3684 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
Cai et al.
31.5 mmol) at rt. The mixture was then stirred at 55 °C for 2
h, cooled to rt, and poured into crashed ice (about 100 g). The
mixture was basified to pH 9 in an ice bath by dropwise
addition of 40% aqueous NaOH and the mixture was extracted
with CHCl3 (5 × 25 mL). The CHCl3 extracts were combined,
washed with brine (20 mL), dried (MgSO4), and rotary
evaporated to give 770 mg (25%) of 9c as a bright yellow
refluxed under N2 for 16 h and then cooled to rt. The
precipitate was filtered, washed with water (4 × 15 mL), and
dried to give 20.26 g (84%) of 11a as a dark brown powder:
1
mp >360 °C; H NMR (DMSO-d6) 7.44 (d, J ) 2.1, 1H), 8.10
(d, J ) 2.1, 1H), 12.04 (bs, 1H), 12.48 (bs, 1H); HRMS calcd
for C7H435ClN3O2 196.9988, found 196.9993. Anal. (C7H4-
ClN3O2‚0.25H2O) C: calcd, 41.60; found, 41.15. H: calcd, 2.24;
found 1.75. N.
1
powder: mp 175-176 °C; H NMR (CDCl3) 2.29 (s, 3H), 6.56
(bs, 2H), 8.22 (s, 1H), 8.24 (s, 1H).
5-Aza -7-br om o-1,4-d ih yd r oqu in oxa lin e-2,3-d ion e (11b)
was prepared similarly to 11a . From a solution of diamine
10b (500 mg, 2.66 mmol) and oxalic acid (360 mg, 4.00 mmol)
in 2N aqueous HCl (3.0 mL) there was obtained 536 mg (83%)
of 11b as a green-yellow powder: mp >370 °C; 1H NMR
(DMSO-d6) 7.55 (s, 1H), 8.16 (s, 1H), 12.01 (s, 1H), 12.46 (s,
1H). Anal. (C7H4BrN3O2) C, H, N.
2-Am in o-3-n itr o-5-(tr iflu or om eth yl)p yr id in e (9d ). To
a stirred solution of 2-amino-5-(trifluoromethyl)pyridine (8d )
(1.70 g, 10.5 mmol) in 10 mL of H2SO4 heated at 50 °C was
added dropwise HNO3 (70%, 1.7 mL, 26 mmol) over 10 min.
The resulting solution was stirred at 80 °C for 46 h and then
allowed to cool to rt, poured into ice-water (100 mL), and
basified to pH 9 with 40% aqueous NaOH. The resulting
mixture was extracted with ethyl acetate (5 × 40 mL). The
extracts were dried (MgSO4) and rotary evaporated to give 1.33
5-Aza -7-m eth yl-1,4-d ih yd r oqu in oxa lin e-2,3-d ion e (11c)
was prepared similarly to 11a . From a solution of diamine
10c (625 mg, 5.08 mmol) and oxalic acid (685 mg, 7.61 mmol)
in 2N aqueous HCl (10 mL) there was obtained 393 mg (44%)
of 11c as a black powder: mp >370 °C (lit.12 mp >300 °C); 1H
NMR (DMSO-d6) 2.26 (s, 3H), 7.25 (s, 1H), 7.90 (s, 1H), 11.95
(s, 1H), 12.24 (s, 1H). Anal. (C8H7N3O2‚0.5 H2O) C, H, N.
5-Aza -7-(tr iflu or om eth yl)-1,4-d ih yd r oqu in oxa lin e-2,3-
d ion e (11d ). A stirred mixture of diamine 10d (800 mg, 4.52
mmol) and diethyl oxalate (7.00 g, 47.9 mmol) was heated at
160 °C for 2 h and cooled to rt. The mixture was diluted with
hexane (20 mL), filtered, washed with hexane (3 × 5 mL), and
dried to give 997 mg (94%) of 11d as a yellow powder: mp
1
g (61%) of 9d as a yellow powder: mp 191-193 °C; H NMR
(CDCl3) 6.14 (bs, 1H), 7.92 (bs, 1H), 8.59 (s, 1H), 8.67 (s, 1H).
2-Am in o-3,5-d in itr op yr id in e (9e). To a stirred mixture
of 2-chloro-3,5-dinitropyridine (7) (2.035 g, 10 mmol) in EtOH
(15 mL) was added dropwise aqueous NH4OH (6 mL) at rt over
20 min. The resulting mixture was stirred at rt for 15 min
and then cooled to 0 °C. The precipitate was filtered, washed
with water (3 × 5 mL), and dried to give 1.64 g (89%) of 9e as
1
a yellow powder: mp 190-191 °C; H NMR (DMSO-d6) 8.70
(bs, 1H), 8.95 (d, J ) 2.5, 1H), 9.16 (d, J ) 2.5, 1H), 9.22 (bs,
1H).
>360 °C;
1H NMR (DMSO-d6) 7.63 (s, 1H), 8.44 (s, 1H), 12.12
2,3-Dia m in o-5-ch lor op yr id in e (10a ). A mixture of 9a
(22.0 g, 127 mmol), Raney Ni (2.2 g), and MeOH (220 mL) was
shaken under H2 (20-40 psi) for 3 h and then filtered. The
filtrate was rotary evaporated and the residual solid was dried
to give 17.6 g (96%) of 10a as a tan powder: mp 169-171 °C
(lit.27 mp 172-173 °C); 1H NMR (DMSO-d6) 4.99 (bs, 2H), 5.56
(bs, 2H), 6.68 (d, J ) 2.1, 1H), 7.20 (d, J ) 2.1, 1H).
(s, 1H), 12.70 (s, 1H); 19F NMR (DMSO-d6) -131.2 ppm. Anal.
(C8H4F3N3O2) C, H, N.
5-Aza -7-n it r o-1,4-d ih yd r oqu in oxa lin e-2,3-d ion e (11e)
was prepared similarly to 11a . From a solution of diamine
10e (308 mg, 2.00 mmol) and oxalic acid (270 mg, 3.00 mmol)
in 2 N aqueous HCl (3 mL) there was obtained 308 mg (74%)
of 11e as a black powder: mp >370 °C (lit.12 mp >300 °C); 1H
NMR (DMSO-d6) 8.09 (d, J ) 2.4, 1H), 8.91 (d, J ) 2.4, 1H),
12.22 (bs, 2H); HRMS calcd for C7H4N4O4 208.231, found
208.233. Anal. (C7H4N4O4‚0.4H2O) C, H, N.
7-Ch lor o-5-(N-oxya za )-1,4-d ih yd r oqu in oxa lin e-2,3-d i-
on e (12a ). (a) To a solution of aza-QX 11a (77 mg, 0.39 mmol)
in 5 mL of trifluoroacetic acid (TFA) was added m-chloroper-
benzoic acid (MCPBA, 280 mg, 0.8 mmol) at rt. The resulting
red solution was refluxed for 15 h and then rotary evaporated
to dryness. The residual solid was washed with MeOH (3 ×
5 mL) and dried to give 80 mg (96%) of 12a as an off-white
powder: mp 321-323 °C; 1H NMR (DMSO-d6) 7.05 (s, 1H),
8.39 (s, 1H), 12.20 (bs, 2H).
2,3-Dia m in o-3-br om op yr id in e (10b). A mixture of 2-
amino-5-bromo-3-nitropyridine (9b) (676 mg, 3.10 mmol), tin-
(II) chloride dihydrate (3.58 g, 14.0 mmol), and EtOH (3 mL)
was heated to boil. The resulting solution was refluxed under
N2 for 15 h, cooled to rt, and evaporated to dryness. To the
residual solid was added H2O (80 mL), and the mixture was
basified to pH 8 with 1 N aqueous NaOH. The resulting
mixture was extracted with ethyl acetate (3 × 50 mL). The
extracts were combined, washed with brine (25 mL), dried
(MgSO4), and rotary evaporated to dryness. The residual solid
was dried at 40 °C under vacuum, giving 565 mg (97%) of 10b
as a pale yellow powder: mp 158-160 °C; 1H NMR (CDCl3 +
DMSO-d6) 3.82 (s, 2H), 4.53 (s, 2H), 6.84 (s, 1H), 7.45 (s, 1H).
2,3-Dia m in o-5-m eth ylp yr id in e (10c). A mixture of ni-
tropyridine 9c (790 mg, 5.17 mmol), methanol (60 mL) and
5% Pd-C (70 mg) was shaken under H2 (20-30 psi) for 3 h
and then filtered and evaporated to give 629 mg (99%) of the
diamine 10c as a thick black oil: 1H NMR (CDCl3) 2.16 (s,
3H), 3.31 (bs, 2H), 4.16 (bs, 2H), 6.74 (s, 1H), 7.46 (s, 1H).
2,3-Dia m in o-5-(tr iflu or om eth yl)p yr id in e (10d ). A mix-
ture of 9d (950 mg, 4.59 mmol), methanol (15 mL), and Raney
Ni (200 mg) was shaken under H2 (30-40 psi) for 2 h and then
filtered. The filtrate was evaporated to dryness, giving 810
mg (100%) of the diamine 10d as a deep yellow powder: mp
(b) To a stirred solution of 30% H2O2 (260 mL) was added
dropwise trifluoroacetic anhydride (130 mL) at 0 °C over 1 h.
After the addition, the resulting solution was stirred at 0 °C
for 30 min, then the aza-QX 11a (25.68 g, 130 mmol) was
added in one portion. The mixture was stirred at 90 °C for 30
min (a lot of gas evolved). The resulting orange solution was
cooled in an ice bath and stirred for 1 h. The precipitate was
filtered, washed with MeOH (2 × 25 mL) and H2O (2 × 25
mL), and dried to give 25.86 g (93%) of 12a as a yellowish
powder: HRMS calcd for C7
H435ClN3O3 212.9939, found
212.9953. Anal. (C7H4ClN3O3‚H2O) C, H, N.
7-Br om o-5-(N-oxya za )-1,4-d ih yd r oqu in oxa lin e-2,3-d i-
on e (12b) was prepared similarly to 12a (method a). From a
mixture of 11b (135 mg, 0.558 mmol), MCPBA (266 mg, 0.76
mmol), and TFA (3.0 mL) there was obtained 65 mg (45%) of
1
97-99 °C; H NMR (CDCl3) 3.39 (bs, 2H), 4.56 (bs, 2H), 7.05
(s, 1H), 7.93 (s, 1H).
2,3-Dia m in o-5-n itr op yr id in e (10e). To a stirred suspen-
sion of 9e (1.62 g, 8.79 mmol) in MeOH (75 mL) was added
dropwise 20% aqueous (NH4)2S (15 mL, 44 mmol) at rt. The
resulting dark-red solution was stirred at rt for 0.5 h, refluxed
for 0.5 h, and then cooled to rt. The resulting mixture was
filtered. The filtrate was concentrated to about 30 mL and
cooled in ice-water. The precipitate was filtered, washed with
cooled EtOH (2 × 5 mL), and dried to give 1.09 g (80%) of 10e
as a deep red powder: mp 260-262 °C (dec); 1H NMR (DMSO-
d6) 5.31 (s, 2H), 6.98 (s, 2H), 7.34 (d, J ) 2.2, 1H), 8.17 (d, J
) 2.2, 1H).
1
12b as a yellowish powder: mp 304-306 °C (dec); H NMR
(DMSO-d6) 7.12 (s, 1H), 8.48 (s, 1H), 12.17 (bs, 2H). Anal.
(C7H4BrN3O3‚1.05H2O) C, H, N.
7-Meth yl-5-(N-oxya za )-1,4-d ih yd r oqu in oxa lin e-2,3-d i-
on e (12c) was prepared similarly to 12a (method a). From a
mixture of 11c (177 mg, 1.0 mmol), MCPBA (542 mg, 1.5
mmol), and TFA (5.0 mL) there was obtained 135 mg (74%) of
12c as a yellow powder: mp 228-230 °C (dec); 1H NMR
(DMSO-d6) 2.22 (s, 3H), 6.85 (s, 1H), 7.99 (s, 1H), 12.12 (s,
2H). Anal. (C8H7ClN3O3‚1.25H2O) C, H, N.
5-Aza -7-ch lor o-1,4-d ih yd r oqu in oxa lin e-2,3-d ion e (11a ).
A solution of the diamine 10a (17.57 g, 122.4 mmol) and oxalic
acid (13.22 g, 146.9 mmol) in 2 N aqueous HCl (160 mL) was
5-(N-Oxya za )-7-(tr iflu or om eth yl)-1,4-d ih yd r oqu in oxa -
lin e-2,3-d ion e (12d ). To 30% H2O2 (4 mL) was added
trifluoroacetic anhydride (2 mL) at 0 °C dropwise with stirring.