A New Strategy for the Construction of the Imidazo[1,5-α ]quinoxalin-4-one Ring System and Its Application to the Efficient Synthesis of BMS-238497, a Novel and Potent Lck Inhibitor

Article abstract of DOI:10.1021/jo0355348

A new efficient strategy was developed for the construction of the imidazo[1,5-α]quinoxalin-4-one ring system. The new method involves condensation of o-nitroaniline with glyoxylate in methanol followed by treatment of the resulting α-(o-nitroanilino)-α-m

Full text of DOI:10.1021/jo0355348

A New Str a tegy for th e Con str u ction of th e
Im id a zo[1,5-a ]qu in oxa lin -4-on e Rin g
System a n d Its Ap p lica tion to th e Efficien t
Syn th esis of BMS-238497, a Novel a n d
P oten t Lck In h ibitor
F IGURE 1.
Bang-Chi Chen,* Rulin Zhao, Mark S. Bednarz,
Bei Wang, J oseph E. Sundeen, and J oel C. Barrish
study on this compound, we required ready access to a
large amount of compound 1 as well as its precursor, 7,8-
dimethoxyimidazo[1,5-a]quinoxalin-4-one (2) (Figure 1).
Previously, two approaches have been reported for the
construction of the imidazo[1,5-a]quinoxalin-4-one ring
system.8,10 The first approach starts with phenylene-1,2-
diamines 3 and is featured by a tosylmethyl isocyanide
(TosMIC) mediated imidazole ring formation of the
N-protected quinoxalin-2-one 5. While useful for the
preparation of certain imidazo[1,5-a]quinoxalin-4-ones,
this approach suffers a number of drawbacks such as the
poor regioselectivity encountered in the formation of
quinoxalin-2-ones 4 when unsymmetrical phenylene-1,2-
diamines are used, the lack of control of chemoselectivity
of N-protection vs O-protection during the protection step,
and the difficulty in separating the regioisomers, in
addition to the air sensitivity of the electron-rich phe-
nylene-1,2-diamines 3.
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical
Research Institute, Princeton, New J ersey 08543
bangchi.chen@bms.com
Received October 16, 2003
Abstr a ct: A new efficient strategy was developed for the
construction of the imidazo[1,5-a]quinoxalin-4-one ring sys-
tem. The new method involves condensation of o-nitroaniline
with glyoxylate in methanol followed by treatment of the
resulting R-(o-nitroanilino)-R-methoxy acetate with tosylm-
ethyl isocyanide (TosMIC) reagent to give 1-(o-nitrophenyl)-
imidazole-5-carboxylate. Reductive cyclization of the nitro
imidazole carboxylate afforded imidazo[1,5-a]quinoxalin-4-
one in three steps and 60% overall yield. The new method
was successfully applied to the synthesis of BMS-238497, a
novel and potent Lck inhibitor.
The second approach reported uses 2-fluoroanilines 9
as the starting materials and involves an intramolecular
nucleophilic aromatic substitution and cyclization of
2-fluoranilino amides of imidazole-5-carboxylic acid 11.12
This approach is much more efficient compared with the
previous one. However, this approach is not without
limitations. It was found that the intramolecular nucleo-
philic aromatic substitution and ring closure failed with
electron-rich fluoroanilines (e.g. R ) OMe).
To address the above-mentioned problems and to
develop a potentially more general method amenable for
large-scale synthesis of imidazo[1,5-a]quinoxalines and
related compounds, a new approach was investigated
that differs strategically from the previous methods in
term of the order and the way the heterocylic rings are
constructed. Herein, we describe a new efficient method
for the construction of such ring systems which is
featured by a preformation of the 1-(2-nitroaryl)-5-
ethoxycarbonylimidazole ring 14 via reaction of R-(o-
nitroanilino)-R-methoxy acetate 13 with TosMIC reagent
followed by a reductive ring closure of the nitro ester 14
to form the desired compounds (Scheme 2).
Imidazo[1,5-a]quinoxalines and related imidazo[1,5-a]-
quinoxalin-4-ones are important heterocycles in the
synthesis of a variety of biologically important and
medicinally useful agents. For example, they were used
in the synthesis of GABA/benzodiazepine receptor ago-
nists/antagonists,1 cAMP and cGMP phosphodiesterase
inhibitors,2 and A1- and A2a-adenosine receptor agonists,3
in addition to many other pharmacologically active
compounds.4-7 More recently, 4-(2-chloro-6-methylphe-
nylamino)-7,8-dimethoxyimidazo[1,5-a]quinoxaline (1;
BMS-238497) emerged as a novel and potent inhibitor
8,9
of Src-family kinase p56Lck
.
BMS-238497 displays
excellent enzymatic activity against Lck (IC50 ) 2 nM)
and good potency in blocking T cell proliferation (IC50
)
0.67 µM).8,9 To support further characterization and SAR
(1) J acobsen, E. J .; Stelzer, L. S.; Belonga, K. L.; Carter, D. B.; Im,
W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J . D. J .
Med. Chem. 1996, 39, 3820.
(2) Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg, S. S.;
Ingebretsen, W. R.; Wiggins, J . J . Med. Chem. 1991, 34, 2671.
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Med. Chem. 1997, 40, 2053.
(5) TenBrink, R. E.; J acobsen, E. J .; Gammill, R. B. U.S. Patent
5541324, J uly 30, 1996; Chem. Abstr. 1996, 125, 195687.
(6) Hansen, H. C.; Watjen, F. EP 344943 A1, December 6, 1989;
Chem. Abstr. 1990, 112, 216962.
Thus, treatment of 2-nitro-4,5-dimethoxyaniline 12
with ethyl glyoxylate in methanol under reflux overnight
afforded a novel compound, ethyl R-methoxy-R-(2-nitro-
4,5-dimethoxy)anilino acetate 13.13 After the solution was
cooled to room temperature, the crystalline compound 13
(7) Lee, T. D.; Brown, R. E. U.S. Patent 4440929, April 3, 1984;
Chem. Abstr. 1984, 101, 7202.
(8) Barrish, J . C.; Chen, P.; Das, J .; Iwanowicz, E. J .; Norris, D. J .;
Padmanaba, R.; Roberge, J . Y.; Schieven, G. L. U.S. Patent 6235740,
May 22, 2001.
(9) Chen, P.; Norris, D.; Iwanowicz, E. J .; Spergel, S. H.; Lin, J .;
Gu, H. H.; Shen, Z.; Wityak, J .; Lin, T.-A.; Pang, S.; De Fex, H. F.;
Pitt, S.; Shen, D. R.; Doweyko, A. M.; Bassolino, D. A.; Roberge, J . Y.;
Poss, M. A.; Chen, B.-C.; Schieven, G. L.; Barrish, J . C. Bioorg. Med.
Chem. Lett. 2002, 12, 1361.
(10) Chen, P.; Barrish, J . C.; Iwanowicz, E.; Lin, J .; Bednarz, M. S.;
Chen, B.-C. Tetrahedron Lett. 2001, 42, 4293.
(11) The O-protected compound 6 reacted with TosMIC sluggishly
and the unprotected compound 4 failed to react with TosMIC reagent.
(12) Norris, D.; Chen, P.; Barrish, J . C.; Das, J .; Moquin, R.; Chen,
B.-C.; Guo, P. Tetrahedron Lett. 2002, 42, 4297.
(13) Chen, B.-C.; Bednarz, M. S.; Zhao, R.; Sundeen, J . E.; Chen,
P.; Shen, Z.; Skoumbourdis, A. P.; Barrish, J . C. Tetrahedron Lett. 2000,
41, 5453.
10.1021/jo0355348 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/13/2004
J . Org. Chem. 2004, 69, 977-979
977

SCHEME 1
SCHEME 2 a
a
Reagents and conditions: (a) OHCCO2Et/MeOH, 17 h; (b) TosMIC/K2CO3, EtOH, 50 °C, 4 h; (c) Na2S2O4, HOAc/H2O, 105 °C, 6 h; (d)
POCl3, Et3N, reflux; (e) 2-Cl-6-MeC6H3NH2/NaHMDS, THF, 70 °C.
was isolated by filtration in 89% yield. Reaction of 13
with TosMIC reagent14 in ethanol and with potassium
carbonate at 50 °C for 4 h gave smoothly 1-(2-nitro-4,5-
dimethoxyphenyl)imidazole-5-carboxylate 14 that was
isolated by filtration in 68% after the reaction was
quenched with water.13
Reductive cyclization of 14 to the corresponding imi-
dazo[1,5-a]quinoxalin-4-one 2 was initially attempted
with use of hydrogenation conditions. Treatment of 14
with formic acid and catalytic amount of palladium on
charcoal in ethanol overnight gave a complex mixture of
products, from which none of the desired compound 2 or
its precyclized aniline intermediate was observed by LC/
MS. Reduction with iron powder in acetic acid was next
investigated.15 Refluxing 14 in acetic acid in the presence
of 5 equiv of iron powder for half an hour afforded cleanly
the desired compound 2; however, difficulty was encoun-
tered in isolation of product 2 from the reaction mixture
due to the contamination of inorganic salts.
conducting the reductive cyclization of 14 to 2. Treatment
of 14 with 4 equiv of sodium dithionite in a mixture of
acetic acid and water at 105 °C for 6 h afforded exclu-
sively compound 2, which was isolated by filtration in
98% yield after the reaction mixture was cooled and
diluted with water. The resulting imidazo[1,5-a]quinoxa-
lin-4-one 2 was next converted to the desired BMS-
238497 following the reported conditions.8
In summary, a new efficient method has been devel-
oped for the construction of the imidazo[1,5-a]quinoxalin-
4-one ring system. The new method involves condensa-
tion of o-nitroaniline with glyoxylate to give an R-(o-
nitroanilino)-R-methoxy acetate followed by treatment
with TosMIC reagent to afford 1-(o-nitrophenyl)imida-
zole-5-carboxylate. Reductive cyclization of the nitro
imidazole carboxylate affords imidazo[1,5-a]quinoxalin-
4-one in three steps and 60% overall yield. The new
process was readily scaled up and no chromatographic
separation of products was involved. The new method has
also been successfully applied to the large-scale synthesis
of the novel Lck inhibitor, BMS-238497, and related
compounds.
Finally, it was found that the combination of sodium
dithionite16 in acetic acid was the condition of choice for
(14) For an excellent review on TosMIC reagent in organic synthesis
including imidazole ring formation, see: van Leusen, D.; van Leusen,
A. M. Org. React. 2001, 57, 417.
(15) Beach, M. J .; Hope, R.; Klaubert, D. H.; Russell, R. K. Synth.
Commun. 1995, 25, 2165.
(16) For a previous reference with sodium dithionite for the reduc-
tion of nitroarenes to anilines, see: Park, K. K.; Oh, C. H.; J oung, W.
K. Tetrahedron Lett. 1993, 34, 7445.
978 J . Org. Chem., Vol. 69, No. 3, 2004

reduced pressure at ∼50 °C. The resulting residue was slurried
in water. The suspended solids were isolated by filtration and
washed with water. The wet cake was slurried in 2-propanol
(50 mL) and then heptane (100 mL). The wet cake was dried at
45 °C to give 3-(4,5-dimethoxy-2-nitrophenyl)imidazole-4-car-
Exp er im en ta l Section
r-(4,5-Dim et h oxy-2-n it r op h en yla m in o)-R-m et h oxya ce-
tic a cid eth yl ester (13): In a 2-L round-bottomed flask
equipped with a magnetic stirrer was placed 4,5-dimethoxy-2-
nitroaniline17 (12, 59.0 g, 297 mmol) and methanol (1 L). The
mixture was stirred at room temperature under argon. Ethyl
glyoxylate (270 mL, 50% in toluene) was added. The reaction
mixture was stirred at 65 °C for 17 h and cooled to room
temperature. The resulting slurry was filtered and washed with
methanol (100 mL) and heptane (100 mL). The cake was dried
under vacuum at 45 °C overnight to give R-(4,5-dimethoxy-2-
nitrophenylamino)-R-methoxyacetic acid ethyl ester (13), 83.3
g (89%). Mp 118-119 °C. 1H NMR (CDCl3) δ 1.36 (t, J ) 7.2 Hz,
3H), 3.34 (s, 3H), 3.88 (s, 3H), 3.95 (s, 3H), 4.35 (q, J ) 7.2 Hz,
2H), 5.35 (d, J ) 5.8 Hz, 1H), 6.59 (s, 1H), 7.67 (s, 1H), 9.13 (d,
J ) 5.8 Hz, 1H). 13C NMR (CDCl3) δ 14.4, 55.8, 56.7, 56.8, 62.7,
82.2, 106.9, 107.9, 140.4, 142.1, 142.3, 157.3, 167.8. Anal. Calcd
for C13H18N2O7: C, 49.68; H, 5.77; N, 8.91. Found: C, 49.52; H,
5.59; N, 8.91.
3-(4,5-Dim et h oxy-2-n it r op h en yl)im id a zole-4-ca r b oxyl-
ic a cid eth yl ester (14): To a 2-L round-bottom flask equipped
with a magnetic stirrer was added R-(4,5-dimethoxy-2-nitrophe-
nylamino)-R-methoxyacetic acid ethyl ester (13, 32.95 g, 104.84
mmol), tosylmethyl isocyanide (27.04 g (138.50 mmol), and
absolute ethanol (1.44 L). The reaction mixture was stirred
under argon and potassium carbonate (36.15 g, 261.56 mmol)
was added. The suspension was heated to ∼50 °C and stirred
for 4 h. The reaction mixture was then concentrated under
1
boxylic acid ethyl ester (14), 23.00 g (68%). Mp 139-140 °C. H
NMR (CDCl3) δ 7.87 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 6.80 (s,
1H), 4.18 (q, J ) 7.1 Hz, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 1.25 (t,
J ) 7.1 Hz, 3H). 13C NMR (CDCl3) δ 14.5, 57.1, 57.2, 61.6, 107.8,
108.4, 112.0, 125.0, 137.5, 138.5, 141.8, 149.8, 153.6, 159.9. Anal.
Calcd for C14H15N3O6: C, 52.34; H, 4.71; N, 13.08. Found: C,
52.26; H, 4.59; N, 12.84.
7,8-Dim eth oxyim id a zoqu in oxa lin -4-on e (2): To a 1-L
round-bottom flask equipped with a magnetic stirrer was added
3-(4,5-dimethoxy-2-nitrophenyl)imidazole-4-carboxylic acid ethyl
ester (14, 19.36 g, 60.26 mmol), glacial acetic acid (100 mL), and
water (100 mL). The mixture was stirred to give a slurry and
sodium dithionite (41.97 g, 241.03 mmol) was added. The
reaction mixture was heated to 105 °C and stirred for 6 h under
nitrogen. Water (500 mL) was added and the slurry was cooled
to room temperature. After 2 h of stirring, the slurry was filtered.
The cake was washed with water (3 × 50 mL) and dried in a
vacuum oven at 45 °C for 42 h to give 7,8-dimethoxyimidazo-
quinoxalin-4-one (2), 14.43 g (98%). Mp >250 °C. 1H NMR
(DMSO-d6) δ 3.79 (s, 3H), 3.87 (s, 3H), 6.90 (s, 1H), 7.79 (s, 1H),
7.81 (s, 1H), 9,02 (s, 1H). 13C NMR (DMSO-d6) δ 56.0, 56.8, 100.3,
100.5, 113.5, 122.6, 122.7, 130.8, 133.0, 145.4, 148.5, 154.0. Anal.
Calcd for C12H11N3O3‚0.2H2O: C, 57.92; H, 4.62; N, 16.89.
Found: C, 57.80; H, 4.55; N, 16.60.
(17) Toeke, L.; Bitter, I.; Agai, B.; Hell, Z.; Lindner, E.; Toeth, K.;
Horvath, M.; Harfouch, S.; Pungor, E. Liebigs Ann. Chem. 1988, 549.
J O0355348
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