Synthesis of new 2-substituted 6-hydroxy-8-azapurines (8-azahypoxanthines)

Full text of DOI:10.1023/A:1021222929824

Pharmaceutical Chemistry Journal
Vol. 36, No. 8, 2002
SYNTHESIS OF NEW 2-SUBSTITUTED 6-HYDROXY-8-AZAPURINES
(8-AZAHYPOXANTHINES)
K. V. Kuleshov,1 A. V. Adamov,1 O. G. Rodin,1 V. P. Perevalov,1 and A. R. El’man1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 8, pp. 44 – 46, August, 2002.
Original article submitted March 25, 2002.
There is lasting interest in purines and their aza analogs
because this class of compounds is considered a promising
source of new drugs for the treatment of viral, allergic, tu-
mor, and other disorders [1 – 6]. It was pointed out [7] that
8-azapurines, also possessing a broad spectrum of biological
activity, exhibit much more pronounced antiviral [8],
antitumor [6, 8], and antimicrobial [9] properties as com-
pared to other purines. In particular, 8-aza analogs produced
a 5 – 8 times stronger antiviral effect than the corresponding
9-xylenefuranosylpurines [8].
2 of the pyrimidine ring significantly increased the antialler-
gic activity of 8-azapurin-6-one [7].
One of the most probable reasons for the pronounced bi-
ological activity of purines and 8-azapurines is their ability
to incorporate into the structure of nucleic acids [7], in par-
ticular, RNA [6]. This ability is related to the planar structure
of the purine fragment [10] and, hence, must significantly
depend on the electron properties of these compounds. With
a view to searching for promising biologically active com-
pounds, we have synthesized a series of new derivatives of
9-(o-chlorobenzyl)-6-hydroxy-8-azapurines
The biological activity of purine derivatives depends to a
considerable extent on the structure of the substituents at po-
sitions 2 and 9. For example, 2,6-diamino-9-tolyl-8-azapu-
rines exhibited 15 – 60 times higher cytotoxicity with respect
to Streptococcus faecalis than did the closely related
2.6-diamino-8-tolyl-8-azapurines [9]. At the same time, at-
tachment of a bulky 2-propoxyphenyl substituent at position
(8-azahypoxanthines) containing a bulky substituent at posi-
tion 2 and studied the influence of this substituent on the
electron and spatial characteristics of these molecules.
All methods used for the synthesis of 8-azapurines can
be separated into two groups [7]. One group involves the for-
mation of a triazole ring as a result of the interaction of func-
tional groups bound to the pyrimidine cycle; the other group
involves the formation of a pyrimidine ring via interaction
between the functional groups linked to the triazole cycle.
1
Mendeleev University of Chemical Engineering, Moscow, Russia.
Cl
Cl
N3
Cl
CONH2
CH2
NaN3
OH
CN
N
O
N
N
Ar
S
N
c)
N
H
N
a)
b)
O
O
O
O
KOH
Ar
Cl
+
HS
Ar
S
XXI – XXX
N
H
OEt
N
H
OEt
Cl
I – X
XI – XX
Compound:
I, XI, XXI
II, XII, XXII
4-CH3C6H4
III, XIII, XXIII
2,4-(CH3)2C6H3
IV, XIV, XXIV
Ar =
2-CH3C6H4
V, XV, XXV
2-C2H5C6H4
2,4,6-(CH3)3C6H2
VIII, XVIII, XXVIII
4-C2H5OC6H4
Compound:
Ar =
VI, XVI, XXVI
2-CH3OC6H4
X, XX, XXX
2-CF3C6H4
VII, XVII, XXVII
4-CH3OC6H4
Compound:
Ar =
IX, XIX, XXIX
4-FC6H4
445
0091-150X/02/3608-0445$27.00 © 2002 Plenum Publishing Corporation

446
K. V. Kuleshov
(ethylmercaptoacetate). The yields and physicochemical
characteristics of the target compounds are presented in Ta-
ble 1.
O
As can be seen, the 1H NMR spectra agree well with the
proposed structure. The most characteristic signals in the
spectra are the peaks of methylene protons in positions
a) – c); the chemical shifts remain virtually the same in all
compounds under consideration. Another group if character-
istic peaks represents the signals from hydroxyl and amide
protons. Also clearly distinguished are signals from protons
of the o- and p-methyl substituents in arylacetamide frag-
ments of compounds XXIII and XXIV. For all of the synthe-
sized compounds, integral processing of the spectra showed
strict correspondence between the peak intensities and the
numbers of protons of each type. The whole body of data, in-
cluding the 1H NMR spectra, mass spectra, and distinct melt-
ing points, shows evidence of the high purity of the synthe-
sized 6-hydroxy-8-azapurines XXI – XXX.
C
N
N
N
C
C
N
C
N
C
C
C
S
C
C
CI
C
C
C
C
C
C
N
C
C
C
C
O
C
O
C
Fig. 1. Electrostatic potential distribution in compound XXVI (ini-
tial level, 0.15; increment, 0.03). Solid and dashed lines correspond
to positive and negative values, respectively.
Figure 1 illustrates the spatial structure of the synthe-
sized 8-azahypoxanthines by showing a projection of the
electrostatic potential distribution in compound XXVI
(Ar = o-methoxyphenyl). The calculation was performed
within the framework of the semiempirical PM3 method us-
ing the HyperChem program package (HyperChemÔ is a
trademark of the Hypercube Inc.) with a molecular geometry
optimized with respect to the total energy by the
Polack–Riber method. As can be seen from the electrostatic
potential distribution, the region of electronegative atoms of
the azapurine fragment retains increased electron density.
This may indicate that the molecules under consideration can
form hydrogen bonds, facilitating their incorporation into the
structure of nucleic acids. Additional evidence of this ability
is provided by the fact that the azahypoxanthine fragment re-
tains a planar structure [10]. Another feature to be noted is
the high electron density on the oxygen atom of the
acetamide fragment. This charged center can additionally fa-
vor the formation of hydrogen bonds and provide for the pos-
Syntheses of the first group are based on the classical method
of W. Traube, nitrosation of 4,5-diaminopyrimidines, which
implies the use of rather complicated initial reactants. In the
second group of methods, one of the most attractive proce-
dures is the synthesis of 8-azapurine from cyanacetamide,
azide, and ester, which allows using relatively simple initial
compounds. Moreover, by using such a pathway, it is possible
to exclude isolation of the intermediate triazole and conduct a
“one-pot” synthesis. For these reasons, we selected this
method for obtaining the target compounds (XXI – XXX).
The initial o-chlorobenzyl azide was synthesized from
o-chlorobenzyl chloride and sodium azide, while esters
XI – XX were obtained using chloroacetanilides (I – X) sub-
stituted at the aromatic ring and 2-thioglycolic acid ethyl ester
TABLE 1. Parameters of the 1H NMR Spectra of 2-({[3-(2-Chlorobenz)-7-hydroxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]me-
thyl}subfanil)-N-arylacetamides (XXI – XXX)
Initial
Molecular
weight
Yield,*
%
Mass spectrum: m/z (Irel)
Compound
chloroace-
tanilide
M.p., °C
Empirical formula
XXI
454
454
468
482
468
470
470
484
458
508
I
II
29.0
26.0
34.0
43.0
34.0
30.0
47.8
30.0
28.0
26.0
169.0 – 170.5
178.0
454 (2), 275 (44),125 (83), 106 (100)
454 (2), 275 (29),125 (82), 106 (100)
468 (2), 275 (35),125 (89), 120 (100)
482 (3), 275 (59),134 (100), 125 (98)
468 (1), 275 (38),125 (100), 106 (78)
470 (4), 275 (51),165 (66), 125 (100)
470 (3), 275 (28),165 (55), 125 (100)
484 (3), 275 (22),137 (51), 108 (100)
458 (2), 275 (45),125 (100), 111 (94)
508 (3), 275 (41),168 (40), 125 (100)
C21H19ClN6O2S
C21H19ClN6O2S
C22H21ClN6O2S
C23H23ClN6O2S
C22H21ClN6O2S
C21H19ClN6O3S
C21H19ClN6O3S
C22H21ClN6O3S
C20H16ClFN6O2S
C21H16ClF3N6O2S
XXII
XXIII
XXIV
XXV
III
IV
V
170.0 – 172.0
180.0
154.0 – 155.0
165.0 – 167.0
183.0 – 184.5
179.5 – 182.0
167.0 – 168.0
159.0 – 161.0
XXVI
XXVII
XXVIII
XXIX
XXX
VI
VII
VIII
IX
X
* Calculated for initial cyanoacetamide.

Synthesis of New 2-Substituted 6-Hydroxy-8-azapurines (8-Azahypoxanthines)
447
TABLE 2. 1H NMR Spectra of 2-({[3-(2-Chlorobenz)yl-7-hydroxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]methyl}sulfanil)-N-arylacetamides
(XXI – XXX)
Proton chemical shift d, ppm
Compound
–CH3
–CH2CH3 (a)–CH2
(b)–CH2
(c)–CH2
Harom
–NH
–OH
12.62 s
XXI
2.18 s (o–CH3)
2.25 s (n-CH3)
–
–
–
3.52 s
3.45 s
3.50 s
3.88 s
3.83 s
3.88 s
5.72 s
5.64 s
5.72 s
7.03 – 7.51 m
7.06 – 7.51 m
6.91 – 7.52 m
9.28 s
9.82 s
9.20 s
XXII
XXIII
12.60 s
12.61 s
2.15 s (o-CH3)
2.23 s (p-CH3)
XXIV
2.10 s (6H, o-CH3)
2.22 s (3H, p-CH3)
–
3.49 s
3.88 s
5.80 s
6.86 – 7.52 m
9.20 s
12.65 s
XXV
1.11 t (o-CH2CH3)
3.78 s (o-OCH3)
3.73 s (p-OCH3)
1.31 t (p-OCH2CH3)
–
2.57 q
3.52 s
3.60 s
3.45 s
3.43 s
3.47 s
3.55 s
3.87 s
3.83 s
3.85 s
3.83 s
3.84 s
3.85 s
5.73 s
5.61 s
5.68 s
5.68 s
5.68 s
5.77 s
7.11 – 7.51 m
6.82 – 7.95 m
6.83 – 7.50 m
6.81 – 7.50 m
7.07 – 7.53 m
7.28 – 7.73 m
9.28 s
9.11 s
9.80 s
9.76 s
9.97 s
9.52 s
12.65 s
12.63 s
12.63 s
12.60 s
12.61 s
12.65
XXVI
XXVII
XXVIII
XXIX
XXX
–
–
3.99 q
–
–
–
sibility of interacting with electrophilic molecules. The max-
imum negative charge (calculated value, –0.355) is concen-
trated at the carbonyl oxygen atom, which agrees with the
electrostatic potential distribution in the compound under
consideration. Apparently, the synthesized 8-azahypoxan-
thines are rather polar compounds, as evidenced by a rela-
tively high calculated dipole moment (m = 3.18 D).
tilled off in vacuum to leave the target ester (oily liquid),
which can be used without additional purification. The esters
are analyzed by TLC on plates eluted with a methylene chlo-
ride – n-hexane (18 : 1) solvent mixture.
General method for the synthesis of 2-({[3-(2-chloro-
benzyl)-7-hydroxy-3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-
yl]methyl}sulfanil)-N-arylacetamides (XXI – XXX). To a
solution of 10 mmole of metallic sodium in isopropyl alcohol
is added 5 mmole of cyanacetamide and about 7 mmole of
o-chlorobenzyl azide and the reaction mass is boiled for 2 h.
Then 5 mmole of an ester (XI – XX) is added and the mix-
ture is boiled for 4 h. The solvent is distilled off in vacuum,
and the residue is diluted with water and acidified with acetic
acid to pH 7, which leads to the formation of a crystalline
product suspended in an oily medium. The target product is
purified by recrystallization from an acetone – methanol
(9 : 1) mixture.
EXPERIMENTAL PART
o-Chlorobenzyl azide and esters XI – XX were used
without additional purification. The final products XXI –
XXX were purified by recrystallization. The purity of sub-
stances was checked by TLC on Sorbfil plates, with the spots
revealed by exposure to iodine vapor and UV radiation
(l = 254 nm). The melting points are listed in Table 1. The
1H NMR spectra were measured on a Bruker WM-250 spec-
trometer (working frequency, 250 MHz) using DMSO as the
solvent and TMS as the internal standard. The mass spectra
were obtained on a Kratos MS-790 instrument at an electron
impact ionization energy of 70 eV.
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