Synthetic access to 2-amido-5-aryl-8-methoxy-triazolopyridine and 2-amido-5-morpholino-8-methoxy-triazolopyridine derivatives as potential inhibitors of the adenosine receptor subtypes

Article abstract of DOI:10.1055/s-2003-40874

Two versatile and complementary synthetic strategies towards 2-amido-5-aryl-8-methoxy-triazolopyridine derivatives and 2-amido-5-morpholino-8-methoxy-triazolopyridine derivatives in five steps are presented. The key step in each synthetic route can be constituted as the formation of the respective triazolopyridine derivative precursors in 78% and 57% yield, respectively, through an intermediately formed 4H-[1,2,4]oxadiazol-5-one. The final Suzuki coupling/amidation allowed the straightforward access to the desired triazolopyridine derivatives which have not been described previously. Notably, these triazolopyridine-scaffold bears three vectors of diversity which offer maximum flexibility in design and combinatorial synthesis of molecules with a potentially useful inhibitory activity towards adenosine receptor subtypes.

Full text of DOI:10.1055/s-2003-40874

PAPER
1649
Synthetic Access to 2-Amido-5-aryl-8-methoxy-triazolopyridine and 2-Amido-
5-morpholino-8-methoxy-triazolopyridine Derivatives as Potential Inhibitors
of the Adenosine Receptor Subtypes
T
riazolopyridine Deriv
a
atives as Po
t
tential
t
Inhibit
h
ors of the
A
d
enosin
a
e
Receptor
s
Subtype
s
Nettekoven,* Bernd Püllmann, Sébastien Schmitt
F. Hoffmann-LaRoche Ltd., Pharmaceutical Research Basel, Discovery Chemistry, Lead Generation, 4070 Basel, Switzerland
Fax +41(61)6886459; E-mail: matthias.nettekoven@roche.com
Received 29 April 2003
(versus Adenosine A1) antagonists based on a small het-
Abstract: Two versatile and complementary synthetic strategies
erocyclic molecule scaffold.3 In order to further investi-
towards 2-amido-5-aryl-8-methoxy-triazolopyridine derivatives
gate the potential of triazolopyridine derivatives with
different substitution pattern to those previously de-
and 2-amido-5-morpholino-8-methoxy-triazolopyridine derivatives
in five steps are presented. The key step in each synthetic route can
be constituted as the formation of the respective triazolopyridine de- scribed 8-methoxy-[1,2,4]triazolo[1,5-a]pyridine deriva-
rivative precursors in 78% and 57% yield, respectively, through an
intermediately formed 4H-[1,2,4]oxadiazol-5-one. The final Suzuki
coupling/amidation allowed the straightforward access to the de-
potential herbicidial agents.4 However, to the best of our
sired triazolopyridine derivatives which have not been described
previously. Notably, these triazolopyridine-scaffold bears three
tives 1 were considered as potentially interesting.
Structurally related compounds have been identified as
knowledge, synthetic access to 5-aryl-8-methoxy-
[1,2,4]triazolo[1,5-a]pyridines 1 and 5-amino-8-meth-
oxy-[1,2,4]triazolo[1,5-a]pyridine derivatives 2 have not
been described. To allow for maximum synergies from
the synthetic point of view our unified synthetic approach
towards both types of triazolopyridines ought to go
through a pivotal aromatic iodo-triazolopyridine 3 inter-
mediate to be transformed into the respective aryl/amino
derivatives through palladium-catalysed reaction se-
quences. Therefore, 2-amino-3-methoxy pyridine 45 was
reacted with ethoxycarbonyl isothiocyanate to yield al-
most quantitatively the thiourea derivative 5 which was
subjected to a cyclisation procedure employing hydroxy-
lamine and DMAP in a protic solvent to afford 8-meth-
oxy-triazolopyridine 6 in 78% yield (Scheme 1).
vectors of diversity which offer maximum flexibility in design and
combinatorial synthesis of molecules with a potentially useful in-
hibitory activity towards adenosine receptor subtypes.
Key words: triazolopyridine derivatives, 4H-[1,2,4]oxadiazol-5-
one, Suzuki coupling, combinatorial chemistry
In the course of a medicinal chemistry project the Adenos-
ine 2a (A2a) receptor was considered as a potential mod-
ulating site towards the treatment of neurodegenerative
deseases.1 A2a receptor antagonists inhibit the motor de-
pressant effects of dopamine antagonists, such as halo-
peridol, which makes them of particular interest for
treatment of neurodegenerative disorders, such as Parkin-
son’s disease.2 It was previously established that triazol-
opyridine derivatives can act as potent and selective
Although this type of procedure was previously described
the reaction mechanism remained ambiguous. We postu-
Scheme 1 Synthetic sequence for preparation of 2-amido-5-aryl-8-methoxy-triazolopyridines 1
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1649,1652,ftx,en;C02503SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

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M. Nettekoven et al.
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late a mechanism starting with the substitution of the thio
moiety in thiourea 5 with hydroxylamine which consecu-
tively forms the 4H-[1,2,4]oxadiazol-5-one 7 upon loss of
ethanol. Subsequent loss of CO2 from 7 and simultaneous
aromatisation can be regarded as the driving force for the
formation of the desired triazolopyridine 6. Regioselec-
tive iodination with KIO3 in sulfuric acid6 yielded iodo-
triazolopyridine 3 in 49% yield. It is noteworthy that this
low molecular weight building block carries 2 ‘handles’
(i.e. aromatic iodide and amino functionality) for orthog-
onal derivatisation. Considering the early introduction of
a methoxy group onto the scaffold these type of triazol-
opyridines constitute a versatile class of heterocyclic
compounds with three orthogonal vectors of diversity.
The aromatic iodide 3 conveniently underwent Suzuki
coupling reactions with a total of 34 boronic acids or es-
ters. Reaction conditions employing Pd(dppf)Cl2·CH2Cl2
in dioxane with sodium carbonate as base at elevated tem-
peratures furnished 5-aryl-8-methoxy-triazolopyridine
derivative 8 in yields up to 83% (Table 1).
Table 1 Representative Selection of 5-Aryl-8-methoxy-triazolopy-
ridine Derivatives 8
Prod Ar
uct
Yield [%]a Prod Ar
Yield
(purity)b
MH+
uct
[%]a (pu-
rity)b
(found)
MH+
(found)
8a
8b
8c
29 (100)
241.3
8g
8h
8i
28 (100)
324.3
33 (100)
270.3
31 (100)
308.3
41 (100)
258.3
38 (79
301.3
8d
8e
11 (100)
258.3
8j
16 (95)
265.3
27 (97)
274.7
8k
59 (100)
309.2
The amidation of 8 with acid chlorides under prolonged
reaction times concluded this 5-step synthetic sequence
giving access to a range of desired triazolopyridines 1
with yields up to 63% (Table 2). This protocol allowed, in
the majority of the performed experiments, straightfor-
ward access to triazolopyrididnes 1. However, the yield of
the final products 1 are mainly influenced by the reactivity
of the starting materials (8/acid chlorides) which are de-
pendent on their respective steric and electronic proper-
ties.
8f
14 (100)
254.3
8l
83 (100)
246.1
a Isolated yields
b Purity was determined by analytical HPLC-MS at 230 nm.
2,6-Dibromo-3-methoxy pyridine (10)9 can be reacted re-
gioselectively with morpholine in DMF to afford in al-
most quantitative yield the morpholino derivative 11.
Under more forcing conditions the bromo-derivative 11
can be transformed into amine 12 by reaction with aque-
ous ammonia in the presence of catalytic amounts of cop-
per at 185 °C and 10 bar pressure in 69% yield.
Subsequent reaction with ethoxycarbonyl isothiocyanate
yielded precursor 13 in 54% supplied to cyclisation under
similar reaction conditions as outlined above to give ac-
Following the initial concept of a unified synthetic se-
quence approach taking advantage of the common inter-
mediate iodo-triazolopyridine
3
proved to be
unsuccessful. Unfortunately, none of the various palladi-
um-catalysed amination reactions tried, described in anal-
ogy by Buchwald7 and Hartwig,8 with 3 and morpholine
as a model amine (and desired replacement for an aryl
moiety) yielded a detectable amount of triazolopyridine 9,
which led to the design of a new synthetic route.
Table 2 Selection of 2-Amido-5-aryl-8-methoxy-triazolopyridine Derivatives 1
Prod- Ar
uct
R
Yield [%]a Prod Ar
R
Yield [%]a Prod Ar
R
Yield[%]a
MH+
MH+
uct
MH+
uct
(found)
(found)
(found)
1a
1b
48
379.3
1e
21
363.1
1i
10
381.3
43
1f
19
1j
10
433.3
345.3
379.3
1c
61
397.2
1g
1h
18
409.3
1k
1l
21
369.2
1d
53
63
12
431.4
455.3
431.3
a Isolated yields; purity was determined by analytical HPLC-MS at 230 nm and greater 95%.
Synthesis 2003, No. 11, 1649–1652 © Thieme Stuttgart · New York

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Triazolopyridine Derivatives as Potential Inhibitors of the Adenosine Receptor Subtypes
1651
Scheme 2 Synthetic sequence for preparation of 2-amido-5-morpholino-8-methoxy-triazolopyridines 2
Table 3 Representative Triazolopyridine Derivatives 2
Pro-
duct
R
Yield (%)a Pro-
MH+ (found) duct
R
Yield (%)a Pro-
MH+ (found) duct
R
Yield (%)a Pro-
MH+ (found) duct
R
Yield (%)a
MH+
(found)
2a
2b
23
388.2
2c
25
384.3
2e
2f
25
398.4
2g
2h
20
384.3
23
2d
36
25
33
388.2
368.3
374.4
346.4
a Isolated yields; purity was determined by analytical HPLC-MS at 230 nm and greater 95%.
Synthesis of 6
cess to 2-amino-5-morpholino-8-methoxy-triazolopyri-
dine 9 in 57% yield. The final amidation with 22 acid
chlorides concluded this novel 5-step synthetic sequence
for the preparation of the desired triazolopyrididnes 2 with
yields up to 36% (Scheme 2).10 Representative examples
are shown in Table 3.
To a solution of hydroxylamine hydrochloride (21.8 g, 313.7 mmol)
and N′-ethyldiisopropylamine (32.2 mL, 188.2 mmol) in a mixture
of CH3OH–EtOH (130 mL, 1:1) was added N-(3-methoxy-2-pyrid-
inyl)-N -carboethoxy-thiourea (5, 16 g, 62.7 mmol) and stirred for
2 h at r.t. and subsequently for 3 h at 60 °C. The volatiles were re-
moved under reduced pressure and the residue was treated with H2O
(100 mL). The resulting precipitate was washed with CH3OH–Et2O
(25 mL, 4:1) and then with Et2O (25 mL). After drying under high
vacuum 6 (8 g, 48.7 mmol, 78%) of was collected as off-white cys-
tals.
1H NMR (250 MHz, DMSO-d6): = 8.13 (dd, J1 = 6.6 Hz, J2 = 1
Hz, 1 H, H-5), 6.89 (dd, J1 = 7.1 Hz, J2 = 1 Hz, 1 H, H-7), 6.77 (dd,
J1 = 7.1 Hz, J2 = 6.6 Hz, 1 H, H-5), 5.88 (br s, 2 H, NH2), 3.90 (s, 3
H, OCH3).
In conclusion, we have designed and developed two ver-
satile and complementary 5-step synthetic strategies for
the preparation of 2-amido-5-aryl-8-methoxy-triazolopy-
ridine derivatives 1 and 2-amido-5-morpholino-8-meth-
oxy-triazolopyridine derivatives 2. The key step in each
synthetic route can be constituted as the formation of the
triazolopyridine-derivative 6 and 9 in 78% and 57% yield,
respectively, through an intermediately formed 4H-
[1,2,4]oxadiazol-5-one. The final Suzuki coupling/amida-
tion concluded the straightforward access to these previ-
MS: m/z (%) = 163.0 (100) [M – H+].
Synthesis of 3
ously not described triazolopyridine derivatives 1 and 2. A mixture of 8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine
(6, 3 g, 18.3 mmol), H2O (6 mL) and sulfuric acid (97%, 6 mL) was
Notably, this triazolopyridine scaffold bears three vectors
heated to 100 °C and KIO3 (4.3 g, 20.1 mmol) was added in portions
of diversity which allowed for maximum flexibility in de-
over a period of 1 h. The mixture was heated to 120 °C for 3 h and
sign and combinatorial synthesis of molecules with poten-
tial A2a inhibitory activity. Based on these results
chemistry efforts towards novel triazolopyridine deriva-
tives with improved biological in vitro activities, and
pharmacological profiles are currently undertaken and
will be reported fully in due course.
further H2O (6 mL) and sulfuric acid (97%, 6 mL) was added. After
cooling to 0 °C the precipitate was collected and washed with H2O
(2 × 15 mL) to yield title compound 3 as beige crystals. The mother
liquid was treated with Na2CO3 and extracted with CH2Cl2 (5 × 250
mL). The combined organic layers were dried (MgSO4) and evapo-
rated to dryness to yield an additional amount of title compound 3.
The product was recrystallised from EtOH to yield a total of 2.59 g
(49%, 8.9 mmol) of 3.
1H NMR (250 MHz, DMSO-d6): = 7.22 (d, J = 8.2 Hz, 1 H, H-7),
6.76 (d, J = 8.2 Hz, 1 H, H-6), 6.10 (br s, 2 H, NH2), 3.89 (s, 3 H,
OCH3).
NMR spectra were recordered on a Bruker AC250 MHz spectromer
and a Bruker Avance 500 MHz spectrometer with Bruker BEST-
System. Mass spectra were recorded on a API 300 Sciex.
MS: m/z (%) = 291.0 (100) [MH+].
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1652
M. Nettekoven et al.
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Synthesis of 8; General Procedure
ing with a mixture of CH2Cl2–MeOH (20:1) to yield after evapora-
A mixture of 3 (50 mg, 0.17 mmol), arylboronic acid (46.2 mg, 0.38
mmol), dichloro[1,1 -bis-(diphenylphosphino)-ferrocene]palladi-
um(II) dichloromethane adduct (6.3 mg, 0.008 mmol) and aq
Na2CO3 solution (2 M, 0.3 mL) in dioxane (1 mL) was heated for
90 min to 80 °C. The mixture was filtered over a short silica pad and
eluted with EtOAc (30 mL). The filtrate was then concentrated un-
der reduced pressure and the residue was purified by preparative
HPLC on reversed phase eluting with a H2O–CH3CN gradient.
tion 127.5 mg (57%) of 9.
1H NMR (250 MHz, CDCl3): = 7.25 (d, J = 8 Hz, 1 H, H-5), 7.07
(d, J = 8 Hz, 1 H, H-4), 4.45 (br s, 2 H, NH2), 3.88 (t, J = 4.8 Hz, 4
H, OCH2), 3.83 (s, 3 H, OCH3), 3.48 (t, J = 4.8 Hz, 4 H, NCH2).
MS: m/z (%) = 250.2 (100) [MH+].
Acknowledgements
8a
The authors are grateful to Drs A. Alanine, C. Riemer, R. Norcross,
R. Jakob-Roetne, A. Flohr for helpful discussions and support.
Thanks for technical assistance to C. Kuratli. For careful proof-
reading and revision of this manuscript the authors are grateful to
Dr. A. Thomas.
Yield: 29%.
1H NMR (250 MHz, DMSO-d6): = 7.82 (dd, J1 = 8.1 Hz, J2 = 1
Hz, 2 H, phenyl), 7.48 (m, 3 H, phenyl), 6.81 (dd, J1 = 8.4 Hz, J2 = 1
Hz, 2 H, H-6 and H-7), 4.53 (br s, 2 H, NH2), 4.03 (s, 3 H, OCH3).
MS: m/z (%) = 241.3 (100) [MH+].
References
Synthesis of 1; General Procedure
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A mixture of acid chloride (0.125 mmol), 8 (0.137 mmol) and Et3N
(27 mg) in dioxane (0.5 mL) was shaken at r.t. for 4 d. After addition
of formic acid (0.05 mL) the mixture was directly subjected to pre-
parative HPLC on reversed phase eluting with a H2O–CH3CN gra-
dient to yield, after evaporation of the product fractions, the title
compound.
1f
(3) (a) Nettekoven, M. Synlett 2001, 1917. (b) Brodbeck, B.;
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Yield: 19%.
1H NMR (500 MHz, DMSO-d6): = 7.95 (m, 4 H, Ph), 7.61 (m, 6
H, Ph), 7.30 (m, 3 H, Ph/NH), 4.05 (s, 3 H, OCH3).
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(6) General procedure described in analogy by: Harrison, J. J.;
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(7) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
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MS: m/z (%) = 345.3 (100) [MH+].
Synthesis of 11
A mixture of 10 (2.64 g, 10 mmol) in DMF (8 mL), morpholine
(1.74 mL, 20 mmol) and Cs2CO3 (4.87 g, 15 mmol) was heated for
16 h to 120 °C. H2O (100 mL) was added and the mixture was ex-
tracted with Et2O (3 × 150 mL). The combined organic layers were
dried (MgSO4) and evaporated to dryness to yield 2.68 g (98%) of
11.
1H NMR (250 MHz, DMSO-d6): = 6.95 (d, J = 8.1 Hz, 1 H, H-5),
6.90 (d, J = 8.1 Hz, 1 H, H-4), 3.82 (m, 7 H, OCH3/OCH2), 3.42 (t,
J = 4.8 Hz, 4 H, NCH2).
MS: m/z (%) = 273.0 (100) [MH+].
Structural identity of 11 was corroborated by NOE expriments.
(8) Hartwig, J. F. Handbook of Organopalladium Chemistry for
Organic Synthesis 2002, 1, 1051–1096.
Synthesis of 9
(9) Chapman, G. M.; Stanforth, S. P.; Berridge, R.; Pozo-
Gonzales, C.; Skabara, P. J. J. Mat. Chem. 2002, 12, 2292.
(10) (a) General procedure for the synthesis of 2 employed
similar reaction conditions as for the synthesis of 1. (b) For
a more detailed description of workflow procedures utilised
in the preparation of compound arrays please refer to:
Nettekoven, M.; Thomas, A. W. Curr. Med. Chem. 2002, 9,
2179.
A solution of hydroxylamine hydrochloride (347.4 mg, 5 mmol)
and DIPEA (513 L, 3 mmol) in MeOH–EtOH (3 mL, 1:1) was
treated with N-(3-methoxy-6-morpholin-4-yl-2-pyridinyl)-N -car-
boethoxy-thiourea (13, 308 mg, 0.9 mmol) in MeOH–EtOH (2 mL,
1:1) and heated to 80 °C for 16 h. The mixture was evaporated to
dryness and purified by flash column chromatography on silica elut-
Synthesis 2003, No. 11, 1649–1652 © Thieme Stuttgart · New York