Discovery and process synthesis of novel 2,7-pyrrolo[2,1- f ][1,2,4]triazines

Article abstract of DOI:10.1021/ol2015237

The synthesis of a new kinase inhibitor template 2-anilino-7-aryl- pyrrolo[2,1-f][1,2,4]triazine is described which includes a late stage orthogonally reactive key intermediate amenable to rapid diversification as well an optimized in situ triflate displa

Full text of DOI:10.1021/ol2015237

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4204–4207
Discovery and Process Synthesis of Novel
2,7-Pyrrolo[2,1-f][1,2,4]triazines
Tho Thieu,*,† Joseph A. Sclafani,*,‡ Daniel V. Levy,‡ Andrew McLean,‡
Henry J. Breslin,† Gregory R. Ott,† Roger P. Bakale,‡ and Bruce D. Dorsey†
Department of Medicinal Chemistry, Worldwide Discovery Research, 145 Brandywine
Parkway, West Chester, Pennsylvania 19380, United States, and Chemical Process
Research & Development, Worldwide Drug Development, Cephalon, Inc., 383
Phoenixville Pike, Malvern, Pennsylvania 19355, United States
tthieu@cephalon.com; jsclafani@cephalon.com
Received June 7, 2011
ABSTRACT
The synthesis of a new kinase inhibitor template 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazine is described which includes a late stage orthogonally
reactive key intermediate amenable to rapid diversification as well an optimized in situ triflate displacement to install the C2-aniline. Furthermore,
an efficient scalable process approach will be highlighted which begins with tert-butyl carbazate to provide the key NÀN bond and generates the
pyrrolotriazine core through a stable bromoaldehyde intermediate followed by condensation with ammonium carbonate.
A unique bridgehead nitrogen heterocycle pyrrolo[2,1-f]-
[1,2,4]triazine (Figure 1) was first reported by Neunhoeffer
via addition/fragmentation of 1,2,4-triazines with dimethyl
acetylenedicarboxylate to give 1.1 It was two years later that
Migliara reported the synthesis of 2 via acid-mediated
cyclization of a semicarbazone onto a pendant R-ketoester,
followed by base-promoted cyclization.2 More than a
decade later Hayashi introduced C7-linked pyrrolotria-
zines to the medicinal chemistry field as novel C-nucleoside
mimics (3), implementing similar chemistry to Migliara.3
A novel pyrrole N-amination approach for formation of
the key NÀN bond, reported by Klein and co-workers,
described syntheses of both C-nucleoside congeners4 and
minimally substituted pyrrolotriazines (4).5 Limited new
developments around this nucleus had been reported6,7
until Hunt and co-workers described the design, synthesis,
and utility of C4-substituted pyrrolotriazines (5) as quina-
zoline hinge-binding mimics in the discovery of ATP-
competitive kinase inhibitors.8 This discovery has had a
profound impact on the kinase inhibitor field and has led to
numerous candidates in late stages of clinical development.
Further expansion of the utility of this heterocycle has led
to the discovery of the clinical level IGF-1R inhibitor 6.9
(7) Quintella, J. M.; Moreira, M. J.; Peinador, C. Tetrahedron 1996,
52, 3037–3048.
(8) Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.; Fargnoli, J.;
Fink, B.; Han, W.-Ch; Mortillo, S.; Vite, G.; Wautlet, B.; Wong, T.; Yu,
C.; Zheng, X.; Bhide, R. J. Med. Chem. 2004, 47, 4054–4059.
(9) Wittman, M. D.; Carboni, J. M.; Yang, Z.; Lee, F. Y.; Antman,
M.; Attar, R.; Balimane, P.; Chang, C.; Chen, C.; Discenza, L.;
Frennesson, D.; Gottardis, M. M.; Greer, A.; Hurlburt, W.; Johnson,
W.; Langley, D. R.; Li, A.; Li, J.; Liu, P.; Mastalerz, H.; Mathur, A.;
Menard, K.; Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.;
Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G.; Zimmermann, K.;
Vyas, D. M. J. Med. Chem. 2009, 52, 7360–7363.
† Department of Medicinal Chemistry.
‡ Chemical Process Research & Development.
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S. V.; Charushin, V. N. Mendeleev Commun. 1992, 3, 85–86.
(10) Ott, G. R.; Tripathy, R.; Cheng, M.; McHugh, R.; Anzalone,
A. V.; Underiner, T. L.; Curry, M. A.; Quail, M. R.; Lu, L.; Wan, W.;
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r
10.1021/ol2015237
Published on Web 07/26/2011
2011 American Chemical Society

The strategy to make these bioactive pyrrolotriazines has
relied mainly on a pyrrole N-amination approach.8
Relying on pyrrole N-amination13 to install the key
NÀN bond, we were precluded from using the C2-
aldehyde due to conversion to the nitrile during amination.
Instead, we opted for the higher ester oxidation state; thus,
methyl-2-pyrrole carboxylate (7, Scheme 1) was treated
with chloramine and the crude material reacted with ben-
zoylisothiocyanate to give 8. Hydrolytic cyclization in 2 M
NaOH followed by methylation afforded 9. The choice of
the thiomethyl moiety at C2 was central to providing both
stability to the intermediates and latent reactivity. At this
stage, we required a lower oxidation state at C4 and
regioselective introduction of a halogen at C7. Attempted
bromination of 9 was severely limited by solubility; how-
ever, if chlorination was effected first, bromination pro-
ceeded smoothly to give 11 and with reasonable regio-
selectivity for C7 vs C5 (ca. 5:1); the regioisomers were
carried forward. Importantly, we had now clearly differ-
entiated C2, C4, and C7 and could take advantage of the
highly reactive C4 position. Interestingly, treatment of 11
with NaBH4 resulted in reduction of not only the chloride
but also the derived imine species. Fortunately, oxidation
to restore aromaticity was quite mild and facile with DDQ
to give the key intermediate 12 which was separated from
the 5-Br regiomer at this stage by chromatography.
Figure 1. Pyrrolo[2,1-f][1,2,4]triazine derivatives.
Recently, we reported novel diaminopyrimidine ATP-
competitive inhibitors of anaplastic lymphoma kinase
(ALK).10,11 In an effort to mimic the bioactive conforma-
tion we proposed constraining the diaminopyrimidine into
a 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazine (Figure 2)
which, tothebest ofourknowledge, isa novel modification
ofthis coretemplate and a new kinase inhibitorplatform.12
Scheme 1. Synthesis of Key 2,7-Substituted Intermediate
Figure 2. Initial design of novel 2-anilino-7-aryl-pyrrolo[2,1-f]-
[1,2,4]triazines.
Herein, we describe the discovery synthesis of this new
kinase inhibitor template which includes a late stage ortho-
gonally substituted core structure amenable to rapid diver-
sification as well as an optimized in situ triflate displace-
ment to install the C2-aniline. Furthermore, an efficient
scalable process approach will be described which begins
with readily available tert-butyl carbazate and benefits
from regioselective bromination and acylation culminating
in the formation of the preferred 2-oxo derivative 16.
The challenges associated with the initial synthesis in-
cluded incorporating the appropriate oxidation state at C4
and installation of orthogonally reactive groups at C2 and
C7 to support a late stage diversification strategy.
Intermediate 12 could be advanced to a target molecule
(15, Scheme 2) via orthogonal approaches. Suzuki cou-
pling to phenylboronic acid, followed by oxidation of the
sulfide to sulfoxide 13, provided an appropriate partner for
SNAr displacement with 3,4,5-trimethoxyaniline. Alterna-
tively, 15 was arrived at via the reverse process where the
phenyl group is installed in the final step. As we diversified
our appendages, especially with regard to poorly nucleo-
philic and/or sterically demanding anilines, the sulfoxide
displacement afforded poor yields with multiple side
products. To circumvent this limitation, we focused on
incorporating a more reactive nucleofuge at C2, namely a
triflate or the like. Toward this end we converted the
sulfoxide to the 2-oxo derivative 16. The in situ 16 to 15
transformation could be carried out by triflate formation
followed by SNAr displacement with the aniline. The
methodology offered significant advantages which in-
cluded a one-pot triflate formation/displacement and
milder reaction conditions (room temperature) and was
amenable to a wide variety of anilines. Furthermore, 12
could also be converted to 14 using this chemistry.
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Org. Lett., Vol. 13, No. 16, 2011
4205

availability of N-aminopyrrole, we were pleased to find
a procedure to furnish Boc-N-aminopyrrole in one step
utilizing the ClausonÀKaas reaction (Scheme 3).18
Reported conditions19 to synthesize 19 were optimized
to allow for direct isolation from the reaction mixture
in a single step by performing the reaction in NMP
followed by addition of water to induce product crys-
tallization. Fine tuning the amount of HCl along with
the number of equivalents of 18 was critical to minimize
side products providing the product in 55% isolated
yield and 99.2 area % purity.
Scheme 2. End-Game Strategy for Synthesis of 2-Anilino-7-
aryl-pyrrolo[2,1-f][1,2,4]triazines
A screen of brominating reagents revealed several con-
ditions which provided 20 with only trace amounts of over-
brominationorremainingstartingmaterial (Table1). Both
N-bromosuccinamide and 5,5-dimethyl-1,3-dibromohy-
dantoin (DBH) demonstrated clean conversion with pyr-
idinium tribromide providing slightly inferior results.
Slightly higher reaction concentrations and different sol-
vents were shown to be tolerated without significant over-
bromination. During scale-up, DBH was slow to dissolve
in MTBE resulting in both conversion and selectivity
issues. To mitigate these solubility problems, DBH was
added as a solution in THF to 19 in NMP (entry 9). These
conditions provided 20 in 87% yield with 98.6% purity
after recrystallization.
In an effort to develop a scalable process, we focused on
the synthesis of an N-aminopyrrole containing a carbonyl at
the desired aldehyde oxidation state. This would avoid the
need to employ POCl3, NaBH4, and DDQ thus eliminating
several steps. We also sought conditions which would
regioselectively brominate exclusively at the 5-position of
the pyrrole due to unsuccessful efforts to develop a crystal-
lization to remove regioisomers from 11 and 12. Separation
was only achieved through chromatography. We also planned
to avoid the less reactive sulfoxide 13 and form 16 directly,
further providing a more succinct route to the final target.
Initial attempts focused on bromination of 1H-pyrrole-
2-carboxaldehyde.14 An extensive screen of common
brominating conditions15 provided the best result which
employed pyridinium tribromide yielding a modest 39%
area by HPLC of the 5-bromo-2-pyrrole carboxaldehyde.
The dark unstable reaction mixture also contained starting
material, a 4-bromo derivative, and overbrominated pro-
ducts, which together decomposed to tar on standing.
Repeated attempts to apply the chloramine chemistry with
1H-pyrrole-2-carboxaldehyde resulted in consumption of
the starting material with no desired product observed.
Unable to achieve a selective monobromination, we
were encouraged by reports of the regioselective dibro-
mination of Boc-protected pyrroles16 and N-aminopyr-
roles.17 Given the high cost and limited commercial
Table 1. Dibromination Screening for the Synthesis of 20
concn
20
entry
reagenta
solvent
THF
(mL/g)
(A%)b
1
2
3
4
5
6
7
8
9
Pyr-Br3
NBS
40
88.6
95.2
98.4
95.6
97.5
95.6
96.7
86.4
97.3
DMF
40
DBH
DBH
DBH
DBH
DBH
DBH
DBH
DMF
40
THF
40
MTBE
NMP
40
40
NMP
20
NMP
NMP/THFc
10
20/10
a Pyr-Br3: pyridinium tribromide. DBH: 1,3-dibromo-5,5-dimethyl-
hydantoin. b Conversion based on HPLC area percent. c DBH added as a
solution in 10 mL/g of THF to 19 dissolved in NMP.
With the desired dibrominated pyrrole 20 in hand, we
sought conditions to effect a single, mild metalÀhalogen
exchange which avoided cryogenic conditions. The
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(19) O’Connor, S. J.; Dumas, J.; Lee, W.; Dixon, J.; Cantin, D.;
Gunn, D.; Burke, Je.; Phillips, B.; Lowe, D.; Shelekhin, T.; Wang, G.;
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4206
Org. Lett., Vol. 13, No. 16, 2011

THF followed by addition of phenyl chloroformate re-
sulted in 90À95% conversion to 23. The crude reaction
mixture when subjected to high pressure ammonia con-
verted to 16 but in low yield. Encouraged by this result,
Lewis acids were screened to activate 23 toward cyclization
and it was discovered that both Yb(OTf)3 and Sc(OTf)3
catalyzed the formation of 16.
Table 2. HalogenÀMetal Exchange Followed by Quenching
with DMF
Given the hindered rotation around the NÀN bond and
the large distance between the aldehyde and phenyl carba-
mate due to steric hindrance, the mechanism of the trans-
formation was probed. Aware of a report21 that LiBr in
acetonitrile could selectively convert di-Boc protected
amines into mono tert-butyl carbamates, control experi-
ments in the absence of ammonia were performed which
revealed that heating 23 with Sc(OTf)3 or Yb(OTf)3 al-
lowed for the preferred removal of the Boc group while
preserving the phenyl carbamate. No decomposition was
noted during this transformation. LiBr however was not as
selective toward removal of the Boc group, and significant
amounts of 22 were observed. Upon removal of the tert-
butyl carbamate, addition of ammonia gas or ammonium
carbonate resulted in immediate formation of 16 as a
precipitate from the reaction mixture. Addition of MTBE
followed by filtration furnished the product in 80% yield
and 99 area % purity for three steps. In situ conversion of
16 to the triflate followed by displacement with 3,4,5-
trimethoxyaniline provided the target15 in very good yield.
In summary, the synthesis of a new kinase inhibitor
template, 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazine, has
been described which relies on a pyrrole N-amination
followed by condensation/cyclization of an isothiocyanate
to form the core ring structure. Chlorination at C4 and
bromination at C7 set the stage for regioselective reduction
to provide an orthogonally substituted key intermediate
amenable for diversification via two routes to the desired
target molecules. An optimized in situ triflate formation
and aniline addition was also devised. Furthermore, a
scalable process which avoids chromatography has been
developed which benefits from a regioselective bromina-
tion at C7 and mild metalÀhalogen exchange. The se-
quence provides a stable intermediate 21 amenable to
funtionalization and through novel, selective removal of
a tert-butyl carbamate followed by addition of an ammo-
nia source, provides a direct route to the important and
preferred pyrrolotriazine core 16.
i-PrMgCl•LiCl
DMF
21
25
entry
(equiv)
(equiv)
(A%)a
(%)b
1
2
3
4.0
2.5
2.5
5.0
5.0
1.6
80.3
91.4
90.8
<1
3.5
NDc
a Conversion based on HPLC area percent. b Determined by 1H
NMR. c Not detected.
commercially available Knochel “Turbo Grignard” i-
PrMgCl•LiCl20 gave a clean monoexchange in 3À6 h at
room temperature with negligible formation of reduced 25
(Table 2). Decreasing the amount of i-PrMgCl•LiCl re-
sulted in a 10% increase in conversion. Reducing the
amount of DMF had little effect on conversion but did
allow for asinglephasecut during workup. Thisallowed21
to be isolated after simple extraction from an ethyl acetate/
heptane recrystallization in 71À81% yield based on scale.
Suzuki coupling with 21 was straightforward requiring
only 0.5% Pd catalyst loading in aqueous ethanol to
cleanly provide 22 in 0.5 h at 80 °C. Crystallization from
ethyl acetate/heptane furnished the product in 73% yield
and 94 area % purity (Scheme 3).
Scheme 3. Process Route toward the Synthesis of 2-Anilino-7-
aryl-pyrrolo[2,1-f][1,2,4]triazines
Acknowledgment. The authors thank Profs. Bruce Lip-
shutz of the University of California, Santa Barbara and
Amos B. Smith, III of the University of Pennsylvania for
fruitful discussions as well as Drs. Mark Olsen and Kevin
Wells-Knecht for analytical support.
We now hoped to subject 22 to high pressure ammonia
to allow for cyclization to give 16. At 60 psi and 70 °C no
product was noted, returning unreacted starting material
along with some cleavage of the Boc group. It was next
surmised that a more reactive carbamate was needed
toward aminolysis. Treatment of 22 with NaHMDS in
Supporting Information Available. Experimental de-
tails and copies of 1H and 13C spectra are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Haug, B. E.; Rich, D. H. Org. Lett. 2004, 6, 4783–4786.
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