3
Scheme 2. Alternative synthetic approach for the synthesis of substituted pyrazolo[3,4-d]pyrimidine analogues.
When amine hydrochlorides were used in the latter step, a
Acknowledgments
different approach was required to accomplish the C4
nucleophilic substitution: the amine salt was suspended in DMF,
This work was partially supported by National Interest
Research Projects (PRIN_2008_5HR5JK and
added with an excess of triethylamine and finally treated with the
o
intermediate 6a under microwave irradiation at 150 C for 10
PRIN_2010_5YY2HL). Financial support has been also received
from the Istituto Toscano Tumori-ITT-Grant proposal 2010. We
are grateful to Lead Discovery Siena Srl and Cost Action
CM1106 “Chemical Approaches to Targeting Drug Resistance in
Cancer Stem Cells”.
minutes. In these conditions, both C4 nucleophilic substitution
and dehydrohalogenation in the N1 linker occurred, giving the
1,4-disubstituted derivative 8a. On the other hands, an interesting
outcome in the C4 nucleophilic substitution was observed when
reacting intermediate 6a with amine 11 depending on the reaction
conditions used. As previously reported, the C4 substituent of
these C6-unsubstitued pyrazolo[3,4-d]pyrimidines seems to be
solvent exposed upon binding to the target kinases and the
hydrophilic amine 11 was prepared accordingly (the synthesis is
reported in the SI file). Since the AcOH/dioxane substitution
protocol was unsuccessful, probably due to piperazine
protonation, and in order to avoid the dehydrohalogenation in
N1, different reaction conditions were used in the coupling with
11: treatment of 6b under-microwave assisted conditions in the
presence of DIPEA/i-PrOH gave, unexpectedly, compound 9b as
result of a dealkylative substitution instead of the expected
derivative 10b. The formation of 9b was proved to be a direct
consequence of microwave irradiation since standard heating
conditions allowed to obtain compound 10b as the only product.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at
References and notes
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In summary, a versatile approach for the synthesis of 1,4-
disubstituted pyrazolo[3,4-d]pyrimidines has been developed.
Starting from commercially available allopurinol, TBAF
mediated N1-functionalization and subsequent C4 nucleophilic
substitution under different reaction conditions represented the
key steps for the decoration of the pyrazolo[3,4-d]pyrimidine
scaffold. Microwave irradiation drastically reduced the reaction
time need for C4 functionalization and allowed to obtain
compounds (such as 9b) inaccessible under standard heating
conditions. The exploitation of this alternative synthetic protocol
will allow to expand the chemical diversity around the
pyrazolo[3,4-d]pyrimidine scaffold for the identification of novel
potential anticancer agents.
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