Combinatorial synthesis of 5-aryl-[1,2,4]-triazolo-[1,5-a]-pyridine derivatives as potential inhibitors of the adenosine 2A receptor

Article abstract of DOI:10.1055/s-2001-18758

A novel and efficient 4-step synthesis of 2,4-diamino-4-bromo-pyridine 4 in 56% overall yield by a double Curtius rearrangement as a key step is reported. N-amination of 2,4-diamino-4-bromo-pyridine 4 with O-mesitylenesulfonylhydroxylamine 10 and subsequent reaction with aldehydes yielded, upon oxidative ring-closure, 5-bromo-triazolopyridines 2a-2f. Thereafter, from a combinatorial parallel Suzuki cross-coupling reaction 260 previously non-described 5-aryl-[1,2,4]-triazolo-[1,5-a]-pyridines 1 were obtained in acceptable overall yield.

Full text of DOI:10.1055/s-2001-18758

LETTER
1917
Combinatorial Synthesis of 5-Aryl-[1,2,4]-triazolo-[1,5-a]-pyridine
Derivatives as Potential Inhibitors of the Adenosine 2A Receptor
S
ynthesisof 5-Aryl-[1
a
t
o-[1,5-
t
a
]-pyri
h
dine
D
erivatives as Nettekoven*
F. Hoffmann-La Roche Ltd., Pharmaceutical Research Preclinical Division, Lead Generation, Discovery Chemistry, CH-4070 Basel,
Switzerland
Fax +41(61)6886459; E-mail: matthias.nettekoven@roche.com
Received 15 August 2001
reaction of intermediate 3 with aldehydes was considered
Abstract: A novel and efficient 4-step synthesis of 2,4-diamino-4-
to be straightforward in terms of regioselective outcome
as the N-aminated 2,6-diamino-4-bromopyridine 3 is
symmetric thus only offering one possibility for the alde-
bromo-pyridine 4 in 56% overall yield by a double Curtius rear-
rangement as a key step is reported. N-amination of 2,4-diamino-4-
bromo-pyridine 4 with O-mesitylenesulfonylhydroxylamine 10 and
subsequent reaction with aldehydes yielded, upon oxidative ring- hyde to react to the desired triazolopyridines 2.
closure, 5-bromo-triazolopyridines 2a–2f. Thereafter, from a com-
2,6-Diamino-4-bromopyridine 4 is not commercially
binatorial parallel Suzuki cross-coupling reaction 260 previously
available and an efficient synthetic route has not been de-
non-described 5-aryl-[1,2,4]-triazolo-[1,5-a]-pyridines 1 were ob-
scribed.7 A suitable precursor for the synthesis of 2,6-di-
tained in acceptable overall yield.
amino-4-bromopyridine 4 is chelidamic acid 58 since this
Key words: Adenosine 2A, double-Curtius rearrangement, N-ami-
molecule already displays the desired tri-substitution pat-
tern on the pyridine ring. The reaction of chelidamic acid
5 with phosphorous pentabromide in CCl4 yielded, after
quenching with ethanol, the desired 4-brominated di-ethyl
ester 6 in 93% as the only regioisomer.9 Conversion of the
ester functionalities to yield the bis-hydrazide 7 was
achieved by treatment with hydrazine hydrate in 90%
yield in pure form after crystallisation. Subsequently, dia-
zotisation to the bis-acylazide 8 was smoothly accom-
plished by treatment with NaNO2 under acidic conditions
in 90%. In order to prevent adverse side reactions of the
intermediately formed bis-isocyanate it was necessary to
remove accompanying water from the bis-acyl-azide 810
before the double Curtius rearrangement.11 In the event
the double Curtius rearrangement was triggered by heat-
ing the bis-acyl-azide 8 in tert-butyl alcohol under reflux
and subsequent elaboration of the isocyanates to bis N-t-
butoxycarbonyl pyridine 9. Pyridine 9 was not isolated
and after removal of excess tert-butyl alcohol was treated
with excess TFA in DCM to liberate the desired 2,6-di-
amino-4-bromopyridine 4 in 74% yield after crystallisa-
tion (Scheme 2).12
nation, Suzuki cross-coupling reaction, 7-amino-triazolopyridine
derivatives
Combinatorial chemistry has developed into a powerful
tool for the synthesis of compounds that are interesting to
the pharmaceutical industry.1 The identification of lead
compounds as well as the evaluation of active substances
is greatly facilitated and accelerated by parallel solution
phase and solid phase chemistry alike.2 In the course of a
medicinal chemistry project focussing on the human Ad-
enosine 2A receptor3 7-amino-triazolopyridines were as-
sumed to modulate neurodegenerative diseases (e.g.
Parkinson, Alzheimer, depression) and therefore allow for
a new entry into the regulation of behavioural disorders.
The previously described synthesis4 of 7-amino-triazol-
opyridines afforded the desired compounds only in very
moderate overall yields due to harsh reaction conditions
and a more generally applicable reaction sequence was
sought. 7-Amino-triazolopyridine derivatives 1 bearing
aromatic residues in 2 and 5 position were considered to
reveal the most potent binding affinities. We therefore de-
signed a new synthetic route and the retrosynthetic analy-
sis is shown in Scheme 1. The bis-aryl C-C bond in 1 may
be formed via a palladium catalysed reaction (e.g. Suzuki
reaction) and the fused [1,2,4]-triazolo unit 2 may be
formed via cyclisation of the appropriate bis-aminopyri-
dine 3 with suitably substituted aldehydes.
This new four-step route constitutes a novel access to the
desired 2,6-diamino-4-bromopyridine 4 from chelidamic
acid 5 in 56% overall yield with a double Curtius rear-
rangement as a key step in the reaction sequence.
Following the initial concept, 2,6-diamino-4-bromopyri-
dine 4 was used for further elaboration to the desired tria-
zolopyridine-derivatives 1. The amination of the pyridine-
nitrogen was successfully achieved employing as the re-
agent of choice O-mesitylenesulfonylhydroxylamine5 10
as aminating source. The intermediate 3 was not isolated
and subsequently treated in one pot6 with aldehydes and
upon addition of aqueous KOH and exposure of the reac-
tion vessel to ambient air, an efficient oxidation took place
to obtain the triazolopyridines 2 (Scheme 2).
It was assumed that 2 should be accessible through appro-
priate manipulation in a one-pot procedure by N-
amination5 of 2,6-diamino-4-bromopyridine 4, reaction of
the intermediate 3 with aldehydes, and subsequent cycli-
sation and oxidation to furnish triazolopyridines 2.6 The
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1917,1920,ftx,en;G17401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1918
M. Nettekoven
LETTER
Scheme 1 Retrosynthetic analysis of 7-amino-[1,2,4]-triazolo-[1,5-a]-pyridine derivatives 1
Scheme 2 Synthesis of 5-bromo-triazolopyridine derivatives 2 via 2,6-diamino-4-bromopyridine 4
Table 1 Representative Examples of Synthesised 5-Bromo-triazol-
opyridine Derivatives 2a-2f
Substituted benzaldehydes, substituted furan-carboxalde-
hydes, substituted thiophene-carboxaldehydes, substitut-
ed pyridine-carboxaldehydes as well as cycloaliphatic
aldehydes worked with the same reaction protocol to ob-
tain variously substituted triazolopyridines 2 in accept-
able yields up to 79%. A representative selection of the
synthesised triazolopyridine derivatives 2a–f is depicted
No.
2a
R
Yield (%)
39
36
2b
1
in Table 1. All products were characterised by H NMR
and MS, the purity was assured by HPLC.
2c
2d
2e
2f
35
37
56
79
The final step of the synthesis, the Suzuki reaction,13
was performed under a wide range of reaction condi-
tions and all variations were found to work reliably with
satisfactory yields. The preferred method employed
Pd(dppf)Cl2 DCM as catalyst and aqueous sodium bicar-
bonate in boiling dioxane.14 This method proved advanta-
geous over other methods using Pd(PPh3)4 as catalyst as
triphenylphosphine oxide was found as a predominant by-
product which hampered the purification of the end prod-
ucts 1. Pleasingly, boronic acids and boronic-esters
worked equally well in the cross-coupling reaction and
dard conditions produced the final products in yields up to
49%.15
only the nature of the substituents appeared to influence All synthesised triazolopyridines 1 were tested in an in
the duration of the reaction (Scheme 3). All products 1 vitro radio ligand displacement assay against the human
were after removal of the catalyst by filtration purified by
reversed phase preparative HPLC eluting with a water–
acetonitrile gradient.
From the 260 products synthesised a representative selec-
tion of [1,2,4]-triazolo-[1,5-a]-pyridines 1a–v is shown in
Table 2. It was found that regardless of the substitution of
the boronic acid/esters the Suzuki reaction under the stan-
Scheme 3 Suzuki cross-coupling
Synlett 2001, No. 12, 1917–1920 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Aryl-[1,2,4]-triazolo-[1,5-a]-pyridine Derivatives
1919
Adenosine 2A receptors to obtain a preliminary structure In conclusion, we have demonstrated an efficient and
activity relationship with some compounds being active in straightforward synthesis of 2,6-diamino-4-bromo-pyri-
the low nano molar range.
dine 4 with a double Curtius rearrangement as the key
step. This sequence proceeded in 56% overall yield, in 4
steps, to afford the desired product. The electrophilic am-
ination of the pyridine nitrogen in 4 with O-mesitylene-
sulfonylhydroxylamine 10 followed by the reaction with
various aromatic and heteroaromatic aldehydes allowed
efficient access to the desired 5-bromo-triazolopyridines
2 in satisfactory yields in a one-pot procedure. Subsequent
Suzuki reaction with Pd(dppf)Cl2 DCM as the catalyst of
choice yielded, in a combinatorial fashion, 260 previously
non described triazolopyridines 1, which were tested in an
in vitro radio ligand displacement assay for the human
Adenosine 2A receptor thus establishing a first structure
activity relationship. The results of the endeavour synthe-
sising new designed triazolopyridines with improved
pharmacological profiles and binding affinities towards
the human Adenosine 2A receptor, taking advantage of
combinatorial parallel chemistry approaches, will be re-
ported in full in due course.
Table 2 Representative Examples of Synthesised 5-Aryl-[1,2,4]-
triazolo-[1,5-a]-pyridine Derivatives
No.
Structure
Ar
Purity (%) Yield (%) MH+
found
R
1a
100
17
344.3
1b
1c
1d
100
100
100
11
33
49
331.3
345.3
337.4
1e
1f
82
39
46
283.3
361.2
100
1g
1h
83
43
31
316.3
305.3
Acknowledgement
This work was supported by Drs. A. Alanine, A. Flohr, R. Jakob-
Roetne, R. Norcross and C. Riemer. Technical assistance is grate-
fully acknowledged from A. Grieder, U. Hilty, D. Morat, B. Puell-
mann and S. Schmitt. Thanks to Dr. A. Thomas for careful proof-
reading and helpful discussions in preparation of this manuscript.
100
1i
1j
100
100
26
12
309.2
348.4
References
1k
100
13
334.4
(1) (a) Jung, G. Combinatorial Chemistry; Wiley-VCH:
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100
100
21
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307.4
323.4
1m
1n
1o
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26
17
323.4
318.3
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94
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345.4
1q
1r
100
80
33
15
345.3
383.3
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W.; Huber, G.; Kilpatrik, G. WO 0117999, 2001; Chem.
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1t
100
100
21
16
341.4
375.3
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100
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30
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297.3
311.3
Synlett 2001, No. 12, 1917–1920 ISSN 0936-5214 © Thieme Stuttgart · New York

1920
M. Nettekoven
LETTER
(7) The 4-Cl-derivative has been described: (a) Kawano, E.;
Nagai, M.; Inubushi, A.; Shimada, K.; Tobari, H. WO
9709982, 1997; Chem. Abstr. 1997, 126, 259187.
(b) Sellstedt, J. H.; Klaubert, D. H. DE 2802508, 1978;
Chem. Abstr. 1978, 89, 180018.
(8) Chelidamic acid can be easily accessed from the reaction of
ammonia with chelidonic acid: Karrer, W. Konstitution und
Vorkommen der organischen Pflanzenstoffe; Birkhäuser
Verlag: Basel, 1976, 556.
(9) (a) Takalo, H.; Kankare, J. Acta Chem. Scand., Ser. B 1987,
B41, 219. (b) Pryor, K. E.; Shipps, W. Jr.; Skyler, D. A.;
Rebek, J. Jr. Tetrahedron 1998, 54, 4107. (c) Schmidt, B.;
Ehlert, D. K. Tetrahedron Lett. 1998, 39, 3999.
(10) A suspension of 1 g (3.65mmol) 4-bromo-pyridine-2,6-
dicarboxylic acid dihydrazide 7 in 32 mL water was treated
with 1.6 mL HCl (37%) at room temperature. The resulting
mixture was cooled to 0 °C and 554 mg NaNO2 in 2.4 mL
water was added slowly maintaining the temperature below
2 °C. Upon completion saturated NaHCO3 solution was
added to pH ~8 and the white precipitate was filtered off and
washed with water. The residue was dissolved in CHCl3 and
dried with MgSO4. The filtrate was concentrated at 20 °C to
yield 975 mg (90%) of the bis acyl azide 8 as a white solid
which was used immediately afterwards in the consecutive
step without further purification. Caution!! The bis acyl
azide 8 has a potential to extrude nitrogen. We found the
handling of 8 to be straightforward even on a multi-gram
scale.
(11) (a) Dodd, R. H.; Ouannes, C.; de Carvalho, L. P.; Valin, A.;
Venault, P.; Chapouthier, G.; Rossier, J.; Potier, P. J. Med.
Chem. 1985, 28, 824. (b) Markees, D. G.; Dewey, V. C.;
Kidder, G. W. J. Med. Chem. 1968, 11, 126. (c) The
Curtius rearrangement: A historical description of its
discovery and explanation: Takebayashi, M. Kagakushi
Kenkyu 1989, 16, 149.
(12) The physical and spectroscopic properties (e.g. 1H NMR,
HPLC, MS, elemental analysis) of all new compounds were
fully consistent with those of the assigned structures.
(13) (a) Miyaura, N.; Suzuki, A. Chem Rev. 1995, 95, 2457.
(b) Diederich, F.; Stang, P. J. Metal Catalyzed Cross-
coupling Reactions; Wiley-VCH: Weinheim, 1998.
(14) General procedure: A mixture of 1 equivalent (typically 0.1
mmol) 5-bromo-triazolopyridine 2, 1.1 equivalent boronic
acid(ester), 3 equivalents 2 M Na2CO3 solution and 5 mol%
Pd(dppf)Cl2 DCM adduct in dioxane was heated to 110 °C
for 16 h. After cooling the mixture was filtered and subjected
to preparative reversed phase column chromatography
(Dynamax pumps and detector in combination with a Gilson
215 liquid handler on a YMC ODS-A column (50 20 mm))
eluting with a gradient of water and acetonitrile (20-95%).
Evaporation of the elution solvents yielded the desired
triazolopyridines 1 in pure form.
(15) The determination of purity and the corroboration of the
chemical structure was performed with analytical HPLC-MS
(HP1100 pumps, Gilson 215 autosampler, Finnigan MS,
water and acetonitrile gradient (20-95%)).
Synlett 2001, No. 12, 1917–1920 ISSN 0936-5214 © Thieme Stuttgart · New York