Synthesis, SAR for AMPA-type Non-NMDA Receptor
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2061
tate was collected and washed with methanol to give 9 (0.67
g, 63%) as a slightly yellow solid: mp >300 °C; 1H NMR δ
12.28 (br, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.51
(s, 1H), 7.45 (s, 1H), 7.12 (s, 1H), 3.26 (q, 2H), 1.38 (t, 3H);
MS (FAB) m/ z 325 (M + 1). Anal. (C15H12N6O3‚1.25H2O) C,
H, N.
) 7.74 Hz, 1H), 8.39 (d, J ) 12.2 Hz, 1H), 3.51 (q, 2H), 1.50 (t,
3H); MS (FAB) m/ z 296 (M + 1).
The title compound: 82% from the intermediate; mp >300
°C; 1H NMR δ 12.25 (s, 1H), 8.13 (d, J ) 9.54 Hz, 1H), 8.11 (d,
J ) 9.90 Hz, 1H), 3.40 (q, 2H), 1.46 (t, 3H); MS (FAB) m/ z
278 (M + 1). Anal. (C11H8N5O3F) H, N; C: calcd, 47.66; found,
47.13. F: calcd, 6.85; found, 7.30.
1,2-Dih yd r o-1-eth yl-8-flu or o-7-n itr o-4(5H)-im id a zo[1,2-
a ]qu in oxa lin on e (10). A solution of 7 in thionyl chloride (5
mL) and chloroform (5 mL) was heated under reflux for 2 h.
After cooling, the reaction mixture was concentrated in vacuo,
and the residue was coevaporated several times with chloro-
form and then ethyl acetate. The crude product thus obtained
was washed with ethyl acetate to afford 1.08 g (57%) of
4-chloro-1,2-dihydro-1-ethyl-8-fluoro-7-nitroimidazo[1,2-a]qui-
noxaline as the intermediate: 1H NMR δ 8.54 (d, J ) 7.74
Hz, 1H), 7.85 (d, J ) 12.3 Hz, 1H), 5.1 (m, 1H), 3.75-4.40 (m,
2H), 1.83 (qu, 2H), 0.92 (t, 3H); MS (FAB) m/ z 297 (M + 1).
The 4-chloro-1,2-dihydro-1-ethyl-8-fluoro-7-nitroimidazo[1,2-
a]quinoxaline (1.08 g, 3.24 mmol) was treated with a mixture
of 4 N HCl (12 mL) and methanol (12 mL) under reflux for 40
min. After cooling, the resulting precipitate was collected and
washed with methanol and water to provide the title compound
10 (0.35 g, 34%): mp >300 °C; 1H NMR δ 13.16 (br, 1H), 8.24
(d, J ) 7.11 Hz, 1H), 7.80 (d, J ) 12.4 Hz, 1H), 5.08 (t, 1H),
4.22 (dd, 1H), 4.01 (dd, 1H), 1.76-1.88 (m, 2H), 0.92 (t, 3H);
NOE between H-9 and 1-ethyl protons observed; MS (FAB)
m/ z 278 (M + 1). Anal. (C12H11N4O3F‚1.25H2O) C, N, F; H:
calcd, 4.52; found, 3.89.
1,2-Dih yd r o-1-eth yl-8-(1H-im id a zol-1-yl)-7-n itr o-4(5H)-
im id a zo[1,2-a ]qu in oxa lin on e (11): prepared by the same
method described for 9; 58% from 10; mp >300 °C; 1H NMR δ
11.93 (brs, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 7.22 (s,
1H), 7.08 (s, 1H), 4.69-4.73 (m, 1H), 4.09 (dd, 1H), 3.85 (dd,
1H), 1.61-1.75 (m, 2H), 0.81 (qu, 3H); MS (FAB) m/ z 327 (M
+ 1). Anal. (C15H14N6O3‚1.5H2O) C, H, N.
Gen er a l Meth od for P r ep a r a tion of 8-Im id a zolyl-7-
n itr o[1,2,4]tr iazolo[4,3-a ]qu in oxalin on es 14a-e. The com-
pounds were prepared by nucleophilic substitution of 6 with
hydrazine followed by cyclic condensation with the appropriate
ortho ester,28 hydrolysis, and then nucleophilic substitution
with imidazole.
(3-Ch lor o-7-flu or o-6-n it r oq u in oxa lin -2-yl)h yd r a zin e
(12). In an ice-salt bath, to a solution of 6 (0.40 g, 1.52 mmol)
in methanol (4 mL) was slowly added dropwise a solution of
hydrazine monohydrate (0.098 g, 1.96 mmol) in methanol (1
mL). With stirring, the reaction mixture was allowed to
gradually warm to 0 °C. After 30 min, the resulting precipitate
was collected and washed with methanol to afford 12 (0.36 g,
92%): 1H NMR δ 8.30 (d, J ) 8.19 Hz, 1H), 7.34 (d, J ) 13.1
Hz, 1H), 6.80 (br, 3H); MS (EI) m/ z 257 (M).
8-F lu or o-7-n itr o-4(5H)-[1,2,4]tr ia zolo[4,3-a ]qu in oxa li-
n on e (13a ). A solution of 12 (0.70 g, 2.72 mmol) in triethyl
orthoformate (3.56 g, 24.0 mmol) was stirred at 130 °C for 15
min. After cooling, the precipitate was collected and washed
with methanol to provide 0.61 g (84%) of 4-chloro-8-fluoro-7-
nitro[1,2,4]triazolo[4,3-a]quinoxaline as an intermediate: 1H
NMR δ 10.20 (s, 1H), 8.84 (d, J ) 7.30 Hz, 1H), 8.81 (d, J )
11.5 Hz, 1H); MS (FAB) m/ z 268 (M + 1).
The same procedure as described for 8 from 4-chloro-1-ethyl-
8-fluoro-7-nitroimidazo[1,2-a]quinoxaline was used for the
preparation of 13a from the intermediate: mp >300 °C; 1H
NMR δ 12.29 (s, 1H), 9.88 (s, 1H), 8.56 (d, J ) 11.6 Hz, 1H),
8.10 (d, J ) 6.70 Hz, 1H); MS (FAB) m/ z 250 (M + 1). Anal.
(C9H6N5O3F) C, H, N.
8-F lu or o-1-m eth yl-7-n itr o-4(5H)-[1,2,4]tr ia zolo[4,3-a ]-
q u in oxa lin on e (13b ). 4-Chloro-8-fluoro-1-methyl-7-nitro-
[1,2,4]triazolo[4,3-a]quinoxaline: 73% from 12; 1H NMR δ 8.79
(d, J ) 7.74 Hz, 1H), 8.44 (d, J ) 11.9 Hz, 1H), 3.13 (s, 1H);
MS (FAB) m/ z 282 (M + 1).
8-F lu or o-7-n it r o-1-p r op yl-4(5H)-[1,2,4]t r ia zolo[4,3-a ]-
q u in oxa lin on e (13d ). 4-Chloro-8-fluoro-7-nitro-1-propyl-
[1,2,4]triazolo[4,3-a]quinoxaline: 91% from 12; 1H NMR δ 8.78
(d, J ) 7.74 Hz, 1H), 8.39 (d, J ) 12.0 Hz, 1H), 3.49 (t, 2H),
1.99 (se, 2H), 1.11 (t, 3H); MS (EI) m/ z 309 (M).
1
The title compound: 79% from the intermediate; H NMR
δ 12.22 (brs, 1H), 8.09 (d, J ) 7.30 Hz, 1H), 8.09 (d, J ) 11.6
Hz, 1H), 3.34 (t, 2H), 1.91 (se, 2H), 1.06 (t, 3H); MS (EI) m/ z
291 (M). Anal. (C12H10N5O3F) C, H, N.
1-Bu tyl-8-flu or o-7-n itr o-4(5H)-[1,2,4]tr ia zolo[4,3-a ]qu i-
n oxa lin on e (13e). 1-Butyl-4-chloro-8-fluoro-7-nitro[1,2,4]-
1
triazolo[4,3-a]quinoxaline: 73% from 12; H NMR δ 8.80 (d,
1H), 8.40 (d, 1H), 3.35 (t, 2H), 1.93 (qu, 2H), 1.54 (se, 2H),
0.99 (t, 3H); MS (FAB) m/ z 324 (M + 1).
The title compound: 77% from the intermediate; mp 250-
1
253 °C dec; H NMR δ 12.24 (brs, 1H), 8.17 (d, J ) 1.35 Hz,
1H), 8.06 (d, J ) 3.33 Hz, 1H), 3.34 (t, 2H), 1.90 (m, 2H), 1.50
(m, 2H), 0.98 (t, 3H); MS (FAB) m/ z 306 (M + 1).
8-(1H-Im idazol-1-yl)-7-n itr o-4(5H)-[1,2,4]tr iazolo[4,3-a ]-
q u in oxa lin on e (14a ): prepared by the method described
1
for 9; 15% from 13a ; mp >300 °C; H NMR δ 12.40 (s, 1H),
9.90 (s, 1H), 8.62 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.48 (t,
1H), 7.15 (t, 1H); MS (FAB) m/ z 298 (M + 1). Anal.
(C12H7N7O3‚H2O) C, H, N.
8-(1H-Im id a zol-1-yl)-1-m eth yl-7-n itr o-4(5H)-[1,2,4]tr i-
a zolo[4,3-a ]qu in oxa lin on e (14b): 88% from 13b; mp >300
°C; 1H NMR δ about 12.00 (br, 1H), 8.13 (s, 1H), 8.11 (s, 1H),
8.02 (t, 1H), 7.52 (t, 1H), 7.13 (t, 1H), 3.04 (s, 3H); MS (FAB)
m/ z 312 (M + 1). Anal. (C13H9N7O3‚1.5H2O) C, H, N.
1-Eth yl-8-(1H-im idazol-1-yl)-7-n itr o-4(5H)-[1,2,4]tr iazolo-
[4,3-a ]qu in oxa lin on e (14c): 81% from 13c; mp >300 °C; 1H
NMR δ 12.41 (br, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 8.00 (t, 1H),
7.50 (t, 1H), 7.13 (t, 1H), 3.43 (q, 2H), 1.46 (t, 3H); MS (FAB)
m/ z 326 (M + 1). Anal. (C14H11N7O3‚1.5H2O) C, H, N.
8-(1H -Im id a zol-1-yl)-7-n it r o-1-p r op yl-4(5H )-[1,2,4]t r i-
a zolo[4,3-a ]qu in oxa lin on e (14d ): 91% from 13d ; mp 294-
295 °C dec; 1H NMR δ 12.43 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H),
8.01 (s, 1H), 7.51 (s, 1H), 7.14 (s, 1H), 2.50 (t, 2H), 1.93 (se,
2H), 1.05 (t, 3H); MS (FAB) m/ z 340 (M + 1). Anal.
(C15H13N7O3‚0.75H2O) C, H, N.
1-Bu tyl-8-(1H-im idazol-1-yl)-7-n itr o-4(5H)-[1,2,4]tr iazolo-
[4,3-a ]qu in oxa lin on e (14e): 87% from 13e; mp 178-180 °C
1
dec; H NMR δ 12.34 (br, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 8.00
(s, 1H), 7.51 (t, 1H), 7.14 (s, 1H), 3.41 (t, 2H), 1.85 (m, 2H),
1.45 (m, 2H), 0.94 (t, 3H); MS (FAB) m/ z 354 (M + 1). Anal.
(C16H15N7O3‚0.5H2O) C, H, N.
7-F lu or o-4-m eth oxy-1-p r op yl[1,2,4]tr ia zolo[4,3-a ]qu i-
n oxa lin e (15): prepared from (6-fluoro-3-methoxyquinoxalin-
2-yl)hydrazine28 using the same method described for the
1
intermediate of 13d ; 74% from starting material; H NMR δ
8.20 (dd, J ) 5.17, 9.35 Hz, 1H), 7.33-7.77 (m, 2H), 4.17 (t,
2H), 1.96 (se, 2H), 1.17 (t, 3H); MS (EI) m/ z 260 (M).
7-F lu or o-1-p r op yl-4(5H )-[1,2,4]t r ia zolo[4,3-a ]q u in ox-
a lin on e (16): prepared by the method described for 13d from
its intermediate; 82% from 15; 1H NMR δ 12.08 (brs, 1H), 8.03
(dd, J ) 5.06, 10.1 Hz, 1H), 7.03-7.23 (m, 2H), 3.30 (t, 2H),
1.92 (se, 2H), 1.08 (t, 3H); MS (EI) m/ z 246 (M).
7-F lu or o-8-n it r o-1-p r op yl-4(5H)-[1,2,4]t r ia zolo[4,3-a ]-
qu in oxa lin on e (17). To an ice-cold solution of 16 (0.51 g,
2.07 mmol) in concentrated H2SO4 (5 mL) was added portion-
wise KNO3 (0.27 g, 2.67 mmol) with the temperature being
maintained below 10 °C. After being stirred at ambient
temperature for 2 h, the reaction mixture was poured onto ice-
water. The resulting precipitate was collected and washed
with water to give 17 (0.53 g, 88%): 1H NMR δ 12.56 (brs,
1H), 8.59 (d, J ) 6.70 Hz, 1H), 7.35 (d, J ) 12.2 Hz, 1H), 3.36
The title compound: 85% from the intermediate; mp >300
°C; 1H NMR δ 12.24 (brs, 1H), 8.19 (d, J ) 7.29 Hz, 1H), 8.08
(s, J ) 6.93 Hz, 1H), 3.01 (s, 3H); MS (FAB) m/ z 264 (M + 1).
Anal. (C10H6N5O3F) C, H, N, F.
1-Eth yl-8-flu or o-7-n itr o-4(5H)-[1,2,4]tr ia zolo[4,3-a ]qu i-
n oxa lin on e (13c). 4-Chloro-1-ethyl-8-fluoro-7-nitro[1,2,4]-
triazolo[4,3-a]quinoxaline: 82% from 12; 1H NMR δ 8.79 (d, J