The identification of a novel highly condensed pentacyclic heteroaromatic ring system 1,3,5,5b,6,8,10,10b-octaazacyclopenta[h,i]aceanthrylene and its application in the synthesis of 5,7-substituted pyrazolo[4,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.2147

Pyrazolo[4,3-d]pyrimidines are of interest as potential kinase inhibitors. This article describes the formation of a novel highly conjugated, condensed, centrosymmetric heteroaromatic compound, 4,9-dichloro-2,7-diisopropyl-1,3,5,5b,6,8,10,10b-octaazacyclopenta[h,i]aceanthrylene (3), during the chlorination of 5,7-dihydroxypyrazolo[4,3-d]pyrimidine (1) with phenylphosphonic dichloride. The nucleophilic attack of benzylamine on 3 afforded N-benzyl-5-chloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-amine (6), which was further substituted to yield a pyrazolo[4,3-d]pyrimidine analogue of roscovitine, a well-known cyclin-dependent kinase inhibitor.

Full text of DOI:10.1002/jhet.2147

Month 2014
The Identification of a Novel Highly Condensed Pentacyclic
Heteroaromatic Ring System 1,3,5,5b,6,8,10,10b-Octaazacyclopenta[h,i]
Aceanthrylene and its Application in the Synthesis of 5,7-Substituted
Pyrazolo[4,3-d]Pyrimidines
a
a
b
b
*
Libor Havlíček, Daniela Moravcová, Vladimír Kryštof, and Miroslav Strnad
aIsotope Laboratory, Institute of Experimental Botany ASCR, Videnska 1083, 142 20 Prague, Czech Republic
bLaboratory of Growth Regulators, Faculty of Science, Palacký University & Institute of Experimental Botany ASCR,
Šlechtitelů 11, 78371 Olomouc, Czech Republic
*
E-mail:miroslav.strnad@upol.cz
Received June 29, 2013
DOI 10.1002/jhet.2147
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Pyrazolo[4,3-d]pyrimidines are of interest as potential kinase inhibitors. This article describes the
formation of a novel highly conjugated, condensed, centrosymmetric heteroaromatic compound, 4,9-
dichloro-2,7-diisopropyl-1,3,5,5b,6,8,10,10b-octaazacyclopenta[h,i]aceanthrylene (3), during the chlori-
nation of 5,7-dihydroxypyrazolo[4,3-d]pyrimidine (1) with phenylphosphonic dichloride. The nucleophilic
attack of benzylamine on 3 afforded N-benzyl-5-chloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7-
amine (6), which was further substituted to yield a pyrazolo[4,3-d]pyrimidine analogue of roscovitine, a
well-known cyclin-dependent kinase inhibitor.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
roscovitine [4]. Roscovitine (Fig. 1) was one of the first
CDK inhibitors to enter clinical trials, and partly because
of this, its structure has been explored by many groups and
optimized in different ways.
Protein kinases have become important targets in the
development of drugs for the treatment of various cancers
[1]. In recent years, 15 new small molecule drugs targeting
kinases such as the oncogenic Bcr–Abl fusion kinase, In
recent years, 15 new small molecule drugs targeting kinases
such as the oncogenic Bcr-Abl fusion kinase, the EGFR
(epidermal growth factor receptor) and VEGFR (vascular
endothelial growth factor receptor) receptor kinases, and
the JAKs (Janus kinases) and B-raf cytoplasmic kinases
have been approved for sale and come onto the market.
and B-raf cytoplasmic kinases have been approved for sale
and come onto the market [1b]. Many more kinase-targeting
compounds are currently undergoing clinical trials, inclu-
ding various cyclin-dependent kinase (CDK) inhibitors [2].
The CDKs are a family of enzymes that are regarded as
attractive targets for the treatment of proliferative diseases
because they regulate processes that are essential for cellular
proliferation and survival such as cell cycling (e.g., CDKs 1,
2, 4, and 6), transcription (CDKs 7, 8, and 9), and apoptosis
(CDKs 2 and 9) [3]. Our research group has identified
several potent purine-based CDK inhibitors, including
With the increasing number of articles describing kinase
inhibitors, it is becoming increasingly difficult to identify
new chemotypes that could be used to develop new
adenosine triphosphate competitive inhibitors. One potential
way of overcoming this hurdle involves modifying the
heterocyclic skeleton that forms the core of the inhibitor. To
this end, we analyzed the binding of roscovitine to various
CDKs and used structure-based reasoning to identify modifi-
cations of the purine core that could potentially yield new
bioisosteric inhibitors. Investigations of compounds based
on such modified core structures have led to the discovery
of several groups of purine bioisosteres; the progress made
in this area has recently been reviewed [5]. Notably, the
bioisosteric approach was applied in the discovery and devel-
opment of dinaciclib, a CDK inhibitor that is currently under-
going clinical trials (Fig. 1). Dinaciclib binds to the active site
of CDK2 in the same orientation as roscovitine but is a more
potent inhibitor because it has substituents that facilitate its
binding [6].
© 2014 HeteroCorporation

L. Havlíček, D. Moravcová, V. Kryštof, and M. Strnad
Vol 000
Figure 1. Structures of roscovitine, dinaciclib, and myoseverin.
One of our early attempts at modifying the purine core of
roscovitine focused on the synthesis of isomeric pyrazolo[4,3-
d]pyrimidine derivatives. A synthetic approach to this skeleton
was used to prepare 5,7-bis-[(4-methoxybenzyl)amino]-3-iso-
propyl-1(2)H-pyrazolo[4,3-d]pyrimidine (Fig. 1), an iso-
mer of the microtubule-interfering agent myoseverin [7].
The starting material for this synthesis was 3-isopropyl-1
(2)H-pyrazolo[4,3-d]pyrimidine-5,7-diol (1), which was
chlorinated with phenylphosphonic dichloride (PhPOCl2)
or pyrophosphoryl dichloride [Cl2(O═)P–O–P(═O)Cl2]
using a protocol developed for use with isomeric xanthine
derivatives [8]. This reaction is assumed to produce the 5,7-
dichlorinated derivative 2 (Scheme 1), although this
compound was not purified and thoroughly characterized.
Instead, the initial reaction mixture was subjected to a
simple extraction and immediately reacted with a large
excess of 4-methoxybenzylamine to yield the desired prod-
uct via an SN process. This procedure provided a 20% yield
of 5,7-bis-[(4-methoxybenzyl)amino]-3-isopropyl-1(2)H-
pyrazolo[4,3-d]pyrimidine after chromatography [7].
To this end, the reaction mixture obtained after the comple-
tion of the chlorination step was mixed with water, and the
product was extracted with benzene. The organic phase
was dried, the benzene was removed by evaporation, and
the residue was dissolved in a minimal volume of toluene.
Cyclohexane was then added, and the first fraction of the
final product was crystallized. Another fraction was
obtained by chromatography of the mother liquor on silica
gel using 1% MeOH in toluene. However, it was found that
the methanol reacted with the product at room temperature
and so in subsequent runs, the methanol was replaced with
the more sterically hindered tert-butanol, which did not re-
act with the product even at elevated temperatures (80°C).
The crystalline product (mp > 300°C) is light yellow-green
and exhibits fluorescence (peaks at 402, 423, and 448 nm);
its fluorescent spectrum is a mirror image of its UV
absorption spectrum. The UV spectrum (measured in tert-
butanol) contains strong and sharp peaks at 364, 382, and
400 nm (with the latter being the strongest peak) and
clearly indicates the formation of a more extensive
conjugated system of double bonds than would be
expected for the expected dichlorinated compound 2. On
the basis of the 1H NMR spectrum of the isolated material
(which did not contain any peaks that could reasonably be
assigned to the HN1 proton when acquired in CDCl3 or
abs. DMSO), CHN analysis, and EI-MS data, we conclude
that rather than the expected product 2, we in fact obtained
RESULTS AND DISCUSSION
In order to adapt this synthesis for the preparation of the
pyrazolo[4,3-d]pyrimidine analogue of roscovitine, which
has two different substituents on the pyrimidines rings, it
was necessary to isolate the presumed intermediate 2 [9].
Scheme 1. Reagents and conditions: (a) 1. PhPOCl2, 145°C, ampoule, 3 h; 2. evaporation 110°C/0.5 Torr; 3. H2O, benzene, 0°C, 24%; (b) MeOH, rt,
1 h, 95%.
Journal of Heterocyclic Chemistry
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The Identification of a Novel Highly Condensed Pentacyclic Heteroaromatic Ring System
1,3,5,5b,6,8,10,10b-Octaazacyclopenta[h,i] Aceanthrylene and its Application
4,9-dichloro-2,7-diisopropyl-1,3,5,5b,6,8,10,10b-octaazacy
clopenta[h,i]aceanthrylene (3) (Scheme 1). This compound
is presumably formed via some sort of condensation process
involving two molecules of 2. Unfortunately, attempts to deter-
mine the structure of this compound directly by X-ray crystal-
lography were unsuccessful; whereas crystals of adequate size
were prepared via multiple methods, and they tended to form
flat and mutually adherent plates that were unsuitable for X-
ray diffraction analysis. However, inspection of the product’s
IR (KBr tablet) and Raman (powder sample) spectra indicated
that it has a center of symmetry, which is consistent with the
proposed dimeric structure; the bands observed in the IR
spectrum were not apparent in the Raman spectrum and vice
versa. This implies that the molecule has a center of symmetry
and is rigid. However, the methyl groups of the isopropyl unit
can obviously rotate freely and so the exclusion principle does
not hold for their bands.
Compound 3 is rather reactive, and the central heterocycle
opens readily at room temperature in MeOH undergoing
near-complete solvolysis (>95%) within 60 min. An analo-
gous reaction occurs in n-BuOH. The course of the reaction
can be readily observed by monitoring the UV spectrum of
the reaction mixture: the absorption peaks of compound 3
disappear gradually and are replaced by new maxima at 341
and 355 nm. The mass spectra of methanolic solutions of
compound 3 acquired using ESI (desolvation temperature
120°C, coin voltage 20 V) in negative ion mode contain only
one peak, at m/z 419 [M À H]À. No detectable signal was ob-
served in positive mode ESI spectra. However, a positively
charged ion at m/z 421 [M + H]+ was observed in the atmo-
spheric pressure chemical ionization mass spectrum of the re-
action mixture. The isotopic patterns observed in both the
positive and negative mass spectra of the undesired product
of solvolysis 4 are consistent with the suggested structure 4.
Unfortunately, we were unable to isolate and fully
characterize compound 4. The second putative bond
between the two pyrazolo[4,3-d]pyrimidine ring systems is
substantially more resistant to nucleophilic attack than the
first and is not cleaved in MeOH even at an elevated temper-
ature of 55°C. However, it is rapidly cleaved even at 25°C if a
drop of 1 M CH3ONa is added to the reaction mixture.
In order to prepare the desired roscovitine analogue,
compound 3 was reacted with benzylamine (Scheme 2) in
tert-butanol, a solvent that does not attack 3. The progress
of this reaction is readily monitored by studying the UV
spectrum of the reaction mixture (in tert-butanol): the peaks
arising from compound 3 disappear gradually and are ini-
tially replaced by those corresponding to intermediate 5,
which occur at 372 and 357nm. The formation of the de-
sired product is reflected by the subsequent appearance of
a peak at 300nm with shoulders at 311 and 324 nm. Unfor-
tunately, this reaction yields a fairly complex mixture of
products. The main contaminant is believed to be compound
7 on the basis of the observation of a positive ion of m/z
Scheme 2. Reagents and conditions: (a) 1. benzylamine, t-BuOH, 60°C, 6 h; 2. LC, silica gel, 0–3% MeOH in CHCl3, 35%.
Scheme 3. Reagents and conditions: (a) 1. 2-amino-1-butanol, 150°C, 6 h; 2. LC 0–3% MeOH in CHCl3, 40%.
Journal of Heterocyclic Chemistry
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L. Havlíček, D. Moravcová, V. Kryštof, and M. Strnad
Vol 000
Instrument, Madison, WI, USA); Raman spectra were acquired on
a Labram HR instrument (Yobin Yvon Ltd., Tokyo, Japan). Merck
silica gel (Merck, Darmstad, Germany) Kieselgel 60 (230–400 mesh)
was used for column chromatography. 3-Isopropyl-1(2)H-pyrazolo
[4,3-d]pyrimidin-5,7-diol (1) was prepared according to the published
synthesis [7].
567.4 and a negative ion of m/z 565.3 in the ESI-MS spec-
trum of the crude material. This compound was not isolated.
The isotopic patterns seen in the positive and negative mass
spectra of the side product 7 are consistent with the
suggested structure 7. The formation of this side product,
which may in fact be a positional isomer or a mixture of
such isomers, results from the small difference in reactivity
between positions 5 and 7 of intermediate 5. The desired
product 6 does not crystallize and was therefore isolated
chromatographically. The final transformation (Scheme 3)
in the synthesis of roscovitine analogue 8 was achieved by
dissolving compound 6 in neat 2-amino-1-butanol and
heating the resulting mixture to 150°C. The chlorine in posi-
tion 5 of the heterocycle is not readily substituted by amines,
and the difference between the electrophilic reactivities of
positions 5 and 7 of the pyrazolo[4,3-d]pyrimidine ring
system seems to be less pronounced than is the case in the
analogous 5,7-dichlorinated purines. In addition to the
desired product 8, the reaction mixture also contained the
undesired derivative 9 and the unconverted starting material 6.
4,9-dichloro-2,7-diisopropyl-1,3,5,5b,6,8,10,10b-octaazacyclope-
nta[h,i]ace-anthrylene (3).
5,7-Dihydroxy-3-isopropylpyrazolo
[4,3-d]pyrimidine (5.1 g; 26.3 mmol) was dissolved in
1
PhPOCl2 (32 mL) and the mixture was heated at 145°C in sealed
ampoule for 3 h. The solution was evaporated in 0.5 Torr
vacuum (bath temperature up to 110°C), and the residue was
cooled and poured in the mixture of crushed ice and benzene.
The benzene extract was once washed by water and immediately
dried over Na2SO4. The extract was evaporated, and the residue
was dissolved in minimum toluene; the first portion of product
was crystallized by adding cyclohexane (0.7 g). The rest of the
product (0.5 g) was isolated from the mother liquor by column
chromatography in toluene–tert-butanol (99:1); yield 1.2 g
(43%), mp (December) > 300°C. UV, λmax (ε): 364 nm (16700),
1
382 nm (40700) 402 nm (59000). H NMR (400 MHz, CDCl3):
1.54 (d, J = 7.0 Hz, 6H, CH3CH-), 3.53 (September, J = 7.0 Hz,
1H, CH3CHÀ). 13C NMR (100 MHz, CDCl3): 21.2 (11, 12);
28.1 (10); 127.0; 145.5; 147.2 (9); 157.9; 161.5 (3). IR (cmÀ1):
2984 (sh), 2970, 2932, 2876, 1635, 1580 (vs), 1524 (vs), 1475,
1456 (vw), 1397, 1386, 1368 (sh), 1341 (w-m), 1290 (sh),
1277 s, 1254, 1214 (vs), 1182, 1134, 1110, 1080, 1010, 892,
864, 817, 785, 725, 712. Raman (cmÀ1): 2987 (vw), 2971 (vw),
2931, 2873, 1643, 1573, 1479, 1454, 1407, 1381, 1369 (sh),
1343 (vw), 1333, 1319, 1307, 1292 (sh), 1284, 1230, 1151,
1120, 1093, 982, 966, 910, 835, 790, 760, 716, 702, 631, 622
CONCLUSIONS
As demonstrated by molecular modeling and its perfor-
mance in biochemical and cellular assays, compound 8 is a
potent CDK inhibitor with interesting anticancer activity
and lower IC50 values than its bioisostere roscovitine [9].
The CDK-inhibiting activity of related substituted pyrazolo
[4,3-d]pyrimidines has been also investigated in some detail
[10]. On the basis of our knowledge of the structure-activity
relationships for the analogous trisubstituted purines, we are
currently aiming to synthesize 3,5,7-trisubstituted pyrazolo
[4,3-d]pyrimidine derivatives, which are expected to have
nanomolar potency.
(sh). EI-MS: 388 (M+, 35), 373 (M À CH3+, 30), 331 (25), 186
35
14
(20), 43(C3H+7, 100). HRMS: Calcd for C16H Cl2N8:
388.07185, found: 388.07095. CHNCl analyses: Calcd for
C16H14 Cl2N8: C, 49.37; H, 3.63; Cl, 18.22; N, 28.79. Found: C,
49.52; H, 3.61; Cl, 18.40; N, 28.47.
N-benzyl-5-chloro-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-
7-amine (6). A mixture of 3 (1 g, 2.58 mmol), 25 mL t-butanol
and 4 mL benzylamine was stirred at 60°C for 6 h. The reaction
mixture was evaporated to dryness. Column chromatography
(stepwise 0%, 1%, 2%, and 3% MeOH in toluene) afforded
product 6, after evaporation noncrystallizable amorphous
yellowish glass, 0.54 g (36%), mp 69–72°C, light green crystals.
MS ESI+: [M +H]+ = 302.3 (100); MS ESIÀ: [M À H]À = 300.2
(100). Isotope pattern corresponds to a single chlorine atom. EI-MS:
301 (M+, 43), 286 (M À CH3+, 33), 106 (C7H8N+, 39), 91 (C7H+7, 70)
EXPERIMENTAL
Melting points were determined on a Kofler block and are
uncorrected. NMR spectra were acquired using a Varian UNITY
Inova-400 spectrometer (Varian Inc., Palo Alto, CA, USA) in CDCl3
at 303 K. The residual signal of the solvent was used as an internal
1
1
36 (100). HRMS: 301.10769 error + 1.7 mmu. H NMR (300 MHz,
standard (CHCl3, δH 7.265 ppm, δC 77.00 ppm). H NMR spectra
CDCl3): 1.37 (d, J=7.1Hz, 6H, CH3CH–); 3.39 (September,
J= 7.1 Hz, 1H, CH3CH–), 6.72 (bs, 1H, –NH), 4.82 (s, 2H, –CH2–
NH–), 7.28 (m, 5H, Ar H). 13C NMR (75 MHz, CDCl3): 22.3 (19);
26.7 (18); 44.9 (11); 127.1 (15); 127.9 (13 + 17); 128.8 (14 + 16);
were zero-filled to fourfold data points and multiplied by a window
function (two-parameter double-exponential Lorentz–Gauss func-
tion) prior to Fourier transformation to improve resolution. Protons
were assigned by COSY and TOCSY, and assignments were trans-
ferred to carbons by HMQC. Chemical shifts are given in δ-scale
(ppm), coupling constants in Hertz. Carbon chemical shifts were read
out from HMQC (protonated carbons) and HMBC spectra. ESI or at-
mospheric pressure chemical ionization mass spectra were acquired
using a Waters Micromass ZMD (Micromass UK Ltd., Manchester,
UK) mass spectrometer (direct inlet, coin voltage 20 V). Standard
electron ionization EI mass spectra were acquired using a Jeol
D100 (Jeol Ltd., Tokyo, Japan) double-focusing mass spectrometer
(ionization energy 75 eV, chamber temperature 200°C, ionizing cur-
rent 300 mA, and accelerating voltage 3 kV). IR spectra were
recorded on a Nicolet 200 FT-IR instrument (Nicolet Analytical
140.3 (12); 143.5; 154.4; 155.2; 156.4; 171.0. HRMS: Calcd for
35
16
C15H ClN5: 301.109423, found: 301.10769. CHClN analyses:
Calcd for C15H16ClN5: C, 59.70; H, 5.34; Cl, 11.75; N, 23.21.
Found: C, 59.56; H, 5.39; Cl, 11.62; N, 23.02.
2-{[7-(benzylamino)-3-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-
5-yl]amino}-1-butanol (8). A mixture of (0.5 g, mmol) compound
6 and 5 mL of 2-amino-1-butanol was heated at 150°C in a sealed
ampoule for 6 h. After cooling, the reaction mixture was partitioned
between water and CHCl3. The organic phase was dried by Na2SO4
and evaporated. Column chromatography (stepwise 0%, 1%, 2%,
and 3% MeOH in CHCl3) afforded product 8 (after evaporation,
Journal of Heterocyclic Chemistry
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Month 2014
The Identification of a Novel Highly Condensed Pentacyclic Heteroaromatic Ring System
1,3,5,5b,6,8,10,10b-Octaazacyclopenta[h,i] Aceanthrylene and its Application
[3] Malumbres, M.; Barbacid, M. Nat Rev Cancer 2009,
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noncrystallizable amorphous colorless glass), 0.15 g (36 %),
amorphous. MS ESI+: [M+H]+ = 355.4 (100), MS ESIÀ:
1
[M À H]À= 353.3 (100). H NMR (300 MHz, DMSO-d6): 0.85 (t,
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J= 7.5 Hz, 3H, 23), 1.32 (d, J= 7.0 Hz, 6H, 19), 1.39–1.68 (m, 2H,
22a, 22b), 3.16 (September, J=7.0Hz, 1H, 18), 3.37–3.51 (m, 2H,
24a, 24b), 3.78 (m, 1H, 21), 4.68 (t, J= 4.8 Hz, 2H, 11), 5.74 (bs,
1H, 20), 7.26 (t, 1H, 15), 7.34 (t, 2H, 14 + 16), 7.39 (d, 2H,
13 + 17), 11.79 (bs, 1H, 10), 13.28 (bs, 1/2H, 1). 13C NMR
(75 MHz, DMSO-d6): 10.6 (23); 21.5 (19); 21.6 (19); 23.8 (22);
25.9 (18); 43.0 (11); 54.2 (21); 63.4 (24); 126.9 (15); 127.5
(13 + 17); 128.3 (14 + 16); 130.7; 130.4; 139.3 (12); 158.8; 158.9;
161.4. CHN analyses: Calcd for C19H26N6O: C, 64.38; H,7.39; N,
23.71; Found: C, 64.51, H, 7.57, N, 23.48.
2,2’-[(3-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5,7-diyl)diimi
no]di(1-butanol) (9). Yield 12%, amorphous. MS ESI+:
[M + H]+ = 337.4 (100), MS ESIÀ: [MÀ H]À= 353.3 (100). 1H
NMR (300 MHz, CD3OD): 0.86 (t, J= 7.5 Hz, 3H, 21), 0.89
(t, J= 7.5 Hz, 3H, 15) 1.32 (d, J= 7.0 Hz, 6H, 23), 1.38–1.52
(m, 2H, 20), 1.63–1.79 (m, 2H, 14), 3.16 (September, J=7.0Hz,
1H, 22), 3.29–3.43 (m, 2H, 18), 3.51–3.64 (m, 2H, 12), 3.78
(m, 1H, 17), 3.83 (m, 1H, 11), 5.69 (bs, 1H, 16), 5.72 (bs, 1H, 10),
12.29 (bs, 1H, 1). 13C NMR (75MHz, CD3OD): 10.5 (21), 10.9
(15), 21.6 (23), 23.9 (20), 24.2 (14), 25.6 (22), 53.9 (17), 54.2 (11),
63.4 (18), 64.6 (12), 139.9, 149.7, 157.2, 157.8, 160.4. CHN
analyses: Calcd for C18 H31N5O2: C, 57.12; H, 8.39; N, 24.98.
Found: C, 57.37; H, 8.50; N, 24.71.
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Acknowledgments. We gratefully acknowledge financial support
from the Czech Science Foundation (305/12/0783).
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Journal of Heterocyclic Chemistry
DOI