Synthetic approaches to 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines

Article abstract of DOI:10.1016/j.tetlet.2010.05.083

The preparation of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines, exemplified by 5-[3-(benzyloxy)phenyl]-7-cyclobutylimidazo[5,1-f][1,2,4]triazin-4-amine, was developed through a linear and three convergent synthetic strategies, with the latter providing the greatest flexibility for diversification at the 5-position at the last step of the synthesis.

Full text of DOI:10.1016/j.tetlet.2010.05.083

Tetrahedron Letters 51 (2010) 3899–3901
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Synthetic approaches to 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines
*
*
Douglas S. Werner , Hanqing Dong , Mridula Kadalbajoo, Radoslaw S. Laufer, Paula A. Tavares-Greco,
Brian R. Volk, Mark J. Mulvihill, Andrew P. Crew
Department of Cancer Chemistry, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of 5,7-disubstituted imidazo[5,1-f ][1,2,4]triazin-4-amines, exemplified by 5-[3-(benzyl-
oxy)phenyl]-7-cyclobutylimidazo[5,1-f ][1,2,4]triazin-4-amine, was developed through a linear and three
convergent synthetic strategies, with the latter providing the greatest flexibility for diversification at the
5-position at the last step of the synthesis.
Received 14 April 2010
Revised 18 May 2010
Accepted 19 May 2010
Available online 25 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Kinases represent a class of proteins that serve as important sig-
nal regulators for a variety of cellular functions such as differentia-
tion, proliferation, and apoptosis. Efforts within our group directed
at identifying inhibitors of such enzymes for use in oncology led to
the 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amine scaffold
as such a chemotype of interest (Fig. 1).1 To the best of our knowl-
edge, only a few papers have reported the syntheses of such
and subsequent displacement with amines. Although certain 4-
chloro imidazotriazine intermediates have been reported to be sta-
ble and isolable,2c our one-pot procedure using POCl3 and quenching
with 1 M NH3 in 2-propanol resulted in no desired product and only
recovery of the starting material 7. However, treatment of com-
pound 7 with POCl3 and 1,2,4-triazole in pyridine and subsequent
displacement of the intermediate 1,2,4-triazole adduct2b using the
above ammonia solution in a one-pot fashion afforded the target
compound 1 in 39% yield.7
While the synthesis of compound 1 via this linear route was
successful, the route was not suitable for the late-stage diversifica-
tion necessary to further explore the SAR at the 5-position of this
new series. Therefore, we undertook the development of a conver-
gent route (I), which would allow for such a late-stage introduction
of various substitutions to the 5-position, ideally in the last step of
the synthesis.
Our first convergent synthetic route is shown in Scheme 3. Ini-
tially we attempted the cyclization of keto-ester 82a with hydrazon-
oformic hydrazide prepared in situ, following the same strategy
used in the linear synthetic route. Unfortunately, the reaction re-
sulted in a complicated mixture, most likely due to degradation of
the phthalimide by the hydrazine component in the reaction mix-
ture. In order to improve this cyclization process, the commercially
available thiosemicarbazide was employed, utilizing sulfur as a
masked hydrogen at the 2-position.8 Formation of the hydrazone
in EtOH at 80 °C and subsequent treatment with N,N-diisopropyl-
ethylamine successfully afforded the thio-1,2,4-triazinone 9 in 81%
a
heterobicyclic skeleton and a logical synthetic precursor
imidazo[5,1-f][1,2,4]triazin-4-one,2 with none being suitable for
late-stage diversification at the key 5-position where substitution
is known to drive structure–activity relationships (SARs) versus a
number of kinase targets.3 Herein, we describe our initial linear
preparation of a proof-of-concept compound 1 starting from methyl
amino[3-(benzyloxy)phenyl]acetate 2, as well as three different
convergent synthetic routes which allowed for late-stage analoging
at the 5-position via Pd-catalyzed transformations. The synthetic
strategy of both linear and convergent routes is shown in Scheme 1.
The details of the linear synthesis are illustrated in Scheme 2. The
amino ester 24 was converted to N-acyl amino acid 3, from which the
keto-ester 4 was prepared via a Dakin–West reaction2d in a modest
16% yield. Attempted cyclization of
4 with formamidrazone
[CH(@NH)NHNH2], generated in situ by mixing hydrazine and
formamidine in a 1:1 ratio, failed to produce the desired 1,2,4-triaz-
inone 6.2d Therefore, we applied hydrazonoformic hydrazide
[CH(@NHNH2)NHNH2], generated in situ by mixing hydrazine and
formamidine in a 2:1 ratio, in the cyclization reaction5 and by using
these conditions, compound 5 was successfully obtained in 45%
yield. Deamination via the diazonium salt using sodium nitrite in
concd HCl afforded 6 in 83% yield.6 Cyclization of compound 6 with
POCl3 provided the desired bicyclic imidazotriazinone 7 in quantita-
tive yield. Installation of a 4-amino group into analogous systems
usually requires a two-step sequence: 4-chlorination using POCl3
NH2
Ar
4
5
N
N
7 R
N
N
1
* Corresponding authors. Tel.: +1 631 962 0600; fax: +1 631 845 5671.
E-mail addresses: dwerner@osip.com (D.S. Werner), hdong@osip.com (H. Dong).
Figure 1. General structure of the imidazo[5,1-f][1,2,4]triazine system.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.083

3900
D. S. Werner et al. / Tetrahedron Letters 51 (2010) 3899–3901
O
N
O
Ar
N
Ar
NH
Ar
HN
HN
MeO
NH2
O
N
N
N
NH2
O
Ar
N
O
N
Linear route
N
N
NH2
OMe
O
I
1
N
N
NH2
HN
NH2
HN
NH2
N
or
or
Ar = m-BnO-C6H4
N
N
N
N
N
N
N
N
H2N
Convergent routes
Scheme 1. Synthetic strategy.
O
O
Ar
O
Ar
O
a, b
c
HO
MeO
O
a
b
N
H
HN
N
O
NH2
N
O
N
O
EtO2C
S
N
H
2
3
O
O
O
N
Ar
8
9
O
O
Ar
H2N
N
NH
O
d
O
EtO
e
N
H
N
O
HN
N
O
c
e
HN
X
N
N
4
O
5
N
N
10
O
N
Ar
O
11 (X = NH2)
12 (X =
Ar
N
d
)
NHCO
HN
NH
g
f
HN
1
N
N
O
HN
NH2
N
O
Y
I
N
g
6
N
7
h
N
N
1
N
N
N
Scheme 2. Linear synthetic route. Reagents and conditions: (a) cyclobutanecar-
bonyl chloride, NaHCO3, THF, 0 °C to rt, 83%; (b) 1 M NaOH, THF/H2O (1:1), 84%; (c)
(i) EtO2CCOCl, pyridine, DMAP, THF, reflux; (ii) NaOEt, EtOH, reflux, 16%; (d) 1 M
N2H4 in THF, HC(@NH)NH2ÁHCl, EtOH, 0 °C to À20 °C to rt, 45%; (e) NaNO2, concd
HCl, EtOH/H2O, 0 °C to rt, 83%; (f) POCl3, 55 °C, 100%; (g) 1,2,4-triazole, POCl3,
pyridine, rt, then 1 M NH3 in i-PrOH, 0 °C to rt, 39%.
15
13 (Y = H)
14 (Y = I)
f
Scheme 3. Convergent route I. Reagents and conditions: (a) thiosemicarbazide,
EtOH, 80 °C, 3 h, then DIEA, 40 °C, 16 h, 81%; (b) Raney Ni (10 equiv), EtOH, reflux,
70%; (c) anhydrous hydrazine, DCM/EtOH (1:1), rt; (d) cyclobutanecarbonyl
chloride, DIEA, DMF, 0 °C to rt, 57% (two steps from 10); (e) POCl3, 55 °C, 41%; (f)
5 equiv NIS (5 equiv), DMF, rt to 55 °C, 53%; (g) 1,2,4-triazole, POCl3, pyridine, rt,
then 1 M NH3 in i-PrOH, 0 °C to rt, 82%; (h) [3-(benzyloxy)phenyl]boronic acid,
PdCl2(dppf), K2CO3, dioxane/H2O (4:1), 100 °C (microwave), 30 min, 72%.
yield. Desulfurization of compound 9 using Raney nickel9 resulted in
compound 10 in 70% yield. Removal of the phthalimide-protecting
group with hydrazine provided key intermediate 11. With com-
pound 11 in hand, various C-5 and C-7 substitutions could be readily
installed. Amidation of compound 11 and subsequent treatment
with POCl3 yielded the bicyclic compound 13. Iodination of 13 pro-
ceeded with 5 equiv of N-iodosuccinimide (NIS) at 55 °C, and the
resulting 5-iodoimidazotriazinone 14 was converted to the versatile
4-amino intermediate 15 in 82% yield, using the method described
previously for the linear route. From key intermediate 15, various
substitutions could be introduced to the C-5 position by Pd-cata-
lyzed coupling reactions. For example, compound 1 was readily syn-
thesized via Suzuki chemistry with [3-(benzyloxy)phenyl]boronic
acid in 72% yield.
Although route I was effective at providing the desired interme-
diate 15, larger scale synthesis proved to be challenging. Firstly, the
keto-ester 8 was not easy to synthesize and required a two-step
procedure using relatively expensive starting materials.2a,10 Sec-
ondly, the poor solubility of intermediates 9–11 and the 1,4-
dihydroxyphthalazine byproduct (10?11) made the scalability
and purification challenging. Thirdly, this synthetic route was still
considered too lengthy. As a result, we continued exploring other
potential routes to prepare the key intermediate 15.
O
O
N
OMe
O
OMe
O
17
b
N
NH
N
N
NH2
a
N
N
O
N
N
16
18
OMe
OMe
I
c
d
d
N
N
15
N
N
N
N
N
19
20
Scheme 4. Convergent route II. Reagents and conditions: (a) 10% aq NaHCO3, THF,
rt, 72%; (b) POCl3, DMF/MeCN, rt, 55%; (c) NIS, DMF, 55 °C, 68%; (d) 7 N NH3 in
MeOH, rt, 89%.
Our second convergent synthetic route is shown in Scheme 4.
Compound 16 was prepared from 6-methyl-4H-[1,2,4]triazin-5-
one in four steps.11 Amidation of 16 with the active ester 17 and
subsequent POCl3 cyclization gave compound 19 in 40% yield.
Iodination of 19 using NIS was realized at 55 °C to give compound

D. S. Werner et al. / Tetrahedron Letters 51 (2010) 3899–3901
3901
exploration based on convergent routes II and III and the biological
significance of this chemotype will be discussed in future
communications.
O
N
O
N
17
b
HN
H2N
NH
HN
H2N
NH2
2HCl
N
N
a
O
Acknowledgments
22
21
We thank Professor Victor Snieckus at Queen’s University, ON
for consultation; Ms. Viorica M. Lazarescu and Dr. Minghui Wang
for their analytical support.
O
Y
HN
d
e
N
14
15
N
N
H2N
References and notes
1. (a) Crew, A. P.; Mulvihill, M. J.; Werner, D. S. WO2006/012422.; (b) Arnold, L.
D.; Cesario, C.; Coate, H.; Crew, A. P.; Dong, H. -Q.; Foreman, K.; Honda, A.;
Laufer, R.; Li, A. -H.; Mulvihill, K. M.; Mulvihill, M. J.; Nigro, A.; Panicker, B.;
Steinig, A. G.; Sun, Y.; Weng, Q.; Werner, D. S.; Wyle, M. J.; Zhang, T. WO2005/
097800.; (c) Chen, X.; Coate, H.; Crew, A. P.; Dong, H. -Q.; Honda, A.; Mulvihill,
M. J.; Tavares, P. A.; Wang, J.; Werner, D. S.; Mulvihill, K. M.; Siu, K. W.;
Panicker, B.; Bharadwaj, A.; Arnold, L. D.; Jin, M.; Volk, B.; Weng, Q.; Beard, J. D.
WO2007/061737.
23 (Y = H)
24 (Y = I)
c
Scheme 5. Convergent route III. Reagents and conditions: (a) 1 M NaHCO3, THF/
MeCN (1:1), rt, 83%; (b) POCl3, 1,2-dichloroethane, reflux, 90%; (c) NIS, DMF, rt, 75%;
(d) t-butylnitrite, 5% DMF/THF (1:5), rt, 91%; (e) 1,2,4-triazole, POCl3, pyridine, rt,
then 1 M NH3 in i-PrOH, 0 °C to rt, 82%.
2. (a) Knutsen, L. J. S.; Judkins, B. D.; Mitchell, W. L.; Newton, R. F.; Scopes, D. I. C. J.
Chem. Soc., Perkin Trans. 1 1984, 229; (b) Knutsen, L. J. S.; Judkins, B. D.; Newton,
R. F.; Scopes, D. I. C.; Klinkert, G. J. Chem. Soc., Perkin Trans. 1 1985, 621; (c)
Heim-Riether, A.; Healy, J. J. Org. Chem. 2005, 70, 7331; (d) Charles, I.; Latham,
D. W. S.; Hartley, D.; Oxford, A. W.; Scopes, D. I. C. J. Chem. Soc., Perkin Trans. 1
1980, 1139.
3. (a) Mulvihill, M. J.; Ji, Q.-S.; Werner, D.; Beck, P.; Cesario, C.; Cooke, A.; Cox, M.;
Crew, A.; Dong, H.; Feng, L.; Foreman, K. W.; Mak, G.; Nigro, A.; O’Connor, M.;
Saroglou, L.; Stolz, K. M.; Sujka, I.; Volk, B.; Weng, Q.; Wilkes, R. Bioorg. Med.
Chem. Lett. 2007, 17, 1091; (b) Mulvihill, M. J.; Ji, Q.-S.; Coate, H. R.; Cooke, A.;
Dong, H.; Feng, L.; Foreman, K.; Rosenfeld-Franklin, M.; Honda, A.; Mak, G.;
Mulvihill, K. M.; Nigro, A. I.; O’Connor, M.; Pirrit, C.; Steinig, A. G.; Siu, K.; Stolz,
K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.; Gibson, N. W. Bioorg. Med. Chem. 2008,
16, 1359; (c) Mulvihill, M. J.; Cooke, A.; Rosenfeld-Franklin, M.; Buck, E.;
Foreman, K.; Landfair, D.; O’Connor, M.; Pirritt, C.; Sun, Y.; Yao, Y.; Arnold, L. D.;
Gibson, N. W.; Ji, Q.-S. Future Med. Chem. 2009, 1, 1153.
20. The 4-MeO group of 20 was readily displaced by ammonia at rt
using 7 N NH3 in MeOH, providing the intermediate 15. The NMR
spectroscopic data of compound 15 were identical to those ob-
tained when 15 was prepared according to route I (Scheme 3). Of
note, there were no solubility issues in this route as was the case
in route I.
Our third convergent synthetic route is shown in Scheme 5.
Condensation of the inexpensive reagents ethyl bromopyruvate,
dibenzylamine, and aminoguanidine bicarbonate, followed by
debenzylation via hydrogenation over Pd–C afforded the known
3-amino-6-(aminomethyl)-1,2,4-triazin-5(4H)-one dihydrochlo-
ride compound 21.12a Selective amidation with the active ester 17
followed by subsequent POCl3 cyclization smoothly afforded com-
pound 23.12b In comparison with the iodination of 13 and 19, the
iodination of 23 was facile using 1.2 equiv of NIS at rt and the iso-
lated yield was improved to 75%. The overall improvement in the
reaction is presumed to be due to the electron-donating effect of
the 2-NH2 group activating the 5-position. Removal of the 2-NH2
group in the imidazotriazinone 24 was the key step in our synthetic
design and was realized using 5.0 equiv t-butyl nitrite in DMF/THF
(1:5, v/v) at rt., affording the desired product 14 in 91% yield.13 The
NMR spectroscopic data of 14 and the subsequent ammonolysis
product 15 were identical to those obtained when 15 was prepared
according to route I (Scheme 3).
4. Compound 2 was prepared in two steps, Strecker reaction of 3-BnO-C6H4CHO
and the treatment of the resulting
a-amino-(3-benzyloxy)phenylacetonitrile
with methanolic HCl (a) Matier, W. L.; Owens, D. A.; Comer, W. T. J. Med. Chem.
1973, 16, 901; (b) Rao, A. V. R.; Reddy, K. L.; Rao, A. S.; Vittal, T. V. S. K.; Reddy,
M. M.; Pathi, P. L. Tetrahedron Lett. 1996, 37, 3023.
5. Draber, W.; Timmler, H.; Dickore, K.; Donner, W. Liebigs Ann. Chem. 1976, 2206.
6. Reitz, A. B.; Goodman, M. G.; Pope, B. L.; Argentieri, D. C.; Bell, S. C.; Burr, L. E.;
Chourmouzis, E.; Come, J.; Goodman, J. H.; Klaubert, D. H.; Maryanoff, B. E.;
McDonnell, M. E.; Rampulla, M. S.; Schott, M. R.; Chen, R. J. Med. Chem. 1994, 37,
3561.
7. Compound 1: a white solid, mp 163–165 °C; 1H NMR (DMSO-d6, 400 MHz): d
(ppm) 7.89 (s, 1H), 7.46–7.51 (m, 2H), 7.38–7.44 (m, 3H), 7.34 (m, 1H), 7.27 (dd,
J = 2.3, 1.5 Hz, 1H), 7.23 (m, 1H), 7.08 (ddd, J = 8.3, 2.5, 0.8 Hz, 1H), 5.17 (s, 2H),
4.04 (quin, J = 8.3 Hz, 1H), 2.42–2.48 (m, 2H), 2.30–2.41 (m, 2H), 2.08 (m, 1H),
1.93 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): d (ppm) 158.7, 155.9, 149.1,
145.4, 137.0, 135.7, 133.7, 130.0, 128.4, 127.8, 127.6, 121.2, 115.0, 114.5, 109.9,
69.3, 30.4, 26.7, 18.3; HRMS (ES) calcd for C22H22N5O [MH+]: 372.1824, found:
372.1819.
8. Adam, F. M.; Burton, A. J.; Cardwell, K. S.; Cox, R. A.; Henson, R. A.; Mills, K.;
Prodger, J. C.; Schilling, M. B.; Tape, D. T. Tetrahedron Lett. 2003, 44, 5657.
9. (a) Chakrabarty, M.; Sarkar, S.; Harigaya, Y. Synthesis 2003, 2292; (b) Lipinski, C.
A.; Stam, J. G.; Pereira, J. N.; Ackerman, N. R.; Hess, H.-J. J. Med. Chem. 1980, 23,
1026.
10. Williams, T. M.; Crumbie, R.; Mosher, H. S. J. Org. Chem. 1985, 50, 91.
11. Abushanab, E.; Bindra, A. P.; Goodman, L.; Peterson, H., Jr. J. Org. Chem. 1973, 38,
2049.
12. (a) Mitchell, W. L.; Hill, M. L.; Newton, R. F.; Ravenscroft, P.; Scopes, D. I. C. J.
Heterocycl. Chem. 1984, 21, 697; (b) Bhattacharya, B. K.; Rao, T. S.; Lewis, A. F.;
Revankar, G. R.; Sanghvi, Y. S.; Robins, R. K. J. Heterocycl. Chem. 1993, 30, 1341.
13. Nagahara, K.; Anderson, J. D.; Kini, G. D.; Dalley, N. K.; Larson, S. B.; Smee, D. F.;
Jin, A.; Sharma, B. S.; Jolley, W. B.; Robins, R. K.; Cottam, H. B. J. Med. Chem.
1990, 33, 407.
In conclusion, multiple synthetic routes to the novel heterobicy-
clic scaffold 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amine
have been achieved. The linear route, while limited in scope and
overall yield, allowed the preparation of an initial proof-of-concept
compound 1, while the three subsequent convergent routes allowed
for the rapid and broad exploration of the C-5 and C-7 positions. Of
the convergent routes, route III proved the most robust and practical
for large-scale synthesis although all of these routes were success-
fully and extensively used in the medicinal chemistry exploration
around this novel core. Based on these chemistries, several oncol-
ogy-focused novel kinase inhibitors have emerged that are now pro-
gressing through the development/clinical stage. Further chemistry