Facile synthesis of 9-substituted 9-deazapurines as potential purine nucleoside phosphorylase inhibitors.

Article abstract of DOI:10.1248/cpb.50.364

A facile synthesis of 9-substituted 9-deazapurines as potential inhibitors of purine nucleoside phosphorylase has been achieved by the direct Friedel-Crafts aroylation or arylmethylation of 9-deazapurines using trifluoromethanesulfonic acid as catalyst. The aroylated 9-deazapurines could be transformed into the corresponding 9-aryimethyl derivatives by the Wolff-Kishner reaction. A novel synthesis of 9-deazahypoxanthine was also developed by treatment of 4-hydroxy-5-phenylazo-6-methylpyrimidin-2-thione with triethyl orthoformate in trifluoroacetic acid (TFA) to yield 8-oxo-7H-2-phenylpyrimido[5,4-c]pyridazin-6-thione followed by Raney nickel reduction.

Full text of DOI:10.1248/cpb.50.364

364
Chem. Pharm. Bull. 50(3) 364—367 (2002)
Vol. 50, No. 3
Facile Synthesis of 9-Substituted 9-Deazapurines as Potential Purine
Nucleoside Phosphorylase Inhibitors
Hsiencheng SHIH,* Howard Brinkerhoff COTTAM, and Dennis Anthony CARSON
Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California, San Diego,
La Jolla, California 92093–0663, U.S.A. Received October 19, 2001; accepted January 4, 2002
A facile synthesis of 9-substituted 9-deazapurines as potential inhibitors of purine nucleoside phosphorylase
has been achieved by the direct Friedel–Crafts aroylation or arylmethylation of 9-deazapurines using trifluo-
romethanesulfonic acid as catalyst. The aroylated 9-deazapurines could be transformed into the corresponding
9-arylmethyl derivatives by the Wolff–Kishner reaction. A novel synthesis of 9-deazahypoxanthine was also devel-
oped by treatment of 4-hydroxy-5-phenylazo-6-methylpyrimidin-2-thione with triethyl orthoformate in trifluo-
roacetic acid (TFA) to yield 8-oxo-7H-2-phenylpyrimido[5,4-c]pyridazin-6-thione followed by Raney nickel re-
duction.
Key words 9-deazahypoxanthine; 9-deazapurine; 9-aroyl-9-deazapurine; 9-arylmethyl-9-deazpurine; purine nucleoside phos-
phorylase inhibitor
Purine nucleoside phosphorylase (PNP) catalyzes re- ceed through carbocation intermediate in the presence of
versibly the phosphorolysis of guanosine, inosine, and their strong acids,11) treatment of 1 with benzoyl chloride in
2Ј-deoxyribonucleoside derivatives to the corresponding free polyphosphoric acid at 100 °C gave unsatisfactory results.
base, a-ribose-1-phosphate, or 2-deoxy-a-ribose-1-phos- However, acylation of 1 with benzoyl chloride using triflic
phate. Inhibition of PNP may cause the selective accumula- acid as catalyst in nitromethane, provided the desired 9-ben-
tion of dGTP,1) selective depletion of T lymphocytes, and in- zoyl-9-deazaxanthine, 4, in low yield. Optimization of the re-
hibition of cellular immune response.2) Thus, a potent PNP action conditions for benzoylation was achieved upon the re-
inhibitor may provide a new and effective immunosuppres- action of 1 with benzoyl chloride (1.2 eq), using triflic acid
sive agent in the treatment of T-cell dependent diseases such (Ͼ10 eq) as catalyst and solvent at temperatures higher than
as rheumatoid arthritis, psoriasis, T-cell leukemia and lym- 60 °C for 48 h providing 75% yield of 4. A similar procedure
phoma. Various derivatives of 9-substituted 9-deazaguanine was applied to yield 9-(p-methylbenzoyl)- and 9-(3Ј,4Ј-
and 9-deazahypoxanthine as potent competitive inhibitors of dichlorobenzoyl)-9-deazaxanthine, 5 and 6, respectively. In
purine nucleoside phosphorylase based on the application these reactions, one major aroylated product at the C-9 posi-
of crystallographic and modeling methods have been de- tion was isolated. 8-Aroyl or 8,9-diaroyl derivatives were not
scribed.3—7) All these derivatives were prepared by multi-step found. The lack of these side products indicated the exclu-
synthesis without using a common building block. Usually, sive aroylation at C-9. The electron-withdrawing aroyl sub-
the last step in these processes was the construction of the stituent at C-9 might play an important role to deactivate fur-
pyrimidine or pyrrole ring of the deazapurine base.3—7) In ther aroylation at the C-8 position of 9-deazaxanthine. How-
order to find a simple and effective method to explore more ever, a limitation in the scope of this electrophilic substitu-
PNP inhibitors, a facile synthesis of these analogues was de- tion was observed. We found that reactions involving aroyl
veloped based on the strategy of the direct aroylation or aryl- chlorides bearing electron-withdrawing groups at the para
methylation of available building blocks, such as 9-deazaxan- position, proceeded with great difficulty due to the limited
thine (1),8) 9-deazaguanine (2),8,9) or 9-deazahypoxanthine availability of in-situ generated carbocation. We then investi-
(3).9) The aroylated compounds could be converted to the gated several procedures to convert the aroyl substituent to
corresponding arylmethyl derivatives or vise versa. These ap- arylmethyl derivatives. Attempts to reduce 4 by the Clem-
proaches would be much more efficient than the previously menson reduction or by catalytic hydrogenation using 10%
reported multi-step synthesis which employed no common palladium on carbon under acidic or basic conditions, failed
building blocks. Herein, we report a facile synthesis of 9- to give product. However, it was found that 4 could be re-
substituted 9-deazapurines and an improved method to pre- duced to 9-benzyl-9-deazaxanthine, 7 (56% yield), by the
pare 9-deazahypoxanthine.
Wolff–Kishner reaction, using 10 eq of NaOH and 10 eq of
hydrazine in ethylene glycol at 100 °C. Similarly, 9-(p-
methylbenzyl)-9-deazaxanthine, 8, was obtained from 5 by
Results and Discussion
Synthesis of 9-Substituted 9-Deazaxanthine As C-de- the Wolff–Kishner reaction. The successful synthesis of 9-
oxyribonucleosides10) had been prepared by the direct C-gly- aroyl-9-deazaxanthine led us to turn our attention to the
cosylation of 7- and 9-deazaguanine using stannic chloride preparation of 9-arylmethyl derivatives by the direct
as catalyst, it was possible to synthesize 9-substituted 9- Friedel–Crafts alkylation of 1. Previously, the Friedel–Crafts
deazapurines by a direct aroylation or arylmethylation of alkylation of 1 with benzyl bromide using a Lewis acid cata-
available 9-deazaxanthine (1), 9-deazaguanine (2) or 9-deaza- lyst such as stannic chloride, or aluminum chloride in ni-
hypoxanthine (3). In our initial attempts, the Friedel–Crafts tromethane, or acetonitrile, produced a mixture of 9-deaza-
benzoylation of 1 in the presence of Lewis acid catalysts xanthines benzylated at C-8, C-9, N-1, or N-7. Attempts to
gave a mixture of 9-deazaxanthine benzoylated at N-1, N-3, prepare the desired compound using silver oxide as cata-
and N-7 as major products. As acylation of olefins could pro- lyst,12) which had been successfully used in an indole system,
To whom correspondence should be addressed. e-mail: hshih@ucsd.edu
© 2002 Pharmaceutical Society of Japan

March 2002
365
dium on carbon,9) or by the condensation of isoxazole and di-
ethyl aminomalonate to form pyrrole derivative followed by
reaction with formamidine acetate,15) or by palladium-cat-
alyzed cross-coupling of 4-methoxy-5-nitro-6-iodopyridine
and trimethyl(tributylstannylethynyl)silane to form 4-methoxy-
5-nitro-6-trimethylsilylethynylpyridine followed by construc-
tion of an annulated pyrrole ring.16) However, in the routes
to synthesize intermediates of 1 and 2, 6,8-dioxo-7H-2-
phenylpyrimido[5,4-c]pyridazine8) and 6-amino-8-oxo-2-
phenylpyrimido[5,4-c]pyridazine,8) respectively, by modify-
ing Klein’s procedure8) using TFA as solvent, we found a
simple two-step synthesis of 3 with an overall yield of 50%.
This new method involved the reaction of 4-hydroxy-5-
phenylazo-6-methylpyrimidin-2-thione, 25,17) with triethyl
orthoformate in TFA at 70 °C to give 8-oxo-7H-2-
phenylpyrimido[5,4-c]pyridazin-6-thione, 26. The subse-
quently concomitant ring constriction and removal of the 2-
thione of this intermediate with Raney-nickel in methanol of-
fered 3 (Chart 2). In this reaction, hydrazine or NaOH could
be used as base catalyst. The chemistry of 3 toward the
Friedel–Crafts acylation or alkylation was expected to be the
same as 1. Accordingly, 9-benzoyl-9-deazahypoxanthine (21),
9-(3Ј,4Ј-dichlorobenzoyl)-9-deazahypoxanthine (22), 9-ben-
zyl-9-deazahypoxanthines (23) and 9-(3Ј,4Ј-dichlorobenzyl)-
9-deazahypoxanthine (24) were obtained by the same proce-
dures used in the preparations of 9-substituted 9-deazaxan-
thines.
resulted in benzylation at N-7 and C-8 positions. Treatment
of 1 with benzyl alcohol, a good source of benzyl cation,13,14)
in triflic acid at room temperature yielded 8,9-dibenzylated
derivatives. The reaction of 1 with benzyl bromide in triflic
acid as catalyst and solvent at 60—100 °C also gave 8,9-
dibenzyl derivatives. In an effort to solve the problem, treat-
ment of 1 with benzyl bromide using triflic acid (Ͼ4 eq) as
catalyst in glacial acetic acid at 100 °C or TFA at 80 °C for
48 h, resulted in 7 as a major product. Similar results were
obtained by the same approach to yield 8 and 9, respectively.
However, the better result of 9 was obtained when aluminum
chloride, a Lewis acid, was added as the second catalyst to
increase the formation of 3,4-dichlorobenzyl cation. In these
reactions, acetic acid or TFA not only helped to dissolve 9-
deazaxanthine but also increased the formation of benzyl
cation for alkylation. We isolated 8,9-diarylmethylated com-
pounds as a minor product. However, we observed no 8-aryl-
methyl-9-deazaxanthin. It was postulated that arylmethyla-
tion occurred first at C-9, followed by further electrophilic
substitution at C-8 to yield 8,9-diarylmethyl derivatives.
Synthesis of 9-Substituted 9-Deazaguanine Unlike 1,
acylation of 2 can occur at 2-amino and C-9 positions. Thus,
reaction of 2 with 2.2 eq of benzoyl chloride in triflic acid
(Ͼ20 eq) at 60 °C resulted in dibenzoyl derivative at 2-amino
and C-9 positions, which could be converted to the desired 9-
benzoyl-9-deazaguanine, 10, by treatment of the reaction
mixture with excess NaOH (Ͼ40 eq) for 2 h at 60 °C, fol-
lowed by neutralization. However, at a higher temperatures
(Ͼ80 °C), 2-acylamide of dibenzoyl derivative was further
hydrolyzed by triflic acid to give 10. Similar procedure by
treatments of 2 with p-methylbenzoyl chloride, 3,4-
dichlorobenzoyl chloride, 3,5-dichlorobenzoyl chloride, or 3-
nitrobenzoyl chloride resulted in 11, 12, 13, or 14, respec-
tively. However, treatment of 2 with p-methoxybenzoyl chlo-
ride at 80 °C for 40 h resulted in 9-(p-hydroxybenzoyl)-9-
deazaguanine, 15, because p-methoxyl substituent was fur-
ther hydrolyzed by triflic acid. We found that the reaction
gave a major product of 9-(p-methoxybenzoyl)-9-deazapu-
rine (ms, 285, MHϩ) at a lower temperature (60 °C) for 20 h,
but failed to give a product at higher temperature (Ͼ100 °C)
for 24 h, due to the early cleavage of the methoxyl group of
p-methoxybenzoyl chloride by triflic acid before it could be
acylated at C-9. The chemistry of electrophilic substitution
of 9-deazaguanine under strong acidic condition was similar
to that of 9-substituted 9-deazaxanthine. Accordingly, treat-
ment of 2 with 1.2 eq of benzyl, p-methylbenzyl, 3,4-
dichlorobenzyl, 3-nitrobenzyl bromide, or p-methoxybenzyl
chloride and 5 eq of triflic acid in glacial acetic acid or TFA
offered 16, 17, 18, 19, or 20 as a major product, respectively.
Synthesis of 9-Deazahypoxanthine and Its 9-Substi-
tuted Derivatives Previously, 3 had been prepared by
dichlorination of 1 with phosphorus oxychloride followed by
partial alkaline hydrolysis of 6-chloro substituent and the
subsequent removal of 2-chloro by hydrogenation with palla-
Summary We had developed a novel synthesis of 9-
deazahypoxanthine and demonstrated more efficient and con-
cise approaches to prepare 9-substituted 9-deazapurines via
the Friedel–Crafts acylation or alkylation, using triflic acid as
catalyst. These approaches were based on the in-situ genera-
tion of available carbocation or arylmethyl cation, so that
aroylation or arylmethylation could occur at the C-9 of 9-
deazapurine. The aroylated compounds could be transformed
into the corresponding arylmethyl analogues by the
Wolff–Kishner reaction or vise verse as evidenced by the
Chart 1
Chart 2

366
Vol. 50, No. 3
conversion of 16 to 10 using CrO3 in acetic acid.18) We are
currently applying these methods to synthesize 7-substituted
7-deazapurines.
7-Benzyl-1H,3H,5H-pyrrolo[3,2-d]pyrimidin-2,4-dione (7): 11% yield from
method B, 77.6% yield from method C; mp 257 °C (decomposed); MS m/z,
1
241 (Mϩ); H-NMR (DMSO-d6) d 3.79 (s, 2H, CH2), 6.93 (d, 1H, Jϭ6 Hz,
C-6H), 7.15 (t, 1H, Jϭ6.5 Hz, CЈ-4H), 7.26 (m, 4H, CЈ-2H, CЈ-3H, CЈ-5H,
CЈ-6H), 10.58 (s, 1H, OH), 10.87 (s,1H, OH), 11.65 (s, 1H, NH). Anal.
Calcd for C13H11N3O2·1/15CF3SO3H: C, 62.41; H, 4.40; N, 16.72. Found:
C, 62.37; H, 4.12; N, 16.37.
7-(p-Methylbenzyl)-1H,3H,5H-pyrrolo[3,2-d]pyrimidin-2,4-dione (8): 58%
yield from method C, 17% yield from method B; mp 283 °C (decomposed);
MS m/z, 256 (MHϩ); 1H-NMR (DMSO-d6) d 2.22 (S, 3H, CH3), 3.72 (s, 2H,
CH2), 6.88 (s, 1H, C-6H), 7.0—7.2 (m, 5H, aromatic H), 10.57 (s, 1H, OH),
10.82 (s, 1H, OH), 11.62 (s, 1H, NH). Anal. Calcd for C14H13N3O2·1/2H2O:
C, 63.57; H, 5.30; N, 15.90, Found: C, 63.95; H, 4.94; N, 15.64.
7-(3Ј,4Ј-Dichlorobenzyl)-1H,3H,5H-pyrrolo[3,2-d]pyrimidin-2,4-dione
(9): 8% yield from method B; mp 278 °C (decomposed); MS m/z, 310
(MHϩ); 1H-NMR (DMSO-d6) d 3.79 (s, 2H, CH2), 7.07 (d, 1H, Jϭ3 Hz, C-
6H), 7.23 (dd, 1H, Jϭ1.5 Hz, CЈ-6H), 7.51 (s, 1H, CЈ-2H), 7.53 (d, 1H,
Jϭ1.5 Hz, CЈ-5H), 10.60 (s, 1H, OH), 10.88 (s, 1H, OH), 11.76 (s, 1H, NH).
Anal. Calcd for C13H9Cl2N3O2·1/9H2O: C, 50.02; H, 2.98; N, 13.46. Found:
C, 50.33; H, 2.96; N, 13.07.
2-Amino-3H,5H-7-benzoylpyrrolo[3,2-d]pyrimidin-4-one (10): 54% yield
from A-2; mp 287 °C (decomposed, lit.18) mp Ͼ250 °C); MS m/z, 255
(MHϩ); 1H-NMR (DMSO-d6) d 6.4 (b, 2H, NH2), 7.49 (t, 2H, Jϭ7.5 Hz, CЈ-
3H, CЈ-5H), 7.56 (s, 1H, C-6H), 7.6 (t, 1H, CЈ-4H), 7.79 (d, 2H, Jϭ7.0 Hz,
CЈ-2H, CЈ-6H). Anal. Calcd for C13H10N4O2·1/6CF3SO3H: C, 56.18; H,
3.94; N, 19.91. Found: C, 56.58; H, 3.64; N, 20.06.
Experimental
All solvents and chemicals were of analytical grade. Melting points were
determined by the capillary method with a MEL-Temp II apparatus, and un-
corrected. NMR spectra in DMSO-d6 were recorded at 500 MHz. Mass spec-
trum was obtained by FAB-MS.
General Procedures. Method A. Aroylation of 9-Deazapurines 1:
The mixture of 1 (200—300 mg as 1.0 eq) or 3 (100 mg as 1.0 eq), and aroyl
chloride (1.2 eq) in triflic acid (10 eq) was stirred at 60—100 °C for 48 h.
After cooling, water was added to the reaction mixture. The resulting precip-
itate was filtered and washed with solvent several times sach as methylene
chloride, ethyl acetate, acetone, or methanol, to give desired product. Further
purification can be done by repeatly boiling the product in methanol and
then filtered several times.
2: The mixture of 2 (200—300 mg) and aroyl chloride (2.2 eq) in triflic
acid (Ͼ20 eq) was stirred at 80—120 °C for 48 h. After cooling, water was
added to the reaction mixture. The resulting precipitate was filtered and
washed several times with solvent sach as methylene chloride, ethyl acetate,
acetone, or methanol, to give desired product. Further purification can be
done by repeatly boiling the product in methanol and then filtered several
times.
B. Arylmethylation of 9-Deazapurines The mixture of 9-deazapurine
(100—300 mg), arylmethyl bromide (1.2 eq) and triflic acid (4—10 eq) in
acetic acid (10 ml) or TFA (10 ml) was stirred at 80—100 °C for 48 h. The
reaction mixture was concentrated under vacuo. The residue was added with
water, neutralized and then extracted with ethyl acetate twice. The combined
organic phase was dried and evaporated. The residue was purified by flash
column chromatography using 5% methanol in methylene chloride as an
eluent to give product. For the synthesis of 9-(3Ј,4Ј-dichlorobenzyl)-9-
deazapurines, a modification was made by adding aluminum chloride
(2.2 eq) as the second catalyst to increase the formation of 3,4-dichloroben-
zyl cation.
2-Amino-3H,5H-7-(p-methylbenzoyl)pyrrolo[3,2-d]pyrimidin-4-one (11):
55% yield from method A-2; mp 267 °C (decomposed); MS m/z, 269
(MHϩ); 1H-NMR (DMSO-d6) d 6.4 (b, 2H, NH2), 7.30 (d, 2H, Jϭ8 Hz, CЈ-
3H, CЈ-5H), 7.55 (s, 1H, C-6H), 7.71 (d, 2H, Jϭ8 Hz, CЈ-2H, CЈ-6H), 10.9
(b, 1H, OH), 12.46 (b, 1H, NH). Anal. Calcd for C14H12N4O2·1/5CF3SO3H:
C, 57.12; H, 4.09; N, 18.78. Found: C, 57.21; H, 4.44; N, 18.44.
2-Amino-3H,5H-7-(3Ј,4Ј-dichlorobenzoyl)pyrrolo[3,2-d]pyrimidin-4-one
(12): 91% yield from method A-2; mp 310 °C (decomposed); MS m/z, 323
1
(Mϩ); H-NMR (DMSO-d6) d 6.8 (s, 2H, NH2), 7.6 (s, 1H, C-6H), 7.78 (d,
2H, CЈ-5H, CЈ-6H), 7.96 (s, 1H, CЈ-2H), 10.18 (s, 1H, OH), 11.03 (s, 1H,
NH); Anal. Calcd for C13H8Cl2N4O2·1.6H2O: C, 44.36; H, 3.21; N, 15.92.
Found: C, 44.27; H, 2.82; N, 15.66.
C. The Wolff–Kishner Reaction The mixture of 9-deazapurine (100—
150 mg), NaOH (10 eq) and hydrazine (10 eq) in ethylene glycol (10 ml) was
stirred at 100—120 °C for 16 h. The reaction mixture was diluted with water
and then neutralized with acetic acid. The mixture was then extracted with
ethyl acetate twice. The combined organic phase was dried and evaporated.
The residue was chromatographed using 10% methanol in methylene chlo-
ride as an eluent to give the product.
2-Amino-3H,5H-7-(3Ј,5Ј-dichlorobenzoyl)pyrrolo[3,2-d]pyrimidin-4-one
(13): 57% yield from method A-2; mp 308 °C (decomposed); MS m/z, 324
(MHϩ); 1H-NMR (DMSO-d6) d 6.41 (b, 2H, NH2), 7.70 (s, 1H, C-6H), 7.75
(s, 2H, CЈ-2H, CЈ-6H), 7.94 (s, 1H, CЈ-4H), 11.03 (b, 1H, OH), 12.6 (s, 1H,
NH). Anal. Calcd for C13H8Cl2N4O2·2/3CH3OH·1/15CF3SO3H: C, 46.49;
H, 3.02; N, 15.79. Found: C, 46.22; H, 2.91; N, 15.61.
3H,5H-Pyrrolo[3,2-d]pyrimidin-4-one (3): The mixture of 4-hydroxy-5-
phenylazo-6-methylpyrimid-2-thione16) (12 g), triethyl orthoformate (100 ml)
in TFA (60 ml) was stirred at 70 °C overnight. After cooling, the reaction
mixture was filtered and washed with CH2Cl2 to give 7.0 g of crude 8-oxo-
7H-2-phenylpyrimido[5,4-c]pyridazin-6-thione [NMR, d 7.70 (m, 3H, aro-
matic H), 7.90 (m, 2H, aromatic H), 8.15 (bs, 1H, C-4H), 9.2 (bs, 1H, C-
3H), 9.57 (d, 1H, NH)]. This crude intermediate in 120 ml of 50%
methanol–water and 5 ml of hydrazine was added Ra-Ni (wet, 40 g) with
stirring at 80 °C overnight. The reaction mixture was filtered and the filtrate
was evaporated to give almost pure product (3.22 g, 49%), which was recrys-
tallized from hot water to give pure compound. mp Ͼ300 °C (lit.9) Ͼ300 °C);
2-Amino-3H,5H-7-(m-nitrobenzoyl)pyrrolo[3,2-d]pyrimidin-4-one (14):
1
72% yield from method A-2; mp Ͼ300 °C; MS m/z, 300 (MHϩ); H-NMR
(DMSO-d6) d 6.36 (b, 2H, NH2), 7.57 (s, 1H, C-6H), 7.77 (t, 1H, Jϭ7.5 Hz,
CЈ-5H), 8.19, (d, 1H, Jϭ7.5 Hz, CЈ-6H), 8.39 (d, 1H, Jϭ8.0 Hz, CЈ-4H),
8.51 (s, 1H, CЈ-2H). Anal. Calcd for C13H9N5O4·0.4CH3OH·0.15CF3SO3H:
C, 48.60; H, 3.21; N, 20.93. Found: C, 48.57; H, 2.91; N, 20.67.
2-Amino-3H,5H-7-(p-hydroxylbenzoyl)pyrrolo[3,2-d]pyrimidin-4-one
(15): 75% yield from method A-2 at 100 °C for 3 d; mp Ͼ300 °C; MS m/z,
271 (MHϩ); 1H-NMR (DMSO-d6) d 6.85 (d, 2H, dϭ8.5 Hz, CЈ-3H, CЈ-5H),
7.62 (s, 1H, C-6H), 7.75 (d, 2H, Jϭ8 Hz, CЉ-2H, CЈ-6H), 10.27 (s, 1H, OH),
12.54 (b, 1H, NH). Anal. Calcd for C13H10N4O3·CH3COCH3·0.65CF3SO3H:
C, 46.95; H, 3.94; N, 13.16. Found: C, 47.32; H, 3.81; N, 12.94.
2-Amino-3H,5H-7-benzylpyrrolo[3,2-d]pyrimidin-4-one (16): 20% yield
from method B, 53% yield from method C; mp 255 °C (decomposed, lit.3)
269—270 °C); MS m/z, 240 (Mϩ); 1H-NMR (DMSO-d6) d 3.77 (s, 2H,
CH2), 5.79 (b, 2H, NH2), 6.90 (s, 1H, C-6H), 7.0—7.3 (m, 5H, aromatic H),
10.25 (b, 1H, OH), 11.2 (b, 1H, NH).
2-Amino-3H,5H-7-(p-methylbenzyl)pyrrolo[3,2-d]pyrimidin-4-one (17):
12% yield from method B; mp 175 °C (decomposed); MS m/z, 254 (Mϩ);
1H-NMR (DMSO-d6) d 2.22 (s, 3H, CH3), 3.75 (s, 2H, CH2), 5.8 (b, 2H,
NH2), 6.90 (d, 1H, Jϭ3 Hz, C-6H), 7.04 (d, 2H, Jϭ7.5 Hz, CЈ-3H, CЈ-5H),
7.10 (d, 2H, Jϭ8 Hz, CЈ-2H, CЈ-6H), 10.32 (s, 1H, NH), 11.2 (1H, NH).
Anal. Calcd for C14H14N4O·2/3CH3COOH: C, 62.52; H, 5.66; N, 19.03.
Found: C, 62.40; H, 5.62; N, 19.20.
1
MS m/z, 136 (MHϩ); H-NMR (DMSO-d6) d 6.36 (d, 1H, C-7H), 7.37 (t,
1H, Jϭ2.5 Hz, C-6H), 7.78 (s, 1H, C-2H), 11.86 (s, 1H), 12.08 (s, 1H).
7-Benzoyl-1H,3H,5H-pyrrolo[3,2-d]pyrimidin-2,4-dione (4): 75% yield
1
from method A-1; mp 340 °C (decomposed); MS m/z, 255 (Mϩ); H-NMR
(DMSO-d6) d 7.55 (t, 2H, Jϭ7.5 Hz, CЈ-3H, CЈ-5H), 7.64 (t, 1H, Jϭ6.5 Hz,
CЈ-4H), 7.68 (d, 1H, Jϭ4 Hz, C-6H), 7.82 (d, 2H, Jϭ7 Hz, CЈ-2H, CЈ-6H),
10.0 (b, 1H, OH), 10.9 (b, 1H, OH), Anal. Calcd for C13H9N3O3·1/2H2O: C,
59.03; H, 3.78; N, 15.90. Found: C, 59.00; H, 3.57; N, 15.92.
7-(p-Methylbenzoyl)-1H,3H,5H-pyrrolo[3,2-d]pyrimidin-2,4-dione (5):
1
79% yield from method A-1; mp Ͼ300 °C; MS m/z, 270 (Mϩ); H-NMR
(DMSO-d6) d 2.37 (s, 3H, CH3), 7.33 (d, 2H, Jϭ8 Hz, CЈ-3H, CЈ-5H), 7.68
(s, 1H, C-6H), 7.73 (d, 2H, Jϭ8 Hz, CЈ-2H, CЈ-6H). 10.3 (s, 1H, OH), 11.0
(s, 1H, OH), 12.85 (b, 1H, NH). Anal. Calcd for C14H11N3O3·1/3CF3SO3H:
C, 53.87; H, 3.76; N, 13.16. Found: C, 54.11; H, 3.93; N, 12.93.
7-(3Ј,4Ј-Dichlorobenzoyl)-1H,3H,5H-pyrrolo[3,2-d]pyrimidin-2,4-dione
(6): 90% yield from method A-1; mp 326 °C (decomposed); MS m/z, 324
(MHϩ); 1H-NMR (DMSO-d6) d 7.77 (m, 3H, C-6H, CЈ-5H, CЈ-6H), 7.95 (s,
1H, CЈ-4H), 10.19 (s, 1H, OH), 11.05 (s, 1H, OH), 12.9 (s, 1H, NH); Anal.
Calcd for C13H6Cl2N3O3·2/3H2O: C, 46.41; H, 2.47; N, 12.50. Found: C,
46.20; H, 2.53; N, 12.24.
2-Amino-3H,5H-7-(3Ј,4Ј-dichlorobenzyl)pyrrolo[3,2-d]pyrimidin-4-one
(18): 14% yield from method B; mp 245 °C (decomposed, lit.3) 278—
1
280 °C); MS m/z, 309 (MHϩ); H-NMR (DMSO-d6) d 3.79 (s, 2H, CH2),
5.82 (b, 2H, NH2), 6.99 (d, 1H, C-6H), 7.21 (m, 1H, CЈ-6H), 7.43 (m, 1H,
CЈ-2H), 7.46 (m, 1H, CЈ-5H), 10.38 (s, 1H, OH), 11.28 (s, 1H, OH).
2-Amino-3H,5H-7-(m-nitrobenzyl)pyrrolo[3,2-d]pyrimidin-4-one (19): 15%

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yield from method B in the solvent of triflic acid; mp 190 °C; MS m/z, 285
(Mϩ); 1H-NMR (DMSO-d6) d 4.05 (s, 2H, CH2), 7.33 (s, 2H, C-6H), 7.57 (t,
1H, CЈ-5H), 7.70 (d, 1H, Jϭ6.9 Hz, CЈ-6H), 8.06 (d, 1H, Jϭ7.5 Hz, CЈ-4H),
8.11 (s, 1H, CЈ-2H), 12.4 (s, 1H, NH). Anal. Calcd for C13H11N5O3·
1.4CF3COOH·0.5H2O: C, 41.81; H, 3.28; N, 15.43. Found: C, 41.80; H,
3.15; N, 15.27.
2-Amino-3H,5H-7-(p-methoxybenzyl)pyrrolo[3,2-d]pyrimidin-4-one
(20): 21% yield from method B using p-methoxybenzyl bromide as alkylat-
ing agents at 80 °C for 24 h; mp 275 °C, decomposed; 1H-NMR (DMSO-d6)
d 3.68 (s, 3H, OCH3), 3.71 (s, 2H, CH2), 5.82 (s, 2H, NH2), 6.78 (d, 2H,
Jϭ8.5 Hz, CЈ-3, CЈ-5H), 6.86 (d, 1H, Jϭ2.5 Hz, C-6H), 7.13 (d, 2H,
Jϭ9 Hz, CЈ-2H, CЈ-6H), 10.4 (b, 1H, NH), 11.19 (s, 1H, NH). Anal. Calcd
for C14H14N4O2·0.8CH3COOH: C, 58.85; H, 5.46; N, 17.60. Found: C,
59.22; H, 5.17; N, 17.27.
References
1) Carson D. A., Carrera C. J., Semin Hematol., 27, 260—269 (1990).
2) Gilbertsen R. B., Josyula U., Sircar J. C., Dong M. K., Wu W. S.,
Wilburn D. J., Conroy M. C., Biochem. Pharmacol., 44, 996—999
(1992).
3) Montgomery J. A., Niwas S., Rose J. D., Secrist 3rd J. A., Babu Y. S.,
Bugg C. E., Erion M. D., Guida W. C., Ealick S. E., J. Med. Chem., 36,
55—69 (1993).
4) Secrist 3rd J. A., Niwas S., Rose J. D., Babu Y. S., Bugg C. E., Erion
M. D., Guida W. C., Ealick S. E., Montgomery J. A., J. Med. Chem.,
36, 1847—1854 (1993).
5) Erion M. D., Niwas S., Rose J. D., Ananthan S., Allen M., Secrist 3rd
J. A., Babu Y. S., Bugg C. E., Guida W. C., Ealick S. E., Montgomery
J. A., J. Med. Chem., 36, 3771—3783 (1993).
7-Benzoyl-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (21): 13% yield from
method A-1; mp Ͼ300 °C; MS m/z, 239 (Mϩ); 1H-NMR (DMSO-d6) d 7.49
(t, 2H, Jϭ7 Hz, CЈ-3H, CЈ-5H), 7.59 (t, 1H, Jϭ7.5 Hz, CЈ-4H), 7.79 (d, 2H,
Jϭ7.5 Hz, CЈ-2H, CЈ-6H), 7.86 (d, 1H, Jϭ3.5 Hz, C-6H), 7.91 (s, 1H, C-
2H). Anal. Calcd for C13H9N3O2·0.1CF3SO3H: C, 61.88; H, 3.61; N, 16.53.
Found: C, 62.18; H, 3.58; N, 16.31.
6) Niwas S., Chand P., Pathak V. P., Montgomery J. A., J. Med. Chem.,
37, 2447—2480 (1994).
7) Sircar J. C., Kostlan C. R., Gilbertsen R. B., Bennett M. K., Dong M.
K., Cetenko W. J., J. Med. Chem., 36, 1605—1609 (1992).
8) Klein R. S., Lim M.-I., Tam S. Y.-K., Fox J. J., J. Org. Chem., 43,
2536—2539 (1978).
7-(3Ј,4Ј-Dichlorobenzoyl)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one
(22):
9) Imai K. I., Chem. Pharm. Bull., 12, 1030—1042 (1964).
15% yield form method A-1; mp 290 °C (decomposed); MS m/z, 308 10) Girgis N. S., Michael M. A., Smee D. F., Alaghamandan H. A., Robins
1
(MHϩ); H-NMR (DMSO-d6) d 7.75 (m, 2H, CЈ-5H, CЈ-6H)), 7.90 (s, 1H,
R. K., Cottam H. B., J. Med. Chem., 33, 2750—2755 (1990).
C-6H), 7.95 (s, 1H, C-2H), 7.98 (s, 1H, CЈ-2H). Anal. Calcd for 11) a) Rand L., Dolinski R., J. Org. Chem., 31, 3063—3065 (1966); b)
C13H7N3O2Cl2·0.12CF3SO3H: C, 48.31; H, 2.20; N, 12.88. Found: C, 48.29;
H, 2.24; N, 12.51.
Idem, ibid., 31, 4061—4066 (1966).
12) Brown F. J., Cronk L. A., Aharony D., Snyder D. W., J. Med. Chem.,
35, 2419—2439 (1992).
7-Benzyl-9-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (23): 20% yield from
method B; mp 249 °C (decomposed, lit.6) 340 °C, decomposed); MS m/z, 13) Shen Y.-S., Liu H.-X., Wu M., Du W.-Q., Chen Y.-Q., Li N.-P., J. Org.
1
226 (MHϩ); H-NMR (DMSO-d6) d 3.91 (s, 2H, CH2), 7.3 (m, 6H, C-6H,
Chem., 56, 7160—7162 (1991).
14) Kife W. K., Ranganathan P., Zeldin M., J. Org. Chem., 55, 5610—
5613 (1990).
aromatic H), 7.78 (s, 1H, C-2H).
7-(3Ј,4Ј-Dichlorobenzyl)-3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (24): 19%
1
yield from method B; mp 275 °C (decomposed); MS m/z, 294 (MHϩ); H- 15) Furneaux R. H., Tyler P. C., J. Org. Chem., 64, 8411—8412 (1999).
NMR (DMSO-d6) d 3.93 (s, 2H, CH2), 7.26 (m, 2H, C-6H, CЈ-6H), 7.50 (m,
2H, CЈ-2H, CЈ-5H), 7.78 (s, 1H, C-2H). Anal. Calcd for C13H9Cl2N3O·
1/2H2O: C, 53.30; H, 3.17; N, 13.34. Found: C, 52.94; H, 3.09; N, 13.69.
16) Brakta M., Daves G. D., Jr., J. Chem. Soc., Perkin Trans. 1, 1992,
1883—1884.
17) Polonovski M., Pesson M., Bull. Soc. Chim. (France), 1948, 688—694.
18) Morris P. E., Jr., Elliott A. J., Walton S. P., Williams C. H., Mont-
gomery J. A., Nucleoside, Nucleotides, Nucleic Acid, 19, 379—404
(2000).