 g, 3.57 mmoles) were dissolved in dry dichloroethane
(40 ml), and the solution was cooled to 5°. Stannic chloride (1 ml,
8.89 mmoles) was added, and the solution was then refluxed for
40 minutes. After cooling the mixture to 0°, ethanol (10 ml) and
sodium bicarbonate (2.7 g) were then added with stirring. The
solvent was evaporated to dryness under reduced pressure. The
residue was triturated with boiling ethyl acetate (50 ml x 2). After
filtering the mixture, the filtrate was coevaporated with silica gel
(4 g) under reduced pressure. The resulting silica gel was applied
to the top of an open-bed silica gel column (2.5 x 30 cm). The
column was eluted with chloroform/methanol (8:2, v/v). After
discarding the first eluent (130 ml), the eluent was collected in
6 ml fraction. The fractions containing the product were
combined and evaporated under reduced pressure to give 4 as
dark brown powder in 70% (1.67 g) yield. Recrystallization of a
small sample from ethyl acetate yielded an analytical sample as
powder. This product was identical with compound 4 that was
prepared by the Method A.
3-Nitro-4-dicyanomethylenepyridazin-6-one derivative
is a useful material for the synthesis of some bi- or tricyclic
heterocycles involving pyridazine such as pyrrrolo[2,3-c]-
pyridazin-3(2H)-one derivative.
Further work including the chemical transformation and
biological activity of novel nucleosides is under way in our
laboratory.
EXPERIMENTAL
Melting points were determined with a Thomas-Hoover
capillary apparatus and are uncorrected. Magnetic resonance
spectra were obtained on a Varian Unity Plus 300 MHz spectrom-
eter with chemical shift values reported in δ units (part per
million) relative to an internal standard (tetramethylsilane).
Infrared spectral data were obtained on a Hitachi 270-50
spectrophotometer. Elemental analyses were performed with a
Perkin Elmer 240C. The presence of water of crystal in the
elemental analyses was verified by pmr spectroscopy.
Nucleosides were detected by treatment with sulfuric acid
followed by charring. Open-bed chromatography was carried out
on silica gel 60 (70-230 mesh, Merck) using gravity flow. The
column was packed as slurries with the elution solvent.
3-Dicyanomethylene-1-β-D-ribofuranosylpyridazin-6-one (5).
Benzoylated nucleoside 4 (0.7 g, 1.16 mmoles) was dissolved
in methanol (150 ml). After adding sodium methoxide (0.9 g,
15.8 mmoles, 95%), the mixture was then stirred for 48 hours at
3-Dicyanomethylene-1-(2,3,5-tri-O-benzoyl-β-D-ribofura-
nosyl)pyridazin-6-one (4).
+
room temperature. Amberlite IRC-50 (H form, 1.5 g) was added
to the solution, and the mixture was then stirred for an additional
24 hours at room temperature. The mixture was filtered and the
resin was then washed with boiling methanol (50 ml). The
combined filtrates were concentrated to about 5 ml. The resulting
solution was applied to the top of an open-bed silica gel column
(1.5 x 40 cm), and the column was then eluted with
chloroform/methanol (7:3, v/v). The fractions containing
nucleoside were combined and evaporated under reduced
pressure to give 5 as dark brown powder in 91% (0.33 g) yield.
Recrystallization of a small sample from ethanol yielded an
analytical sample as powder, mp 294° (dec.); ir (potassium
Method A.
A mixture of malononitrile (0.45 g, 6.8 mmoles), sodium
hydride (0.3 g, 7.5 mmoles, 60% in oil) and dry dimethyl
sulfoxide (15 ml) was stirred for 0.5 hours at room temperature
under a nitrogen atmosphere. The solution of 3 [5] (2 g,
3.48 mmoles) in dry dimethyl sulfoxide (10 ml) was added to the
above mixture, and the reaction mixture was stirred for 43 hours
at room temperature under nitrogen atmosphere. The reaction
was quenched by the addition of aqueous acetic acid (10%,
30 ml), and the reaction mixture was then stirred for an additional
0.5 hours at room temperature. After the mixture was poured into
water (200 ml), the product was extracted with ethyl acetate
(200 ml x 3). The extract was washed with water (100 ml x 4),
and dried over anhydrous magnesium sulfate and filtered. The
filtrate was coevaporated with silica gel (4 g), and applied to the
top of an open-bed silica gel column (2.0 x 45 cm). The column
was eluted with chloroform/methanol (8.5:1.5, v/v). The
fractions containing the product were combined and evaporated
under reduced pressure to furnish 4 as dark brown powder in 43%
(0.85 g) yield. Recrystallization of a small sample from ethyl
acetate yielded an analytical sample as powder, mp 216-218°; ir
-1
1
bromide) 2210, 2170, 1640 cm . H nmr (DMSO-d ): δ 3.70
6
(m, 1H + 1H + 1H + 2H ), 5.01 (m, OH + OH + OH ,
2’
3’
4’
5’
2’
3’
5’
D O exchangeable), 6.18 (d, 1H , J
= 4), 6.51 (d, 1H , J = 8),
2
1’ 1’,2’
5
6.95 (d, 1H , J = 8).
4
Anal. Calcd. for C H N O : C, 49.32; H, 4.14; N, 19.17.
12 12
4 5
Found: C, 49.48; H, 4.39; N, 19.41.
5-Chloro-4-dicyanomethylene-1-(2,3,5-tri-O-benzoyl-β-D-ribo-
furanosyl)pyridazin-6-one (9).
A mixture of malononitrile (0.325 g, 4.92 mmoles), sodium
hydride (0.215 g, 5.37 mmoles, 60% in oil) and dry dimethyl
sulfoxide (10 ml) was stirred for 0.5 hours at room temperature
under nitrogen atmosphere. The solution of 8 [5] (2 g,
3.28 mmoles) in dry dimethyl sulfoxide (15 ml) was added to
above mixture, and the reaction mixture was then stirred for
3.5 hours at room temperature under nitrogen atmosphere. The
reaction was quenched by the addition of aqueous acetic acid
(10%, 30 ml), and the mixture was then stirred for an additional
0.5 hours at room temperature. After the mixture was poured into
water (200 ml), the product was extracted with ethyl acetate
(100 ml x 4). The ethyl acetate solution was washed with water
(200 ml x 4), and dried over anhydrous magnesium sulfate. The
solution was coevaporated with silica gel (4 g) under reduced
pressure. The resulting silica gel was applied to the top of an
-1
1
(potassium bromide) 2210, 2170, 1725, 1640 cm . H nmr
(DMSO-d ): δ 4.71 (m, 1H + 2H ), 6.04 (m, 1H + 1H ), 6.60
6
4’
5’
2’
3’
(d, 1H , J
= 4), 7.55 ppm (m, 1H + 1H + benzoyl-5H).
1’ 1’, 2’
4 5
Anal. Calcd. for C H N O •1(1/2)H O: C, 62.76; H, 4.31;
33 24
4
8
2
N, 8.87: Found; C, 62.61; H, 4.10; N, 8.71.
Method B.
3-Dicyanomethylenepyridazin-6-one (2, 0.6 g, 3.75 mmoles)
[6] was silylated by refluxing for 3 hours in hexamethyl-
disilazane (20 ml) in the presence of a catalytic amount of
ammonium sulfate. The excess hexamethyldisilazane was
removed by distillation under reduced pressure, and the resulting

1182
S.-G. Lee, D.-H. Kweon and Y.-J. Yoon
Vol. 38
open-bed silica gel column (2 x 40 cm). The column was eluted
with chloroform/methanol (8.5:1.5, v/v). The fractions
containing the product were combined and evaporated under
reduced pressure to give 9 as dark brown powder in 74% (1.5 g)
yield. Recrystallization of a small sample from ethyl acetate
yielded an analytical sample powder, mp 221-223°; ir (potassium
were combined and evaporated under reduced pressure to give 14
as dark brown powder in 49% (1.29 g) yield. Recrystallization of
a small sample from ethyl acetate yielded an analytical sample as
powder, mp 204-206°; ir (potassium bromide) 2200, 2170, 1725,
-1
1
1640, 1550, 1350 cm . H nmr (DMSO-d ): δ 3.99 (m, 1H
+
6
2’
1H + 1H + 1H ), 4.48 (t, OH , D O exchangeable), 4.91 (d,
3’
4’
5’
5’
2
-1
1
bromide) 2200, 2160, 1700, 1620 cm . H nmr (DMSO-d ): δ
OH , J = 5, D O exchangeable), 5.28 (d, OH , J = 5, D O
6
3’
2
2’
2
4.75 (m, 1H + 2H ), 6.05 (m, 1H + 1H ), 6.53 (d, 1H , J
exchangeable), 6.55 ppm (d, 1H , J = 4).
4’
5’
2’
3’
1’ 1’,2’
1’
= 2), 7.65 (m, 1H + benzoyl-5H).
Anal. calcd. for C H N O Cl•1/2H O; C, 57.19; H, 3.35;
3
33 22
5
10
2
Anal. calcd. for C H N O Cl•1/2H O; C, 61.16; H, 3.73; N,
N, 10.11. Found: C, 57.18; H, 3.08; N, 10.07.
33 23
4
8
2
8.65: Found; C, 61.09; H, 4.00; N, 8.80.
Fractions 186-215 (Rf = 0.21, chloroform/methanol =
8.5:1.5, v/v) were combined and evaporated under reduced
pressure to give 13 as dark brown powder in 19% (0.5 g) yield.
recrystallization of a small sample from ethyl acetate yielded an
analytical sample as powder, mp 274-275°; ir (potassium
5-Chloro-4-dicyanomethylene-1-β-D-ribofuranosylpyridazin-6-
one (10).
Benzoylated nucleoside 9 (1.6 g, 2.51 mmoles) was dissolved
in methanol (60 ml). After adding sodium methoxide (0.9 g,
15.8 mmoles, 95%) to the solution, the mixture was then stirred
-1
1
bromide) 2200, 2170, 1720, 1640 cm . H nmr (DMSO-d ): δ
6
4.60 (m, 1H + 2H ), 5.93 (m, 1H + 1H ), 6.65 (d, 1H , J =
4’
5’
2’
3’
1’
+
for 14 hours at room temperature. Amberlite IRC-50 (H form,
2), 7.67 ppm (m, benzoyl-5H).
Anal. calcd. for C H N O Cl •1/2H O; C, 58.08; H, 3.40;
1.7 g) was added, and the mixture was then stirred for an
additional 24 hours at room temperature. The mixture was
filtered, and the resin was washed with boiling methanol (50 ml).
The combined filtrates were coevaporated with silica gel (2 g)
under reduced pressure. The resulting silica gel was applied to
the top of an open-bed silica gel column (1.5 x 40 cm), and the
column was then eluted with ethyl acetate/methanol (8:2, v/v).
The fractions containing nucleoside were combined and
evaporated under reduced pressure to give 10 as dark brown
powder in 92% (0.75 mg) yield. Recrystallization of a small
sample from ethanol yielded an analytical sample as powder, mp
33 22
4
8
2
2
N, 8.21. Found: C, 57.99; H, 3.44; N, 8.57.
Fractions 295-370 (Rf = 0.19, chloroform/methanol;
8.5:1.5, v/v) were combined and evaporated under reduced
pressure to give 12 as dark brown powder in 5% (0.133 g) yield.
Recrystallization of a small sample from ethyl acetate yielded an
analytical sample as powder, mp 271-273°; ir (potassium
-1
1
bromide) 2200, 2190, 1720, 1650, 1550, 1350 cm . H nmr
(DMSO-d ): δ 4.66 (m, 1H + 2H ), 5.89 (m, 1H + 1H ), 6.50
6
4’
5’
2’
3’
(d, 1H , J = 2), 7.68 ppm (m, benzoyl-5H).
1’
Anal. calcd. for C H N O Cl•1/2H O; C, 57.19; H, 3.35;
33 22
5
10
2
-1
1
250° (dec.); ir (potassium bromide) 2200, 2170, 1620 cm . H
nmr (DMSO-d ): δ 3.95 (m, 1H + 1H + 1H + 2H ), 4.63
N, 10.11. Found: C, 57.17; H, 3.21; N, 10.04.
6
2’
3’
4’
5’
4,5-Dichloro-3-dicyanomethylene-1-β-D-ribofuranosylpyri-
dazin-6-one (15).
(t, OH , D O exchangeable), 4.90 (d, OH , J = 4, D O
5’
2
3’
2
exchangeable), 5.28 (d, OH , J = 4, D O exchangeable), 6.20
2’
2
(d, 1H , J = 2), 8.10 (s, 1H ).
Benzoylated nucleoside 13 (0.4 g, 0.59 mmoles) was dissolved
in methanol (30 ml). After adding sodium methoxide (0.5 g,
8.79 mmoles, 95%), the mixture was stirred for 22 hours at room
1’
3
Anal. calcd. for C H N O Cl; C, 44.12; H, 3.39; N, 17.15.
12 11
4 5
Found: C, 44.29; H, 3.65; N, 17.37.
+
temperature. Amberlite IRC-50 (H form, 4 g) was added, and
4-Chloro-5-dicyanomethylene-3-nitro-1-(2,3,5-tri-O-benzoyl-β-
D-ribofuranosyl)pyridazin-6-one (12), 4,5-Dichloro-3-
dicyanomethylene-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)
pyridazine-6-one (13) and 5-Chloro-4-dicyanomethylene-3-nitro-
1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyridazin-6-one (14).
the mixture was then stirred for an additional 24 hours at room
temperature. After filtering the mixture, the resin was washed
with boiling methanol (50 ml). The combined filtrate was
coevaporated with silica gel (3 g) under reduced pressure. The
resulting silica gel was applied to the top of an open-bed silica gel
column (1.5 x 40 cm), and the column was then eluted with
chloroform/methanol (7:3, v/v). The fractions containing nucleo-
side were combined and evaporated under reduced pressure to
give 15 as dark brown powder in 90% (0.24 g) yield.
Recrystallization of a small sample from ethanol yielded an ana-
lytical sample as powder, mp 291° (dec.); ir (potassium bromide)
A mixture of malononitrile (0.33 g, 4.99 mmoles), sodium
hydride (0.207 g, 5.18 mmoles, 60% in oil) and dry dimethyl
sulfoxide (10 ml) was stirred for 0.5 hours at room temperature
under nitrogen atmosphere. The solution of 11 [5] (2.5 g,
3.82 mmoles) in dry dimethyl sulfoxide (10 ml) was added to the
above mixture, and the reaction mixture was then stirred for
6 hours at room temperature under nitrogen atmosphere. The
reaction was quenched by the addition of aqueous acetic acid
(10%, 40 ml), and the mixture was then stirred for an additional
0.5 hours at room temperature. After the mixture was poured into
water (100 ml), the product was extracted with ethyl acetate
(100 ml x 4). The organic solution was washed with water
(200 ml x 4), and dried over anhydrous magnesium sulfate. The
solution was coevaporated with silica gel (5 g) under reduced
pressure. The resulting silica gel was applied to the top of an
open-bed silica gel column (2 x 45 cm). The column was eluted
with chloroform/methanol (8.5:1.5, v/v). After discarding the
first fraction (150 ml), the eluent was collected in 6 ml fraction.
Fractions 45-162 (Rf = 0.26, chloroform/methanol=8.5:1.5, v/v)
-1
1
2210, 2170, 1650 cm . H nmr (DMSO-d ): δ 4.66 (m, 1H
+
6
4’
2H ), 5.91 (m, 1H + 1H ), 6.52 (d, 1H , J = 2), 7.70 ppm
5,
2’
3’
1’
(m, benzoyl-5H).
Anal. Cacd. For C H N O Cl ; C, 39.91; H, 2.79; N, 15.51.
12 10
4
5
2
Found: C, 39.67; H, 2.86; N, 15.87.
5-Chloro-4-dicyanomethylene-3-nitro-β-D-ribofuranosyl-
pyridazin-6-one (16).
Benzoylated nucleoside 14 (1.2 g, 1.76 mmoles) was dissolved
in methanol (50 ml). After adding sodium methoxide (0.5 g,
8.79 mmoles, 95%), the mixture was stirred for 19.5 hours at
+
room temperature. Amberlite IRC-50 (H form, 2 g) was added,
and the mixture was then stirred for an additional 22 hours at

Sep-Oct 2001
Synthesis of Novel Pyridazine Nucleosides
1183
room temperature. After filtering the solution, the resin was
washed with boiling methanol (50 ml). The combined filtrate was
coevaporated with silica gel (3 g) under reduced pressure. The
resulting silica gel was applied to the top of an open-bed silica gel
column (1.5 x 40 cm), and the column was then eluted with ethyl
acetate/methanol (9:1, v/v). The fractions containing nucleoside
were combined and evaporated under reduced pressure to give 16
as dark brown powder in 88% (0.57 g) yield. Recrystallization of
a small sample from ethanol yielded an analytical sample as
powder, mp 273° (dec.); ir (potassium bromide) 2210, 2170,
1 g) was added, and the mixture was then stirred for an additional
48 hours at room temperature. The mixture was filtered, and the
resin was washed with boiling methanol (50 ml). The combined
filtrate was coevaporated with silica gel (2 g) under reduced
pressure. The resulting silica gel was applied to the top of an
open-bed silica gel column (1.5 x 40 cm), and the column was
then eluted with ethyl acetate/methanol (6:4, v/v). The fractions
containing nucleoside were combined and evaporated under
reduced pressure to give 18 as dark brown powder in 73% (0.23 g)
yield. Recrysatllization of a small sample from ethanol yielded an
analytical sample as powder, mp 241-243°; ir (potassium
-1
1
1660, 1555, 1350 cm . H nmr (DMSO-d ): δ 3.99 (m, 1H
+
6
2’
-1
1
bromide) 2200, 1660, 1450 cm . H nmr (DMSO-d ): δ 4.60
1H + 1H + 2H ), 4.48 (t, OH , D O exchangeable), 4.98
6
3’
4’
5’
5’
2
(m, 1H + 1H + OH , D O exchangeable), 4.95 (d, OH , J = 4,
(d, OH , J = 4, D O exchangeable), 5.30 (d, OH , J = 4, D O
4’
5’
5’
2
3’
3’
2
2’
2
D O exchangeable), 5.27 (d, OH , J = 4, D O exchangeable),
exchangeable), 6.55 ppm (d, 1H , J = 4).
2
2’
2
1’
5.99 (m, 1H + 1H ), 6.69 (d, 1H , J = 2), 8.48 (s, NH , D O
Anal. calcd. for C H N O Cl; C, 38.78; H, 2.71; N, 18.84.
2’
3’
1’
2
2
12 10
5 7
exchangeable), 11.95 ppm (s, NH, D O exchangeable).
Found: C, 38.97; H, 2.44; N, 19.13.
2
Anal. calcd, for C H N O Cl; C, 42.18; H, 3.54; N, 20.50.
12 12
5 5
6-Amino-4-chloro-5-cyano-2-(2,3,5-tri-O-benzoyl-β-D-ribofura-
nosyl)-7H-pyrrolo[2,3-c]pyridazin-3(2H)-one (17).
Found: C, 41.97; H, 3.90; N, 20.73.
Acknowledgements.
Compound 14 (1.5 g, 2.19 mmoles) was dissolved in ethyl
acetate (200 ml). After adding sodium borohydride (0.3 g,
7.9 mmoles) and stannous chloride dihydrate (1.5 g, 7.9 mmoles),
the mixture was refluxed for 22 hours. The mixture was cooled to
room temperature and filtered. The filtrate was coevaporated
with silica gel (3 g) under reduced pressure. The resulting silica
gel was applied to the top of an open-bed silica gel column
(2.5 x 30 cm). The column was eluted with ethyl acetate/n-
hexane (7:3, v/v). The fractions containing the product were
combined and evaporated to give 17 as beige powder in 63%
(0.883 g) yield. Recrystallization of a small sample from ethyl
acetate yielded an analytical sample as powder, mp 183-185°; ir
(potassium bromide) 3400, 3300, 3200, 2200, 1720, 1650, 1570,
This work was supported by the Brain Korea 21 Project.
REFERENCES AND NOTES
[1] D. J. Katz, D. S. Wise and L. B. Townsend, J. Heterocyclic
Chem., 12, 609 (1975).
[2] D. J. Katz, D. S. Wise and L. B. Townsend, J. Med. Chem., 25,
813 (1982).
[3] L. C. Bloomer, L. L. Wortring and L. B. Townsend, Cancer
Research, 42, 100 (1982).
[4] D. J. Katz, D. S. Wise and L. B. Townsend, J. Org. Chem., 48,
3765 (1983).
[5] D. J. Katz, D. S. Wise and L. B. Townsend, J. Heterocyclic
Chem., 20, 369 (1983).
[6] S. G. Lee and Y. J. Yoon, Bull. Kor. Chem. Soc., 10 (6), 614
(1989).
[7] S. G. Lee, S. Y. Choi and Y. J. Yoon, J. Heterocyclic Chem.,
29, 1409 (1992).
-1
1
1455, 1450 cm . H nmr (DMSO-d ): δ 4.63 (m, 1H + 2H ),
6
4’
5’
6.03 (m, 1H + 1H ), 6.69 (d, 1H , J = 2), 7.68 (m, benzoyl-
2’
3’
1’
5H), 8.48 (s, NH , D 0 exchangeable). 11.95 ppm (s, NH).
2
2
Anal. calcd. for C H N O Cl•H O; C, 58.98; H, 3.90; N,
33 24
5
8
2
10.42. Found; C, 58.81; H, 4.00; N, 10.39.
[8] J. W. Park, D. H. Kweon, Y. J. Kang, W. S. Lee, S. D. Cho and
Y. J. Yoon, J. Heterocyclic Chem., 37, 5 (2000).
[9] S. D. Cho, J. W. Chung, W. Y. Choi, S. K. Kim and Y. J. Yoon,
J. Heterocyclic Chem., 31, 1199 (1994).
[10] A. J. Borror and A. F. Haeberer, J. Org. Chem., 30, 243
(1965).
6-Amino-4-chloro-5-cyano-2-β-D-ribofuranosyl-7H-
pyrrolo[2,3-c]pyridazin-3(2H)-one (18).
Nucleoside 17 (0.6 g, 9.24 mmoles) was dissolved in methanol
(30 ml) and 1,2-dichloroethane (20 ml). After adding sodium
methoxide (0.6 g, 10.55 mmoles, 95%), the mixture was stirred
+
for 48 hours at room temperature. Amberlite IRC-50 (H form,
[11] S. G. Lee and Y. J. Yoon, Unpublished results.