First synthesis of piperazine-derived [1,2,4]triazolo[1,5-a]pyrazine as an adenosine A2a receptor antagonist

Article abstract of DOI:10.3987/COM-05-10493

Synthesis of piperazine-derived 2-furan-2-yl-[1,2,4]triazolo[1,5-a] pyrazines was achieved using methyl 3-amino-2-pyrazinecarboxylate. Introduction of the piperazine to the pyrazine template was achieved through a pteridin-4-one intermediate (7). Cyclization of the [1,2,4]triazolo[1,5-a]pyrazine ring was accomplished by amination of pyrazine (8) followed by condensation with 2-furaldehyde. Curtius rearrangement installed the amine to afford template (11). As one example of derivatizing 11, 6N-(4-(2,4,6-trifluorobenzyl)piperazin-1-yl)-2-(furan-2-yl)-[1,2,4]triazolo-[1,5-a]pyrazin-8-amine (12) showed moderate adenosine A_2a receptor binding affinity and selectivity over the A₁ receptor.{A figure is presented}.

Full text of DOI:10.3987/COM-05-10493

HETEROCYCLES, Vol. 65, No. 10, 2005
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HETEROCYCLES, Vol. 65, No. 10, 2005, pp. 2321 - 2327
Received, 24th June, 2005, Accepted, 15th August, 2005, Published online, 23rd August, 2005
FIRST SYNTHESIS OF PIPERAZINE-DERIVED
[1,2,4]TRIAZOLO[1,5-a]PYRAZINE AS AN ADENOSINE A2A RECEPTOR
ANTAGONIST
Hairuo Peng,* Li Sha, He Xi Chang, Jeffery T. Vessels, Serajul Haque,
Patrick R. Conlon, James E. Dowling, Joy Wang, Thomas M. Engber,
Gnanasambandam Kumaravel, Daniel M. Scott, and Russell C. Petter
Departments of Medicinal Chemistry and Pharmacology, Biogen Idec Inc., 14
Cambridge Center, Cambridge, MA 02142, USA
Abstract – Synthesis of piperazine-derived 2-furan-2-yl-[1,2,4]triazolo[1,5-a]
pyrazines was achieved using methyl 3-amino-2-pyrazinecarboxylate.
Introduction of the piperazine to the pyrazine template was achieved through a
pteridin-4-one intermediate (7). Cyclization of the [1,2,4]triazolo[1,5-a]pyrazine
ring was accomplished by amination of pyrazine (8) followed by condensation
with 2-furaldehyde. Curtius rearrangement installed the amine to afford template
(11). As one example of derivatizing 11, 6N-(4-(2,4,6-trifluorobenzyl)piperazin-1-
yl)-2-(furan-2-yl)-[1,2,4]triazolo-[1,5-a]pyrazin-8-amine (12) showed moderate
adenosine A2a receptor binding affinity and selectivity over the A1 receptor.
In recent years, significant effort has been directed at the development of adenosine A2a receptor
antagonists because of their potential for the treatment for Parkinson’s disease.1 As represented by
compounds in Figure 1, a variety of bicyclic or tricyclic heterocyclic templates have been discovered as
potent A2a antagonists.2-7 Effort in our lab to develop adenosine A2a antagonist has led to the recent
disclosure of several diamine-derived triazolotriazine and triazolopyrimidine series as highly potent and
selective A2a antagonists, some of them showed good oral efficacy in rodent models of Parkinson’s
disease.8-10 The diamines along with their capping groups in these antagonists were shown to be
instrumental to the favorable in vitro/in vivo activities observed. 8-10 In hope to achieve improved potency,
selectivity and oral efficacy, we have recently developed a novel [1,2,4]triazolo[1,5-a]pyrazine template
(4) (Scheme 1). However, introduction of diamine through Pd-catalyzed amination, to the 6-position of this

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HETEROCYCLES, Vol. 65, No. 10, 2005
template, was found to be very difficult. We report here the first synthesis of a piperazine
derived-triazolopyrazine as an adenosine A2a antagonist.8-10
Figure 1
NH2
NH2
N
N
O
HO
N
N
N
N
O
N
N
N
N
H
CGS-15943
ZM-241385
Zeneca, 1995
A2a Ki = 2 nM, A1 Ki = 257 nM
No oral activity
Cl
Ciba-Geigy, 1987
A2a Ki = 3 nM, A1 Ki = 21 nM
No oral activity
NH2
NH2
N
N
O
N
N
N
N
O
N
N
N
N
N
N
SCH-58261
Schering-Plough, 1995
BIO-012817
Biogen Idec, 2004
A2a Ki = 2.3 nM, A1 Ki = 121 nM
No oral activity
A2a Ki = 63 nM, A1 Ki = 1100 nM
Orally active
The initial attempts to the synthesis of piperazine-derived [1,2,4]triazolo[1,5-a]pyrazine were directed at
amination of bromide (4) using Buchwald/Hartwig conditions for the ease of preparing bromide (4),11 as
well as for our previous success on Sonogashira11 and Suzuki12 couplings with this bromide under standard
Pd-catalyzed conditions (Scheme 1). However, we encountered significant difficulties with Pd-catalyzed
amination of triazolopyrazinyl bromide (4). Intensive screening of a variety of ligands, catalyst-ligand-base
combinations, and solvents13-20 was unsuccessful, mostly resulting in decomposition or recovery of the
uncoupled starting materials. (Some examples24 are shown in Table 1, Entries 1-9). Converting the bromide
to chloride, iodide or triflate did not solve the problem. Protection of the 8-amine as an imide did not
improve the coupling reaction, either.
Scheme 1
NH
Pd(PPh ) , CuI,
NH
2
2
3 4
8
o
Et N, DMF, 100 C
N
N
O
N
N
O
3
N
N
2
N
N
OH
6
Br
OH
R
5
1
R
1
4
R
2
R
2
NH
2
Pd(PPh ) , Na CO ,
3 4
2
3
N
N
O
O
N
N
o
DMF, 80-85 C
N
R
N
R-B(OH)
2
NH
2
N
N
Pd catalyst
ligand
N
1-Boc-piperazine
BocN

HETEROCYCLES, Vol. 65, No. 10, 2005
2323
Although the results were discouraging, it is not surprising since the current scope of transition
metal-catalyzed amination of heteroaromatic halides with alkyl amines is still limited, especially for aryl
halides containing functional groups with acidic protons, such as hydroxyl, amide, or enolizable keto
groups.19,20 The problem that we encountered likely arose from the presence of an acidic proton at the
5-position, in addition to the 8-amine.25 Proton signals from both positions disappeared in NMR spectrum
when using methanol-d4 as solvent. Eventually, we decided to synthesize piperazinyltriazolopyrazines
from scratch by introducing piperazine before cyclizing the furanyltriazole.
Scheme 2
NH2
CO2Me
N
N
N
O
O
N
N
N
N
N
N
H
N
N
N
12
9
R
Boc
CO2Me
NH2
CO2Me
NH2
O
N
N
O
N
N
Br
N
N
Boc
8
5
We envisioned a retrosynthetic strategy (Scheme 2) whereby the amino group at the 8-position of 12 may
arise from the carboxylate of the pyrazine intermediate (9). The furanyltriazolo ring in 9 would be installed
by amination of the pyrazine (8) followed by condensation with 2-furaldehyde. Intermediate (8) would be
available via piperazinylation of bromide (5). As shown in Scheme 3, the synthesis of 12 commenced with
bromination of commercial methyl 3-amino-2-pyrazinecarboxylate to afford a corresponding bromide (5)
in 94% yield. However, attempts at nucleophilic displacement of the bromide in 5 to obtain 8 using
Boc-piperazine were unsuccessful. At the time we explored the chemistry, there were no successful
examples in the literature on the Pd-catalyzed amination of pyrazines, especially those bearing a free amino
group. Based on the previous difficulties with amination of triazolopyrazinyl bromide (4), we decided to
take an alternative route by cyclizing bromide (5) into its pteridin-4-one analogue (6), a chloride version of
which was reported to undergo facile nucleophilic aromatic substitution.21 Therefore,
6-bromo-3-methyl-3H-pteridin-4-one (6) was synthesized in two steps (90% and 89% yield, respectively)
by converting 5 to its methyl amide analogue followed by condensing with triethyl orthoformate in acetic
anhydride at reflux. Bromide (6) was then easily displaced by Boc-piperazine to give 7 in 92% yield.
Hydrolysis followed by methylation of the free carboxylate using trimethylsilyldiazomethane gave the key
intermediate (8) in reasonable yield.

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HETEROCYCLES, Vol. 65, No. 10, 2005
Scheme 3
Boc
O
.
N
O
N
N
N
CO2Me
NH2
Br
N
CO2Me
NH2
Br
N
N
Me
b, c
e, f
N
N
N
Me
a
d
N
N
N
N
5
6
7
Boc
CO2Me
NH2
CO2Me
N
N
O
N
N
N
CO2Me
NH2
O
N
g, h
air
i, j
N
N
+
N
N
N
N
N
N
N
9
8
Boc
O
Boc
NHR
NH2
N
F
N
N
O
N
N
N
k, l
N
N
N
N
R =
F
F
N
10 R = Boc, 54 %
11 R = H, 15 %
N
Boc
12
R
Reagents and Conditions: a) Br2, AcOH, H2O, 94%; b) 40 % aq. MeNH2, rt, 90%; c) triethyl orthoformate, acetic anhydride,
reflux, 89%; d) 1-Boc-piperazine, 2-methoxyethanol,100°C, 92%; e) 10 % NaOH, MeOH, rt, formic acid, 67%; f) TMSCHN2,
benzene, MeOH, rt, 96%; g) O-mesitylsulfonylhydroxylamine, CH2Cl2, rt; h) 2-furaldehyde, 1,4-dioxane, 100°C, 19 % for
two steps; i) 1 N KOH/MeOH, rt, 68%; j) DPPA, triethylamine, t-BuOH, reflux; k) TFA/CH2Cl2; l) 2,4,6-trifluorobenzaldehyde,
NaBH(OAc)3, AcOH, 56% for two steps.
With 8 in hand, we then pursued incorporation of the furanyltriazole. Since our previous report11 on the
synthesis the furanyltriazole moiety in compound (4), we have improved the procedure by using
acid-catalyzed condensation of the aminopyrazine with 2-furonitrile, followed by oxidation/cyclization
using lead tetraacetate.12 Unfortunately, we were not able to convert 8 to 9 using 2-furonitrile and AlCl3, or
milder Lewis acids such as TiCl4 and Et2AlCl. Base-catalyzed conditions using potassium t-butoxide were
also unsuccessful. Therefore, we turned our attention to the amination-condensation-cyclization method
using O-mesitylsulfonylhydroxylamine and 2-furaldehyde. Treatment of pyrazine (8) with aminating agent
O-mesitylsulfonylhydroxylamine22 gave a pyrazinium salt, which was condensed with 2-furaldehyde in
1,4-dioxane at 100 ºC, and oxidized by air to give 9 with combined yield of 19% for the two steps after
chromatography on silica. Hydrolysis of 9 using 1N KOH in methanol gave the acid intermediate in 67%
yield, which was then rearranged under Curtius conditions using DPPA in refluxing t-butanol to afford 10
(54%) and 11 (15%). The Boc protecting groups were removed using 10% TFA/CH2Cl2. As one example of
derivatizing this piperazinyl-triazolopyrazine template, compound (12) was synthesized by reductive
alkylation with 2,4,6-trifluorobenzaldehyde using NaBH(OAc)3. Compound (12) was tested in competition
binding assays23 against the adenosine A2a and A1 receptors and showed moderate binding potency and
selectivity (A2a Ki = 260 nM, A1 Ki = 8490 nM).
In summary, we have demonstrated, for the first time, the synthesis of a piperazine-derived
[1,2,4]triazolo[1,5-a]pyrazine, a novel addition to the current collection of heterocyclic templates that are
explored as A2a antagonists (Figure 1). A preliminary derivative with a hydrophobic capping group

HETEROCYCLES, Vol. 65, No. 10, 2005
2325
exhibited encouraging potency and selectivity, suggesting a potentially new avenue to pursue A2a
antagonists with good potency, selectivity and oral efficacy. Optimization of the conditions is underway to
improve the yield of the key steps, and to conduct more extensive optimization of the capping group.
ACKNOWLEDGEMENTS
We thank Azita Kaffashan for carrying out the high–resolution MS spectrum.
REFERENCES AND NOTES
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HETEROCYCLES, Vol. 65, No. 10, 2005
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24. All proton and 13C magnetic resonance spectra were determined in the indicated solvent using a 300
MHz Bruker NMR spectrometer with the appropriate internal standard. HRMS spectra were obtained
on a MALDI-TOF MS (Voyager-DE STR, Perseptive Biosystems) in the reflector mode with delayed
extraction and an accelerating voltage of 20 kV. Preparative HPLC was carried out using a Gilson
platform equipped with UV/VIS detector and an automatic fraction collector. The data for target
compound (12) is included as an example: white amorphous powder, 1H NMR (300 MHz, CDCl3) δ
2.66 (t, J = 4.5 Hz, 4H), 3.34 (t, J = 4.5 Hz, 4H), 3.73 (s, 2H), 5.61 (s, 2H), 6.54 (dd, J = 1.8, 3.6 Hz,
1H), 6.67 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 7.26 (s, 1H), 7.57 (d,
J = 1.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 46.5, 48.4, 51.5, 95.6, 99.8, 100.1, 100.3, 110.2, 111.7,
134.8, 143.8, 146.0, 146.4, 149.0, 155.1; HRMS calculated for C20H18N7OF3 (M+ + H) 429.1525,
found 429.1531; Anal. Calcd for C20H18N7OF3: C, 55.94; H, 4.23; N, 22.83. Found: C, 55.60, H, 4.28,
N, 23.00.
25. To address the problem of acidic protons in the Pd-catalyzed coupling reaction of compound (4), we
chose Buchwald’s conditions using LHMDS as the base, which was proposed to protect the
deprotonated species in situ as lithiate/aggregate, to prevent deactivation of the Pd catalyst.20 We were
delighted to observe a clean reaction potentially forming the desired product as monitored by LC-MS
spectrum. However, the crude product decomposed into baseline material during work-up (Table 1,
Entry 9). So far, we haven’t been able to figure out the underlining problem.
26. Table 1
Entry Solvent Catalyst
Ligand
Base
Conditions
Results
(4 eq.)
1
2
3
Toluene Pd2(dba)3
DMF Pd (OAc)2
Dioxane CuI
dppp
1
NaOBu-t 85 oC/4 h
SM/decompa
decompb
NaOBu-t 95 oC /5 h
(rac)-trans-1,2-cyclo- K3PO4
100 oC/18 h SM/decompa
hexanediamine

HETEROCYCLES, Vol. 65, No. 10, 2005
2327
4
5
6
7
8
9
Dioxane Pd (OAc)2 (rac)PPF-OMe
Cs2CO3
Cs2CO3
K3PO4
100 oC/18 h SM/decompa
Dioxane Pd2(dba)3
Dioxane Pd2(dba)3
dppf
2
100 oC/18 h SM/decompa
100 oC/18 h decompb
DMF
THF
THF
POPd2
Pd (OAc)2
Pd2(dba)3
Ref. 18
3
2
KOBu-t
100 oC/18 h SM/decompa
NaOBu-t 65 oC/18 h
SM/decompa
decompc
LHMDS
65 oC/18 h
a) Starting material partially decomposed. No product observed. b) No product formed. Starting
material decomposed completely. c) Crude product formed as monitored by LC-MS, but decomposed
during work-up.
Cl
P(t-Bu)2
i-Pr
i-Pr
P(t-Bu)2
N
N
i-Pr
(Cy)2N
i-Pr
3
2
1