High throughput synthesis of extended pyrazolo[3,4-d]dihydropyrimidines

Article abstract of DOI:10.1021/co300063x

Thirteen 5-hetarylaminopyrazoles were synthesized in 62-93% yield through the arylation of 1-isopropyl- and 1-phenyl-5-aminopyrazoles with electrophilic hetarylhalides under optimized conditions. Condensation of 5- hetarylaminopyrazoles with carbonyl compounds facilitated by AcOH or Me ₃SiCl furnished 23 pyrazolo[3,4-d]dihydropyrimidines in 69-86% yield. The target compounds were isolated through simple crystallization. The scope and limitation of the method are discussed.

Full text of DOI:10.1021/co300063x

Research Article
pubs.acs.org/acscombsci
High Throughput Synthesis of Extended
Pyrazolo[3,4-d]dihydropyrimidines
Sergey V. Ryabukhin,*,†,‡ Dmitry S. Granat,‡ Andrey S. Plaskon,‡ Alexander N. Shivanyuk,*,†,§
Andrey A. Tolmachev,∥ and Yulian M. Volovenko‡
†The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov str., Building 5, Kyiv, 03187, Ukraine
‡Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska str., Kyiv, 01601, Ukraine
§The Institute of Pharmacology and Toxicology, The National Academy of Medical Sciences, 14 Ejen Pottier str, Kyiv, 03680,
Ukraine
∥Enamine Ltd., 23 A. Matrosov str., Kyiv, 01103, Ukraine
S
* Supporting Information
ABSTRACT: Thirteen 5-hetarylaminopyrazoles were synthesized in 62−93%
yield through the arylation of 1-isopropyl- and 1-phenyl-5-aminopyrazoles
with electrophilic hetarylhalides under optimized conditions. Condensa-
tion of 5-hetarylaminopyrazoles with carbonyl compounds facilitated by
AcOH or Me3SiCl furnished 23 pyrazolo[3,4-d]dihydropyrimidines in
69−86% yield. The target compounds were isolated through simple
crystallization. The scope and limitation of the method are discussed.
KEYWORDS: aldehydes, aminopyrazoles, dihydropyrimidines, chlorotrimethylsilane, high throughput synthesis
compounds was chosen as the synthetic approach for the exten-
sion of the pyrazolo[3,4-d]pyrimidine ring system (Scheme 1).
INTRODUCTION
■
Pyrazolo[3,4-d]pyrimidine is an isomer of imidazolo[3,4-d]-
pyrimidine (purine), the central core of adenine, cytosine, xanthine
alkaloids, and other important biomolecules.1 Various pyrazolo-
[3,4-d]pyrimidine derivatives have been shown to possess remark-
able biological activities. For example, 1H-pyrazolo[3,4-d]
pyrimidin-4(2H)-one (allopurinol), a drug used for treatment
of hyperurecemia and gout,1 was synthesized through acid
catalyzed condensation of 4-carboxamido-5-aminopyrazole
with formamide.2 The methylation of allopurinol with
methyliodide followed by the reaction with POCl3 resulted in
4-chloro-1-methyl-pyrazolo[3,4-d] pyrimidine which reacted
with 5-substituted oxindoles to give the inhibitors of glycogen
synthase, kinase 3 and cyclin dependent kinase 5.3 The reaction
of 4-chloro-1-methylpyrazolo[3,4-d]pyrimidine with amines
gave a library of inducible nitric oxide synthase inhibitors.4 A
one pot procedure afforded pyrazolo[3,4-d]pyrimidine deriva-
tives possessing potent and selective inhibitory activity against
p38α, EphB4 receptors and VEGFR2 kinase.5 The reaction of
1-methyl-3-cyano-5-aminopyrazole with formamide resulted in
4-aminopyrazolo[3,4-d]-pyrimidine whose oxidation with H2O2
gave the corresponding 5-oxide possessing antitumor activity.6
The extension of pyrazolo[3,4-d]pyrimidine system through
annulation of an additional aromatic ring is a potentially
promising approach to new molecular scaffolds for rational
drug discovery. Herein we report a facile synthesis of extended
pyrazolo[3,4-d]dihydropyrimidines which to the best of our
knowledge have not been described in the literature.7
Scheme 1
RESULTS AND DISCUSSION
■
In the process optimization study aminopyrazoles 1(1−2) were
reacted with halopyridines 2(1−3) under several sets of condi-
tions (Table 1).
Under conditions A (Cs2CO3/LiF/DMF) the reactions of
1(1−2) and 2 (1−3) resulted in formation of mixtures of 3 and
3a or exclusively in compounds 3a (Figure 1). Surprisingly
under conditions B (NaH/DMF/100 °C) 5-aminopyrazoles
1(1) and 1(2) reacted with DMF to give amidines 3b rather
than reacting with 2-halopyridine 2(1), whereas the more
reactive compounds 2(2) and 2(3) were converted to mixtures
of 3 and 3b. In the later case, the minor amounts of 3b could
be removed from the target products 3 through simple
recrystallization.
Received: January 19, 2012
Revised: July 9, 2012
Published: July 9, 2012
The reaction of 5-aminopyrazoles with reactive 2-halo-
genazines or azoles followed by [1 + 5]cyclization with carbonyl
© 2012 American Chemical Society
465
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Research Article
were purified through simple crystallizations. The reactions of
carbonyl compound 4(5) gave noncyclic products 6 (Scheme 2,
Table 3) and the reaction of 4(6−8) failed to give compounds
5 under both sets of conditions most probably due to some side
Table 1. Optimization of Reaction Conditions
reactions.7b Me3SiCl showed somewhat better condensing
−d
activity (entries 1, 6, 7, 12, 29) and therefore was used as water
scavenger in majority of the parallel syntheses.
The structure and composition of compounds 3 and 5 were
1
established through H, 13C and NOE, NMR spectroscopy,
LC-MS and elemental analysis. For example, methine protons
of the dihydropyrimidine ring (H1) in 5{1(1)−2(4)−4(1)}
gave NOE and in 5{1(2)−2(2)−4(1)} gave NOESY cor-
relations to the closest protons both in the pyrazole and in
pyridine rings appropriately (Figure 1). These effects unambig-
uously prove the proposed structure of expended pyrazolo-
[3,4-d]pyrimidines.
More than 500 pyrazolo[3,4-d]dihydropyrimidines were synthe-
sized through the optimized synthetic procedures. Physico chemical
properties of 250 of them (see Experimental Procedures and
Supporting Information) were calculated9 to evaluate their “drug
likeness” (Table 4, Figures 3−8).
Molecular weight and cLogP are the most important
parameters determining the number of “drug-” and “lead-like”
compounds in the library. Molecular weight varies between 282
and 554 Da with mean value of 422 Da, whereas the range of
cLogP is 0.27−7.35 with mean value of 4.18. Figure 9 shows the
distribution of number of pyrazolo[3,4-d]dihydropyrimidines in
Mw cLog P plot. 162 (65%) compounds strictly obey the Lipinsky
rule of 510a and are drug-like: 106, 45, and 6 compounds pass
through finer filters of physicochemical properties suggested by
Oprea,10b Gleeson,10c and Churcher,10d respectively (Figure 9).
yield of
c
yield of
d
yield of
d c
a
a
b
c
entry
1
2
conditions
3 (%)
3a (%)
3b (%)
1
1(1)
2(1)
2(2)
2(3)
2(1)
2(2)
2(3)
A
B
17
2
84
27
6
3
C
D
A
B
71
60
11
58
74
63
14
84
88
58
4
5
5
63
6
7
C
D
A
B
8
23
67
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
C
D
A
B
12
47
1(2)
69
22
11
C
D
A
B
87
64
25
68
83
49
28
82
79
57
13
26
C
D
A
B
26
20
CONCLUSION
■
In conclusion, the reaction of 5-hetarylaminopyrazoles with
carbonyl compounds furnish annulated pyrazolo[3,4-d]-
dihydropyrimidines in preparative yields. The optimized
synthetic and purification procedures allow high throughput
synthesis of extended pyrazolo[3,4-d]dihydropyrimidines bear-
ing various functional groups. The new scaffolds have four
variation points which allow synthesis of large and diverse
combinatorial arrays for high throughput screening of biological
activity. More than 500 compounds of such type have been
synthesized in our laboratories (some examples (221 additional
compounds) are shown in the Supporting Information).
C
D
12
a
b
The pyrazole/pyridine ratio was 1:1 in all experiments. Conditions:
(A) Cs2CO3/LiF/DMF, 100 °C, 12 h; (B) NaH/DMF, 100 °C, 12 h;
(C) NaH/THF, 60 °C, 12 h; (D) t-BuOK/t-BuOH, 60 °C, 12 h.
According to HPLC APCI MS of the reaction mixture Structures of
c
d
compounds 3a and 3b are shown in Figure 1
EXPERIMENTAL PROCEDURES
■
General. All chemicals were obtained from commercially
available sources and used without further purification (Aldrich,
Fluka, Enamine Ltd.). All solvents for the reactions (DMF,
THF, t-BuOH) were freshly distilled and dried by standard
methods, monitoring of the water concentration in solvents
(all solvents had <0.05%, usually 0.02% of water) was per-
formed using Mettler Toledo DL31 KF Titrator. Column
chromatography was performed using Kieselgel Merck 60
(230−400 mesh) as the stationary phase. Melting points were
measured on a Buchi melting point apparatus and are
Figure 1.
The reactions of compounds 1(1,2) and 2(1−10) under
optimal conditions C or B gave 13 compounds 3 in 62−93%
yield (Table 2) which were purified by simple crystallization.
The pyrimidine ring closing reaction of aminopyrazoles 3
and carbonyl compounds 4 were carried out under two sets of
conditions using Me3SiCl8 or AcOH as activators of carbonyl
groups and water scavengers (Table 3). As a result, 36 parallel
syntheses afforded 23 compounds 5 (39−85% yield) which
1
uncorrected. The H NMR spectra were recorded on a Bruker
Avance DRX 500 using DMSO-d6 as a solvent and TMS as an
internal standard. LC/MS spectra were recorded on Agilent
1100 HPLC equipped with diode-matrix and mass-selective
detector Agilent LC\MSD SL. Column, Zorbax SB-C18,
1.8 μm, 4.6 mm ×15 mm. Eluent, A, MeCN−water with
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Table 2. Synthesis of Compounds 3
0.1% of TFA (95:5); B, water with 0.1% of TFA. Flow rate:
1.8 mL/min. The volume of the injected sample was 1 μL. UV-
detectors operate at 215, 254, and 265 nm. Ionization method:
chemical ionization under atmospheric pressure (APCI).
Ionization mode: simultaneous scanning of positive and
negative ions in the mass range of 80−1000 m/z. According
to HPLC/MS data all the synthesized compounds have purity
over 95%.
General Procedures for Arylation of Aminopyrazoles 1.
Method A. Arylating agent 2 (0.01 mol) was added in one por-
tion to the vigorously stirred solution of pyrazole 1 (0.01 mol),
Cs2CO3(0.015 mol), and LiF (0.015 mol) in DMF (30 mL)
in a round-bottom flask. The reaction mixture was heated at
100 °C for 12 h. After it was cooled to r.t., the reaction mixture
was poured into water (300 mL) and was sonicated at r.t. in
ultrasonic bath for 1 h. The precipitate formed was filtered off
and washed with i-PrOH−water (1:1) and recrystallized from
EtOH. In the cases where an oil formed, these were purified by
HPLC on silica (hexane−EtOAc 9:1).
Method B. NaH (0.015 mol, 60% suspension in oil) was
added by four equal portions during 10 min to the vigorously
stirred solution of pyrazole 1 (0.01 mol) in DMF (30 mL) in a
round-bottom flask. The reaction mixture was maintained at r.t.
for 30 min, than arylating agent 2 (0.01 mol) was added in one
portion, and the reaction mixture was heated at 100 °C over 12 h.
Isolation/purification was achieved as described in method A.
Method C. NaH (0.015 mol, 60% suspension in oil) was
added in four equal portions during 10 min to the vigorously
stirred solution of pyrazole 1 (0.01 mol) in THF (50 mL) in a
round-bottom flask. The reaction mixture was maintained at r.t.
for 30 min, than arylating agent 2 (0.01 mol) was added in one
portion, and the reaction mixture was stirred at 60 °C over 12 h.
Isolation/purification was achieved as described in method A.
Method D. t-BuOK (0.012 mol) was added in one equal por-
tion to the vigorously stirred solution of pyrazole 1 (0.01 mol)
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Table 3. [5 + 1] Cyclocondensation of 3 and 4
yield
(%)
a
3
4
product
conditions
7
8
9
3{1(2)−2(5)}
3{1(2)−2(3)}
3{1(2)−2(7)}
4(1) 5{1(2)−2(5)−4(1)}
4(2) 5{1(2)−2(3)−4(2)}
4(2) 5{1(2)−2(7)−4(2)}
4(2) 5{1(2)−2(8)−4(2)}
4(2) 5{1(2)−2(9)−4(2)}
A/B
A
78/49
84
A
76
10 3{1(2)−2(8)}
11 3{1(2)−2(9)}
A
77
A
85
12 3{1(2)−2(10)} 4(2) 5{1(2)−2(10)−4(2)}
A/B
A
81/58
78
13 3{1(2)−2(3)}
14 3{1(2)−2(6)}
15 3{1(2)−2(7)}
16 3{1(2)−2(8)}
4(3) 5{1(2)−2(3)−4(3)}
4(3) 5{1(2)−2(6)−4(3)}
4(3) 5{1(2)−2(7)−4(3)}
4(3) 5{1(2)−2(8)−4(3)}
A
73
A
81
A
83
17 3{1(2)−2(10)} 4(3) 5{1(2)−2(10)−4(3)}
A
85
18 3{1(2)−2(5)}
19 3{1(2)−2(6)}
20 3{1(2)−2(7)}
21 3{1(2)−2(8)}
22 3{1(2)−2(9)}
4(4) 5{1(2)−2(5)−4(4)}
4(4) 5{1(2)−2(6)−4(4)}
4(4) 5{1(2)−2(7)−4(4)}
4(4) 5{1(2)−2(8)−4(4)}
4(4) 5{1(2)−2(9)−4(4)}
A/B
A
84/58
82
A
80
A
83
A
82
yield
(%)
a
3
4
product
conditions
23 3{1(2)−2(10)} 4(4) 5{1(2)−2(10)−4(4)}
A
85
24 3{1(1)−2(1)}
25 3{1(1)−2(2)}
26 3{1(1)−2(3)}
27 3{1(1)−2(4)}
28 3{1(2)−2(2)}
29 3{1(2)−2(5)}
4(5) 6{1(1)−2(1)−4(5)}
4(5) 6{1(1)−2(2)−4(5)}
4(5) 6{1(1)−2(3)−4(5)}
4(5) 6{1(1)−2(4)−4(5)}
4(5) 6{1(2)−2(2)−4(5)}
4(5) 6{1(2)−2(5)−4(5)}
A
64
1
2
3
4
5
6
3{1(1)−2(1)}
3{1(1)−2(2)}
3{1(1)−2(3)}
3{1(1)−2(4)}
3{1(2)−2(1)}
3{1(2)−2(2)}
4(1) 5{1(1)−2(1)−4(1)}
4(1) 5{1(1)−2(2)−4(1)}
4(1) 5{1(1)−2(3)-4(1)}
4(1) 5{1(1)−2(4)−4(1)}
4(1) 5{1(2)−2(1)−4(1)}
4(1) 5{1(2)−2(2)−4(1)}
A/B
A
69/42
82
A
67
A
68
A
84
A
64
A
79
A
68
A
81
A/B
62/32
A/B
86/57
a
Conditions: (A) Me3SiCl, DMF, 100 °C; (B) AcOH, reflux.
Scheme 2
Figure 3. Molecular weight distribution.
Figure 2. Important NOE and NOESY correlations in representative
compounds 5. H1(H2) = 17%, H1(H3) =17%, H1(H4) = 3%.
Table 4. Physicochemical Properties of Compounds
Synthesized
Figure 4. cLog P distribution.
property
range
mean value
in t-BuOH (40 mL) in a round-bottom flask. The reaction
mixture was maintained at r.t. for 30 min, than arylating agent 2
(0.01 mol) was added in one portion, and the reaction mixture
was stirred at 60 °C over 12 h. Isolation/purification was achieved
as described in method A.
General Procedures for Synthesis of Pyrazolodi-
hydropyrimidines 5. Method A. A solution of compound 3
Mw
282−554
0.27−7.35
3−10
0−3
1−6
422
cLogP
HBA
HBD
RB
4.18
5.86
0.32
2.94
67.76
TPCA
33.4−136.8
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Figure 5. H-bond acceptors distribution.
Figure 9. cLogP−MW plot for 250 pyrazolo[3,4-d]dihydropyrimidines.
filtered off and washed with aq. NaHCO3, (8 mL of 5% aq.
solution), i-PrOH (1 mL), and MeCN (1 mL).
Method B. A solution of compound 3 (1 mmol) and 4
(1.1 mmol) in glacial AcOH (1 mL) was heated at 120 °C for
16 h in sealed tube (10 mL). Isolation/purification was
achieved as described in method A.
ASSOCIATED CONTENT
* Supporting Information
■
S
Compound data for representative set of compounds
synthesized and 1H NMR, 13C NMR, NOE, and NOESY
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 6. H-bond donors distribution.
AUTHOR INFORMATION
Corresponding Author
*E-mail: s.v.ryabukhin@gmail.com, a.shivanyuk@univ.kiev.ua.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Mr. Vitaliy V. Polovinko (Enamine Ltd) for
NMR measurements.
■
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