4540 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Gangjee et al.
H, 7-H/8-H), 7.19 (t, 2 H, C6H4), 7.52 (d, 2 H, C6H4), 7.60 (br s,
2 H, 4-NH2, exch), 7.72 (d, 1 H, 7-H/8-H). Anal. (C14H13N5O3S)
C, H, N, S.
(1.0 g, 6.0 mmol) in anhydrous THF (10 mL) at -78 °C was
added 2 M LDA solution in hexane (3.0 mL, 6.0 mmol). After
20 min, the solution was allowed to warm to room temperature
and then added dropwise to a 50-mL round-bottom flask
containing a solution of 3-nitro-6-chloro-2-pyridinecarbonitrile
(26) (1.0 g, 5.4 mmol) in anhydrous THF (15.0 mL) at -78 °C
over a period of 10 min. The reaction mixture was stirred at
-78 °C for an additional 30 min and was allowed to warm to
room temperature. The reaction was continued for 2 h at room
temperature and quenched with saturated NH4C1 solution (1.0
mL), and the solvent THF was removed with a rotary evapora-
tor. Chloroform (30.0 mL) was then added to the flask, and
the resulting solution was transferred into a separatory funnel,
washed with water and saturated sodium chloride solution
successively, and dried over anhydrous Na2SO4 for 40 min.
After removal of chloroform under reduced pressure, the
residue was loaded onto a silica gel column and eluted
gradually with CHCl3 and CHCl3-AcOEt (95:5) to afford 1.21
g (70%) of 38: 1H NMR (CDC3) δ 3.51 (s, 3 H, NCH3), 3.75,
3.77 (d, 6 H, 2′-OCH3 and 5′-OCH3), 6.33 (d, 1 H, 5-H), 6.72
(d, 1 H, 6′-H), 6.97 (m, 2 H, 3′-H and 4′-H), 8.06 (d, 1 H, 4-H).
3-Nitr o-6-(N-m eth yl-1′-n a p h th yla m in o)p yr id in e-2-ca r -
bon itr ile (41). Using the procedure described for the syn-
thesis of 38, compound 26 (0.87 g, 4.7 mmol) was reacted with
N-methyl-2-naphthylamine (0.82 g, 5.2 mmol) to afford 0.58 g
(40%) of 41: 1H NMR (DMSO-d6) δ 3.41 (s, 3 H, NCH3), 7.04
(d, 1 H, 5-H), 7.21 (d, 1 H, C10H7), 7.34 (t, 1 H, C10H7), 7.57
(m, 2 H, C10H7), 7.82 (d, 1 H, C10H7), 7.96 (dd, 1 H, C10H7),
8.17 (d, 1 H, 4-H).
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
44-59 Exem p lified by th e Syn th esis of 3-Am in o-6-a n ili-
n op yr id in e-2-ca r bon itr ile (44). To a suspension of 3-nitro-
6-anilino-2-pyridocarbonitrile (28) (0.83 g, 3.5 mmol) in metha-
nol (20 mL) and concentrated hydrochloric acid (36%, 4.0 mL)
was added iron powder (0.65 g, 11.6 mmol). The mixture was
refluxed until all the starting material had reacted (monitored
on TLC). The hot reaction mixture was poured into water (20
mL) and stirred for 5 min. The unreacted iron was removed
using a stirring bar retriever, and the aqueous solution was
neutralized with ammonium hydroxide to pH 4. The solution
was then extracted with chloroform (3 × 20 mL), and the
combined organic layer was washed with water (2 × 5.0 mL),
sodium bicarbonate solution (5.0 mL), and brine (5.0 mL) and
dried over anhydrous sodium sulfate. Chromatographic pu-
rification on a silica gel column using AcOEt-CHCl3-MeOH
(12:8:1) as eluent afforded 0.52 g (71%) of 3-amino-6-anilino-
2-pyridinocarbonitrile (44): 1H NMR (DMSO-d6) δ 5.66 (br s,
2 H, 3-NH2, exch), 6.80 (t, 1 H, 4′-H), 6.93 (d, 1 H, 4-H/5-H),
7.16 (d, 1 H, 4-H/5-H), 7.20 (t, 2 H, 3′-H and 5′-H), 7.52 (d, 2
H, 2′-H and 6′-H), 8.56 (br s, 1 H, NH, exch).
2,4-Dia m in o-6-[(4′-m eth oxyp h en yl)su lfon yl]p yr id o[3,2-
d ]p yr im id in e (8). A mixture of 5 (0.20 g, 0.7 mmol) and 30%
hydrogen peroxide (1.8 mL, 18 mmol) in glacial acetic acid (9.0
mL) was stirred at room temperature for 2 days. Following
the workup procedure described above for compound 7 and
column chromatographic purification using 15% methanol in
chloroform as eluent afforded 0.12 g (54%) of 8: TLC Rf 0.16
1
(MeOH/CHCl3, 1:9); mp 216-218 °C; H NMR (DMSO-d6) δ
3.73 (s, 3 H, 4′-OCH3), 6.47 (br s, 2 H, 2-NH2, exch), 7.03 (d, 2
H, C6H4), 7.53 (br, 2 H, 4-NH2, exch), 7.67 (d, 1 H, 7-H/8-H),
7.72 (d, 2 H, C6H4), 7.88 (d, 1 H, 7-H/8-H). Anal. (C14H13N5O3S‚
0.15H2O) C, H, N, S.
2,4-Diam in o-6-[(3′,4′-dim eth oxyph en yl)su lfon yl]pyr ido-
[3,2-d ]p yr im id in e (9). Using the same procedure as de-
scribed above for 7, compound 6 (0.18 g, 0.5 mmol) was
oxidized with 30% hydrogen peroxide (1.5 mL, 15 mmol) in
glacial acetic acid (8.0 mL) to afford 0.09 g (40%) of 9: TLC Rf
1
0.18 (MeOH/CHCl3, 1:9); mp 231-233 °C; H NMR (DMSO-
d6) δ 3.75, 3.72 (2 s, 6 H, 3′-OCH3 and 4′-OCH3), 6.46 (br s, 2
H, 2-NH2, exch), 7.05 (d, 1 H, aryl H), 7.32-7.36 (m, 2 H, aryl
Hs), 7.57 (br d, 2 H, 4-NH2, exch), 7.66 (d, 1 H, aryl H), 7.89
(d, 1 H, aryl H). Anal. (C15H15N5O4S‚0.05C6H14) C, H, N, S.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
10-25 Exem p lified by th e Syn th esis of 2,4-Dia m in o-6-
(3′,4′-d im eth oxya n ilin o)p yr id o[3,2-d ]p yr im id in e (15). A
mixture of 2-cyano-3-amino-6-(3′,4′-dimethoxyanilino)pyridine
(49) (0.56 g, 2.1 mmol), chloroformamidine hydrochloride (0.48
g, 4.2 mmol), and dimethyl sulfone (2.0 g) was heated in an
oil bath at 140 °C under nitrogen for 15 min. The oil bath
was removed, and water (10 mL) was added slowly to the hot
reaction mixture. The aqueous solution was cooled to room
temperature and extracted with chloroform (3 × 5 mL) to
remove dimethyl sulfone. The aqueous phase was made basic
to pH 10 with ammonium hydroxide, followed by removal of
water under reduced pressure. The residue was dissolved in
a mixture of 50:50 methanol-acetone (v/v), and silica gel was
added (3.0 g). After the removal of solvent with a rotary
evaporator, the silica gel plug was loaded onto a column and
eluted with 3:10:9 MeOH-CHCl3-(CH3)2CO (v/v/v) to afford
0.41 g (63%) of 15: 1H NMR (DMSO-d6) δ 3.72, 3.78 (2 s, 6 H,
3-OCH3 and 4-OCH3), 5.99 (br s, 2 H, 2-NH2, exch), 6.30-7.27
(collapsed br, 2 H, 4-NH2, exch), 6.90 (d, 1 H, 5′-H), 7.14 (d, 1
H, 7-H/8-H), 7.34 (dd, 1 H, 6′-H), 7.41 (d, 1 H, 2′-H), 7.47 (d, 1
H,7-H/8-H),9.14 (s,1 H,N9-H,exch). Anal. (C15H16N6O2‚0.5CH3-
OH) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
28-37, 39, 40, 42, a n d 43 Exem p lified by th e Syn th esis
of 3-Nitr o-6-(3′,4′-d im eth oxya n ilin o)p yr id in e-2-ca r bon i-
tr ile (33). A solution of 6-chloro-3-nitro-2-pyridinecarbonitrile
(26) (0.50 g, 2.7 mmol), 4-aminoveratrole (0.53 g, 3.5 mmol),
and pyridine (0.26 g, 3.3 mmol) in 2-ethoxyethanol (10 mL)
was heated at 120 °C under nitrogen. After 4 h, the solution
was concentrated under reduced pressure and the concentrated
solution poured into water and stirred at room temperature
for 30 min. The precipitate obtained was filtered, washed
twice with water and twice with ether successively, transferred
into a 100-mL round-bottom flask, and redissolved in ethanol
(20 mL). To this solution was added silica gel (3.5 g), and the
solvent removed by evaporation. The silica gel plug obtained
was loaded onto a silica gel column and eluted with 1:1 ethyl
acetate-methylene chloride (v/v). The fractions containing the
desired product (monitored on TLC) were pooled, and the
solvent was evaporated to afford 0.71 g (87%) of 33: 1H NMR
(DMSO-d6) δ 3.73, 3.74 (2 s, 6 H, 3′-OCH3 and 4′-OCH3), 6.96
(d, J ) 8.8 Hz, 1 H, 5′-H), 7.01 (d, J ) 9.5 Hz, 1 H, 5-H), 7.13
(d, J ) 8.8 Hz, 1 H, 6′-H), 7.25 (br s, 1 H, 2′-H), 8.30 (d, J )
9.5 Hz, 1 H, 4-H), 10.34 (s, 1 H, NH, exch).
Ack n ow led gm en t. This work was supported in part
by NIH Grants GM 40998 (A.G.), AI 30900 (A.G.), and
AI 41743 (A.G.) and Contracts NO1-AI-87240 (S.F.Q.)
and NO1-AI-35171 (S.F.Q.).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR data for
compounds 10-25, 28-32, 34-47, and 49-59 (Tables 6-8)
(6 pages). Ordering information is given on any current
masthead page.
Refer en ces
(1) Presented in part at the 212th American Chemical Society
National Meeting, Orlando, FL, August 1996; Abstr. MEDI 138.
(2) Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichol, C. A.
Synthesis and Antitumor Activity of 2,4-Diamino-6-(2′,5′-
dimethoxybenzyl)-5-methylpyrido[2,3d]pyrimidine. J . Med. Chem.
1980, 23, 327-336.
(3) de Vries, E. G. E.; Gietema, J . A.; Workman, P.; Scott, J . E.;
Crawshaw, A.; Dobbs, H. J .; Dennis, I.; Mulder, N. H.; Sleijfer,
D. Th.; Willemse, P. H. B. A Phase II and Pharmacokinetic Study
with Oral Piritrexim for Metastic Breast Cancer. Br. J . Cancer
1993, 68, 641-644.
(4) de Wit, R.; Kaye, S. B.; Roberts, J . T.; Stoter, G.; Scott, J .;
Verweij, J . Oral Piritrexim, an Effective Treatment for Meta-
static Urothelial Cancer. Br. J . Cancer 1993, 67, 388-390.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
38 a n d 41 Exem p lified by th e Syn th esis of 3-Nitr o-6-(N-
m et h yl-2′,5′-d im et h oxya n ilin o)p yr id in e-2-ca r b on it r ile
(38). To a stirred solution of N-methyl-2,5-dimethoxyaniline