Synthesis of novel pyrazolo[3,4-d]pyrimidines peri-fused with 1,4-diazepine, 1,4-thiazepine, and 1,2,4-triazepine rings

Article abstract of DOI:10.1002/jhet.724

A simple and efficient synthesis of novel ortho- and peri-annulated heterocyclic systems-2,6,7,9-tetrahydro-8H-pyrazolo[5,4,3-de]pyrimido[4,5-e][1, 4]diazepine, 2,6,7,9-tetrahydro-8H-pyrazolo[5,4,3-de]pyrimido [5,4-f][1,4]thiazepine, and 6,9-dihydro-2H-pyrazolo[3,4,5-ef]pyrimido[5,4-f][1, 2,4]triazepine is described. Copyright

Full text of DOI:10.1002/jhet.724

March 2012
Synthesis of Novel Pyrazolo[3,4-d]pyrimidines peri-Fused with
315
1
,4-Diazepine, 1,4-Thiazepine, and 1,2,4-Triazepine Rings
Viktoras Masevicius, Robertas Juskenas, and Sigitas Tumkevicius*
Department of Organic Chemistry, Vilnius University, Naugarduko 24,
LT-03225 Vilnius, Lithuania
*
E-mail: sigitas.tumkevicius@chf.vu.lt
Received July 9, 2010
DOI 10.1002/jhet.724
Published online 19 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient synthesis of novel ortho- and peri-annulated heterocyclic systems—2,6,7,9-tetrahy-
dro-8H-pyrazolo[5,4,3-de]pyrimido[4,5-e][1,4]diazepine, 2,6,7,9-tetrahydro-8H-pyrazolo[5,4,3-de]pyrimido
[
5,4-f][1,4]thiazepine, and 6,9-dihydro-2H-pyrazolo[3,4,5-ef]pyrimido[5,4-f][1,2,4]triazepine is described.
J. Heterocyclic Chem., 49, 315 (2012).
INTRODUCTION
crystallization conditions or heating in 1,4-dioxane eas-
ily underwent cyclization to pyrazolo[3,4-d]pyrimidine 3
The importance of fused pyrimidines, which are com-
mon sources for the development of new potential thera-
peutic agents, is well known. Among them, the pyra-
zolo[3,4-d]pyrimidine and their tricyclic relatives are
of considerable interest. They are reported to possess
tyrosine kinase inhibitory [1–3], antimicrobial [4,5],
antifungal [6], adenosine deaminase inhibitory [7,8],
antibacterial [9], DNA polimerase III inhibitory [10],
antihypertensive [11], and anticancer [12] activities.
Some derivatives are useful in DNA sequencing [13] or
as antiproliferative and proapoptotic agents toward some
cancer cells [14,15]. Pyrazolo[3,4-d]pyrimidine nucleo-
sides fused with azepinone moiety were expected to
form base pairs with deoxythymidine or 2,6-diaminopur-
ine [16]. In this context and continuing our studies on
the synthesis of fused pyrimidine heterocycles [17–19]
with anticipated biological and pharmaceutical activities,
we report herein a synthesis of hitherto unreported het-
erocyclic systems containing pyrazolo[3,4-d]pyrimidine
framework.
[
21] (Scheme 1). To obtain compounds 3 and 4 useful
for further cyclization reactions, we reinvestigated the
interaction of 1 with methylhydrazine. It was found that
formation of 3 takes place already at room temperature,
when the reaction of 1 with 2 equivalents of methylhy-
drazine is carried out for several hours. After 4 h, pyra-
zolo[3,4-d]pyrimidine 3 was obtained in 76% yield.
Performing the reaction of 1 with five equivalents of
methylhydrazine at room temperature gave 3-amino-1-
methyl-4-(1-methylhydrazino)-6-methylthiopyrazolo[3,4-
d]pyrimidine (4) in 85% yield already after 1.5 h.
Compound 4 was also obtained by treatment of 3 with
an excess of methylhydrazine at room temperature
1
(
Scheme 1). In the H NMR spectrum of compound 4,
additional signals of methyl and amino groups at 3.34
ppm and 6.32 ppm, respectively, are observed when
13
C
compared with the spectrum of compound 3. The
NMR spectrum of 4 is characterized by an additional
N–Me signal at 41.1 ppm.
In our preliminary communication [22], we reported
on an unexpected course of the reaction of methyl N-(6-
chloro-2-methylthiopyrimidin-4-yl)-N-methylaminoetha-
noate (5) [17] with methylhydrazine to give tricyclic
heterocycle—pyrazolo[5,4,3-de]pyrimido[4,5-e][1,4]dia-
zepine (6) (Scheme 2). The same derivative 6 was also
obtained by the reaction of 4-chloro-6-methylthiopyra-
zolo[3,4-d]pyrimidin-3-amine (3) with methyl N-meth-
ylaminoethanoate in the presence of potassium carbon-
ate at reflux temperature of tetrahydrofuran (THF). To
RESULTS AND DISCUSSION
For the synthesis, an easily available 4,6-dichloro-2-
methylthiopyrimidine-5-carbonitrile (1) [20] has been
used as starting material. Earlier, we reported that com-
pound 1 under the treatment with a slight excess of
methylhydrazine in several minutes forms 4-(1-methyl-
hydrazino)pyrimidine-5-carbonitrile 2, which under the
V
C
2011 HeteroCorporation

3
16
V. Masevicius, R. Juskenas, and S. Tumkevicius
Vol 49
Scheme 1
expand this methodology for the synthesis of similar
ortho- and peri-fused heterocycles, compound 3 was
treated with methyl aminoethanoate. However, under
conditions described for the synthesis of 6, only starting
materials were recovered. Heating the reaction mixture
dine 7. Attempts to stop the reaction at the formation of
hydrazinopyrimidine 12 failed. Compound 12 appeared
to undergo smooth cyclization to pyrazolopyrimidine 7
even under the isolation procedures or under purification
by column chromatography and as a result mixtures of
12 and 7 were always obtained. Nevertheless, this mix-
ture can be used for the synthesis of 10. Thus, heating
of the mixture of 7 and 12 in glacial acetic acid afforded
compound 10 in 52% yield. Taking into account these
results we decided to perform the synthesis of 10 by
one-pot procedure using tandem substitution/annulation
reactions of compound 11 with methylhydrazine. Com-
pound 11 reacted with an excess of methylhydrazine at
room temperature, then glacial acetic acid was added,
and the reaction mixture was refluxed for 13 h to give
compound 10.
ꢀ
at 100 C in dimethylformamide (DMF) in the presence
of potassium carbonate led to the substitution reaction
product 7. Formation of ortho- and peri-annulated hetero-
cycle was not observed. Conversely, the reaction of 3 with
methyl mercaptoethanoate under the analogous conditions
ꢀ
(
K CO /DMF/90 C) proceeded with the formation of 2-
2
3
methyl-4-methylthio-2,6,7,9-tetrahydro-8H-pyrazolo [5,4,3-
de]pyrimido[5,4-f][1,4]thiazepin-8-one (8). The same reac-
tion under milder reaction conditions (K CO /THF/D) gave
2
3
the substitution product 9.
Intramolecular cyclocondensation reaction of methyl
N-(3-amino-6-methylthiopyrazolo[3,4-d]pyrimidin-4-yl)
aminoethanoate (7) to form tricyclic heterocycle 10
under basic conditions was not successful. The reason
for such behavior, probably, is the formation of an
unreactive anion in the reaction of 7 with bases due to
rather acidic NH group in the aminoethanoate side
chain. We have found that conversion of 7 into 10 can
be achieved under acidic conditions. Thus, heating of
compound 7 in acetic acid gave the desired diazepine 10
in 62% yield. This prompted us to elaborate a more effi-
cient method for the preparation of the desired tricyclic
system 10. For this purpose, compound 11 was synthe-
sized by the reaction of 1 with methyl aminoethanoate
in the presence of sodium carbonate. Reaction of 11
with methylhydrazine proceeded with the formation of a
mixture of substitution product 12 and pyrazolopyrimi-
Amino and hydrazino groups in compound 4 are
properly positioned for construction of a triazepine moi-
ety with one carbon electrophile. Indeed, when 4 reacted
with an excess of triethyl orthoformate in the presence
of ammonium chloride as an acidic catalyst, pyrazolo-
[3,4,5-ef]pyrimido[5,4-f][1,2,4]triazepine was formed
(Scheme 3).
Cyclocondensation of compound 4 with triethyl ortho-
formate can give either heterocycle 13 or isomeric triaze-
1
pine 13a. We expected that simple H NMR NOE experi-
ment showing interaction between protons of NACH and
3
NH groups could be an effective method to elucidate the
structure of an isomer formed in the reaction. However, a
signal of protons of NACH group partially overlapped
3
with a signal of residual water in DMSO-d (because of
6
low solubility of compound 13, NOE experiment was not
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Synthesis of Novel Pyrazolo[3,4-d]pyrimidines peri-Fused with 1,4-Diazepine,
317
1,4-Thiazepine, and 1,2,4-Triazepine Rings
Scheme 2
Reagents and conditions: (i) MeNHNH
ꢀ
2
, MeOH, 4 days, room temperature; (ii) MeNHCH
ꢀ
2
CO
2
MeꢁHCl, K
CO Me, K
, MeOH 1 h, , room temperature; (ix) 1. MeNHNH
2
CO
3
, THF, 8 h, D; (iii) NH
3
, THF, 6 h, D; (vi) AcOH, 1.5 h,
2
CH
2
CO2-
MeꢁHCl, K
2
CO
3
, DMF, 2 h, 100 C; (iv) HSCH
2
CO
2
Me, K
2
CO
3
, DMF, 5.5 h, 90 C; (v) HSCH
2
2
2
CO
ꢀ
6
0 C; (vii) NH
2
CH
2
CO
2
MeꢁHCl, Na
2
CO
3
, MeOH, 0.5 h, room temperature; (viii) MeNHNH
2
2
,
MeOH, 75 min, room temperature; 2. AcOH, 12 h, D.
possible to carry out in other solvents), and the experi-
ment could not give trustworthy results. Nevertheless, per-
NH groups. This together with the earlier obtained results
on an analogous reaction in the thieno[2,3-d]pyrimidine
series [23] allowed to conclude that formation of deriva-
tive 13 took place.
1
formed long range H- H COSY NMR experiment did
1
not show any interaction between protons of NACH and
3
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

3
18
V. Masevicius, R. Juskenas, and S. Tumkevicius
Vol 49
CONCLUSIONS
In summary, we have developed a simple and effi-
was added. The mixture was stirred at room temperature for
.5 h and then water was added. The resulting solid was fil-
tered off, washed with diethyl ether, and dried in drying pis-
0
cient methods for the preparation novel ortho- and peri-
fused heterocyclic systems consisting of structural units of
pyrimidine, pyrazole, and 1,4-diazepine, 1,4-thiazepine, or
ꢀ
tol to give 0.18 g (58%) of compound 4, mp 250–251 C.
2,6-Dimethyl-4-methylthio-2,6,7,9-tetrahydro-8H-pyra-
zolo[5,4,3-de]pyrimido[4,5-e][1,4]diazepin-8-one (6). To
solution of compound 3 (0.10 g, 0.44 mmol) in THF (10 mL),
methyl N-methylaminoethanoate hydrochloride (0.09 g, 0.65
mmol) and potassium carbonate (0.18 g, 1.30 mmol) were
added. The mixture was refluxed for 8 h and cooled to room
temperature. Then, water was added to the reaction mixture
and the resulting precipitate was filtered off, dried, and recrys-
1
,2,4-triazepine. Tandem substitution/annulation reactions
of 3-amino-4-chloro-6-methylthiopyrazolo[3,4-d]pyrimi-
dine with methyl N-methylaminoethanoate or mercaptoe-
thanoate to give 2,6,7,9-tetrahydro-8H-pyrazolo[5,4,3-
de]pyrimido[4,5-e][1,4]diazepin-8-one and –[5,4-f][1,4]
thiazepin-8-one, respectively, were found to proceed under
basic conditions, whereas the lactam formation of methyl
N-(3-aminopyrazolo[3,4-d]pyrimidin-4-yl)aminoethanoate
can be achieved under acidic conditions. The chemical
potential of these novel heterocycles described herein
are currently under investigation.
ꢀ
tallized to give 0.08 g (70%) of compound 6, mp 264–268 C
1
(dec.) (from benzene). H NMR (DMSO-d
): d 2.54 (s, 3H,
6
SCH
CH ), 11.23 (s, 1H, NH). C NMR (DMSO-d
7.0, 60.0, 91.9, 141.0, 154.1, 159.1, 167.2, 170.4. IR, cm
344 (NH), 1670 (CO). Anal. Calcd. for C H N OS: C,
3
), 3.19 (s, 3H, NCH
3
), 3.75 (s, 3H, NCH ), 4.20 (s, 2H,
3
1
3
2
6
): d 14.3, 33.7,
ꢂ1
3
3
4
:
10 12 6
5.44; H, 4.58; N, 31.80. Found: C, 45.77; H, 4.97; N, 32.18.
Methyl N-[3-amino-1-methyl-6-methylthio-1H-pyrazolo
3,4-d] pyrimidin-4-yl]aminoethanoate (7). To a solution of
EXPERIMENTAL
[
General. Melting points were determined in open capillaries
using digital melting point IA9100 series apparatus (Fischer
Scientific) and are uncorrected. Infrared (IR) spectra were run
on a Perkin-Elmer FT-IR spectrophotometer Spectrum BX II
compound 3 (0.10 g, 0.43 mmol) in DMF (5 mL), methyl ami-
noethanoate hydrochloride (0.08 g, 0.65 mmol) and potassium
carbonate (0.16 g, 1.18 mmol) was added. The mixture was
ꢀ
stirred at 100 C for 2 h and cooled to room temperature.
1
13
in KBr. H NMR and C NMR spectra were recorded on a
Varian Unity Inova spectrometer (300 and 75 MHz, respec-
tively) using residual solvents signals as internal standard. All
reactions and purity of the synthesized compounds were moni-
tored by TLC using Silica gel 60 F254 aluminium plates
Then, water was added and the product was extracted with
dichloromethane. Solvent was evaporated under reduced pres-
sure and the residue was recrystallized to give 0.03 g (24%) of
ꢀ
1
compound 7, mp >200 C (dec.) (from benzene). H NMR
(DMSO-d ): d 2.42 (s, 3H, SCH ), 3.57 (s, 3H, NCH ), 3.66
(s, 3H, OCH ), 5.78 (br s, 2H,
), 4.17 (d, J ¼ 5.7, 2H, CH
NH ): d 14.0,
6
3
3
(Merck). Visualization was accomplished by UV light.
3
2
1
3
4-Chloro-1-methyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-3-
amine (3). To a solution of compound 1 (2.00 g, 9.09 mmol)
2
), 7.93 (t, J ¼ 5.7, 1H, NH). C NMR (CDCl
3
33.1, 42.8, 52.4, 88.4, 147.6, 154.3, 156.0, 168.4, 171.4. IR,
cm : 3379, 3355, 3270 (NH, NH
ꢂ1
in methanol (70 mL), a solution of methylhydrazine (0.99 mL,
.86 g, 18.6 mmol) in methanol (10 mL) was added dropwise.
2
), 1730 (CO). Anal. Calcd.
S: C, 42.54; H, 5.00; N, 29.77. Found: C,
0
for C10
H
14
N
42.85; H, 5.26; N, 30.07.
6
O
2
The mixture was stirred at room temperature for 4 h, the pre-
cipitate was filtered off, dried, and recrystallized to give 1.58 g
2-Methyl-4-methylthio-2,6,7,9-tetrahydro-8H-pyrazolo[5,4,3-
de]pyrimido[5,4-f][1,4]thiazepin-8-one (8). To a solution of
compound 3 (0.20 g, 0.87 mmol) in DMF (10 mL), methyl
mercaptoethanoate (0.082 mL, 0.10 g, 0.91 mmol) and anhy-
drous potassium carbonate (0.13 g, 0.96 mmol) were added.
ꢀ
(
[
1
76%) of compound 2, mp 188–189 C (from 2-propanol). Lit.
ꢀ
13
21]: mp 190–192 C. C NMR (CDCl
3
): d 14.7, 33.4, 100.8,
). Anal.
ꢂ1
46.7, 153.1, 153.9, 170.8. IR, cm : 3467, 3287 (NH
2
Calcd. for C
.78.
-Methyl-4-(1-methylhydrazino)-6-methylthio-1H-pyra-
7 8 5
H ClN S: C, 36.60; H, 3.51. Found: C, 36.85; H,
ꢀ
3
The mixture was stirred at 90 C for 5.5 h. Then, water was
added, and the precipitate formed was filtered off, dried, and
recrystallized to give 0.14 g (60%) of compound 8, mp
1
zolo[3,4-d]pyrimidin-3-amine (4).
ꢀ
1
265 C (dec.) (from acetonitrile). H NMR (DMSO-d
>
6
): d
),
A. To a solution of compound 1 (0.50 g, 2.27 mmol) in THF
2
11.26 (s, 1H, NH). C NMR (DMSO-d
.58 (s, 3H, SCH ), 3.84 (s, 3H, NCH ), 4.00 (s, 2H, CH
3
3
2
13
(
25 mL), methylhydrazine (0.6 mL, 0.52 g, 11.3 mmol)
6
): d 14.4, 33.8, 35.2,
103.6, 140.8, 152.5, 167.9, 168.2, 169.4. IR, cm : 3092
ꢂ1
was added. The mixture was stirred at room temperature
for 1.5 h and then water (25 mL) was added. THF was
evaporated under reduced pressure, the resulting solid was
filtered off, washed with diethyl ether, and dried in drying
pistol to give 0.46 g (85%) of compound 4, mp 250–
9 9 5 2
(NH), 1670 (CO). Anal. Calcd. for C H N OS : C, 40.44; H,
3.39; N, 26.20. Found: C, 40.26; H, 3.60; N, 26.22.
Methyl (3-amino-1-methyl-6-methylthio-1H-pyrazolo[3,4-
d] pyrimidin-4-yl)thioethanoate (9). To a solution of com-
pound 3 (0.10 g, 0.44 mmol) in THF (5 mL), methyl mercap-
toethanoate (0.046 mL, 0.055 g, 0.52 mmol) and anhydrous
potassium carbonate (0.072 g, 0.52 mmol) were added. The
mixture was refluxed for 6 h and cooled to room temperature.
Then, water was added, and the resulting precipitate was fil-
tered off, dried, and recrystallized to give 0.108 g (83%) of
ꢀ
1
2
51 C. H NMR (DMSO-d
6 3
): d 2.47 (s, 3H, SCH ), 3.34
(
s, 3H, NCH ), 3.57 (s, 3H, NCH ), 5.48 (s, 2H, NH ),
3
3
2
1
3
6
4
3
4
.32 (s, 2H, NH2). C NMR (DMSO-d ): d 14.1, 33.1,
6
ꢂ1
1.1, 87.8, 148.4, 155.0, 159.1, 167.0. IR, cm : 3407,
250, 3147 (2ꢃNH
2 8 7
). Anal. Calcd. for C H13ClN S: C,
0.15; H, 5.48. Found: C, 40.29; H, 5.58.
ꢀ
1
B. To a solution of compound 3 (0.30 g, 1.31 mmol) in THF
15 mL), methylhydrazine (0.208 mL, 0.18 g, 3.92 mmol)
compound 9, mp 168–169 C (from 2-propanol). H NMR
(DMSO-d ): d 3.65 (s, 3H, NCH ), 3.68 (s, 3H, OCH ), 4.21
(
6
3
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Synthesis of Novel Pyrazolo[3,4-d]pyrimidines peri-Fused with 1,4-Diazepine,
,4-Thiazepine, and 1,2,4-Triazepine Rings
319
1
(
sidual DMSO signals; C NMR (DMSO-d
s, 2H, CH
2
), 5.55 (s, 2H, NH
1
2
), SCH
3
signal overlaps with re-
): d 14.4, 31.2,
¼ 5.7 Hz, 2H, CH
2
); 5.06 (s, 2H, NH
2
); 7.31 (t, J ¼ 5.7
3
6
Hz, 1H, NH).
ꢂ1
33.1, 35.2, 100.9, 146.8, 152.5, 161.5, 169.3, 169.5. IR, cm
3287, 3165 (NH2), 1740 (CO). Anal. Calcd. for
:
2,6-Dimethyl-4-methylthio-6,9-dihydro-2H-pyrazolo[3,4,5-
ef]pyrimido[5,4-f][1,2,4]triazepine (13). To a suspension of 9
(0.10 g, 0.42 mmol) in dioxane (5 mL), triethyl ortoformate
(0.35 mL, 0.31 g, 2.1 mmol) and ammonium chloride (0.11 g,
2.1 mmol) were added. The mixture was refluxed for 13 h and
then cooled to room temperature. Water was added; the result-
ing precipitate was filtered off and dried to give 0.07 g (67%)
C H N O S : C, 40.12; H, 4.38, N; 23.39. Found: C, 40.09;
10 13 5 2 2
H, 4.36; N, 22.85.
-Methyl-4-methylthio-2,6,7,9-tetrahydro-8H-pyrazolo
5,4,3-de]pyrimido[4,5-e][1,4]diazepin-8-one (10).
2
[
ꢀ
1
of compound 13, mp 264–266 C (dec.) (from benzene).
NMR (DMSO-d ): d 2.50 (s, 3H, SCH ), 3.40 (s, 3H, NCH
.72 (s, 3H, NCH
H
A. A solution of compound 7 (0.04 g, 0.14 mmol) in glacial
acetic acid (10 mL) was heated at 60 C for 1.5 h and then
6
3
3
),
ꢀ
3
3
), 6.49 (d, J ¼ 4.2 Hz, 1H, CH), 9.91 (d, J
cooled to room temperature. The resulting precipitate was
filtered off, dried, and recrystallized to give 0.022 g (63%)
13
¼
4.2 Hz, 1H, NH). C NMR (DMSO-d ): d 14.4, 33.6, 39.1,
6
ꢂ1
1
8
4.8, 131.2, 142.1, 152.7, 153.7, 169.6. IR (KBr), cm : 3260,
198 (NH). Anal. Calcd. for C H N S: C, 43.36; H, 4.45.
ꢀ
of compound 10, mp >280 C (dec.) (from DMF).
NMR (DMSO-d ): d 2.51 (s, 3H, SCH ), 3.75 (s, 3H,
NCH ), 8.20 (br s, 1H,
), 4.00 (d, J ¼ 3.3 Hz, 2H, CH
NH), 11.19 (br s, 1H, NHCO). C NMR (DMSO-d ): d
4.2, 33.6, 51.6, 91.5, 141.3, 154.3, 160.3, 167.9, 170.7.
H
3
Found: C, 43.44; H, 4.33.
9
11 7
6
3
3
2
1
3
6
1
REFERENCES AND NOTES
ꢂ1
IR, cm : 3102, 3107 (NH), 1682 (CO). Anal. Calcd. for
OS: C, 43.19; H, 4.03. Found: C, 43.20; H, 4.18.
9 10 6
C H N
[
1] Hanke, J. H.; Gardner, J. P.; Dow, R. L.; Changelian, P. S.;
B. A solution of a mixture of compounds 7 and 12 (0.2 g) in
glacial acetic acid (10 mL) was heated at 60 C for 75 min
Brissette, W. H.; Weringer, E. J.; Pollok, B. A.; Connelly, P. A. J Biol
Chem 1996, 271, 695.
ꢀ
and then cooled to room temperature. The resulting precip-
itate was filtered off, dried, and recrystallized to give
0.092 g (52%) of compound 10, mp >280 C (dec.) (from
DMF).
[2] Bishop, A. C.; Kung, C.; Shah, K.; Witucki, L.; Shokat, K.
M.; Liu, Y. J Am Chem Soc 1999, 121, 627.
ꢀ
[3] Bain, J.; Plater, L.; Elliott, M.; Shpiro, N.; Hastie, C. J.;
McLauchlan, H.; Klevernic, I.; Arthur, J. S. C.; Alessi, D. R.; Cohen,
P. Biochem J 2007, 408, 297.
C. To a suspension of compound 11 (0.05 g, 0,183 mmol) in
methanol (5 mL), methylhydrazine (0.039 mL, 0.034 g,
[
4] Abunada, N. M.; Hassaneen, H. M.; Kandile, N. G.; Miq-
dad, O. A. Molecules 2008, 13, 1501.
5] Abdel-Gawad, S. M.; Ghorab, M. M.; El-Sharief, A. M. Sh.;
El-Telbany, F. A.; Abdel-Alla, M. Heteroatom Chem 2003, 14, 530.
6] Vicentini, C. B.; Romagnoli, C.; Andreotti, E.; Mares, D.
J Agric Food Chem 2007, 55, 10331.
7] La Motta, C.; Sartini, S.; Mugnaini, L.; Salerno, S.; Simor-
0
.734 mmol) was added. The mixture was stirred at room
[
temperature for 75 min, then glacial acetic acid (0.5 mL)
was added and the reaction mixture was refluxed for 12 h.
After cooling to room temperature the precipitate was fil-
tered off and recrystallized to give 0.014 g (30%) of com-
[
[
ꢀ
pound 10, mp >280 C (dec.) (from DMF).
ini, F.; Taliani, S.; Marini, A. M.; Da Settimo, F.; Lavecchia, A.; Nov-
ellino, E.; Antonioli, L.; Fornai, M.; Blandizzi, C.; Del Tacca, M.
J Med Chem 2009, 52, 1681.
Methyl
N-(6-chloro-5-cyano-2-methylthiopyrimidin-4-
yl)aminoethanoate (11). To a solution of compound 1 (0.40
g, 1.82 mmol) in methanol (15 mL), methyl aminoethanoate
hydrochloride (0.46 g, 3.64 mmol) and sodium carbonate (0.60
g, 5.64 mmol) were added. The mixture was stirred at room
temperature for 0.5 h, then water was added and the resulting
precipitate was filtered off, dried, and recrystallized to give 0.4
[
8] Da Settimo, F.; Primofiore, G.; La Motta, C.; Taliani, S.;
Simorini, F.; Marini, A. M.; Mugnaini, L.; Lavecchia, A.; Novellino,
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2010, 45, 647.
ꢀ
g (81%) of compound 11, mp 173–174 C (from 2-propanol).
[10] Ali, A.; Taylor, G. E.; Ellsworth, K.; Harris, G.; Painter, R.;
Silver, L. L.; Young, K. J Med Chem 2003, 46, 1824.
1
H NMR (CDCl ): d 2.53 (s, 3H, SCH ), 3.84 (s, 3H, OCH ),
3
3
3
13
[
11] Tseng, S. S.; Epstein, J. W.; Levin, J. I. U.S. Patent
,013,737, 1991. Available at: http://www.freepatentsonline.com/
5013737.pdf, accessed July 2009.
12] Kawasaki, A. M.; Wotring, L. L.; Townsend, L. B. J Med
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13] Brown, D.; Loakes, D.; Williams, D.; Hill, F.; Kumar,
4
.32 (d, J ¼ 5.4 Hz, 2H, CH ), 6.23 (br s, 1H, NH). C NMR
2
5
(DMSO-d
6
): d 14.4, 43.6, 52.7, 85.6, 114.3, 161.2, 161.6,
70.2, 175.4. IR, cm : 3277 (NH); 2218 (CN); 1739 (CO).
ꢂ1
1
[
9 9 4 2
Anal. Calcd. for C H N ClO S: C, 39.64; H, 3.33; N, 20.54.
Found: C, 40.16; H, 3.34; N, 20.44.
Methyl N-(3-amino-1-methyl-6-methylthio-1H-pyrazolo[3,4-d]
pyrimidin-4-yl)aminoethanoate (7) and methyl N-[5-cyano-6-(1-
methylhydrazino)-2-methylthiopyrimidin-4-yl]aminoethanoate
[
S.; Nampalli, S.; McDougall, M.; Hamilton, A.; Smith, C.; Sim-
monds, A. C.; Cummins, W. J.; Finn, P. U.S. Patent 6,600,028,
2
003. Available at: http://www.freepatentsonline.com/6600028.pdf,
accessed July 2009.
14] Schenone, S.; Bruno, O.; Bondavalli A, F.; Ranise, A.;
(
12). To a solution of compound 11 (0.2 g, 0.73 mmol) in meth-
anol (10 mL), a solution of methylhydrazine (0.13 mL, 0.108 g,
.35 mmol) in methanol (10 mL) was added dropwise. The mix-
[
2
Mosti, L.; Menozzi, G.; Fossa, P.; Donnini, S.; Santoro, A.; Ziche, M.;
Manetti, F.; Botta, M. Eur J Med Chem 2004, 39, 939.
ture was stirred at room temperature for 1 h, then filtered
through 1 cm silica gel (Merck Silica gel 60, 40–63 lm) layer.
Solvent was evaporated under reduced pressure to give 0.16 g
[
15] Carraro, F.; Naldini, A.; Pucci, A.; Locatelli, G. A.; Maga,
G; Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; Brullo, C.;
Fossa, P.; Menozzi, G.; Mosti, L.; Modugno, M.; Tintori, C.; Manetti,
F.; Botta, M. J Med Chem 2006, 49, 1549.
(
76%) of a mixture of compounds 7 and 12 in a ratio 1:1.
1
Compound 12: H NMR (DMSO-d
6
): d 2.35 (s, 3H,
); 4.08 (d, J
SCH ); 3.26 (s, 3H, NCH ); 3.64 (s, 3H, OCH
3
3
3
[16] Seela, F.; Zulauf, M. J Chem Soc Perkin 1, 1998, 19, 3233.
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[
[
18] Tumkevicius, S.; Masevicius, V. Synlett 2004, 13, 2327.
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