1830 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Rewcastle et al.
[(CD3)2SO] δ 11.79 (br s, 1 H, NH), 8.74 (s, 1 H, H-5), 7.97 (s,
1 H, H-2), 6.76 (s, 2 H, 7-NH2), 6.38 (s, 1 H, H-8); 13C NMR δ
163.71, 160.20, 154.78 (3 s, C-4,7,8a), 150.14, 149.09 (2 d,
C-2,5), 108.95 (s, C-4a), 98.87 (d, C-8). Anal. (C7H6N4O) C,
H, N.
Further elution with 4% MeOH/CH2Cl2 gave 5f (30 mg,
29%). Further elution with 8-15% MeOH/CH2Cl2 gave 4,7-
bis(methylamino)pyrido[4,3-d]pyrimidine (14) (16 mg, 27%) as
a brown solid: mp (MeOH/CHCl3) >300 °C dec; 1H NMR
[(CD3)2SO] δ 9.93 (br s, 1 H, 4-NH), 9.24 (s, 1 H, H-5), 8.59 (s,
1 H, H-2), 7.73 (br s, 1 H, 7-NH), 6.33 (br s, 1 H, H-8), 3.10 (d,
A solution of 22 (5.00 g, 30.9 mmol) in 50% HBF4 (125 mL)
at 0 °C was treated with solid NaNO2 (4.25 g, 61.6 mmol, added
in portions over 4 h), then stirred at 0 °C for a further 2.5 h,
and kept at -20 °C for 16 h. The resulting mixture was
neutralized with solid Na2CO3/ice, keeping the temperature
below -10 °C, and extracted with EtOAc (6 × 200 mL). The
combined extracts were washed with water and filtered
through silica gel, eluting with EtOAc, to give 7-fluoropyrido-
[4,3-d]pyrimidin-4(3H)-one (23) (2.91 g, 57%): mp (EtOAc)
>258 °C dec; 1H NMR [(CD3)2SO] δ 12.69 (br s, 1 H, NH), 9.01
(s, 1 H, H-5), 8.31 (s, 1 H, H-2), 7.34 (s, 1 H, H-8); 13C NMR δ
166.25 (d, J C-F ) 238 Hz, C-7), 159.66 (s, C-4), 158.31 (d, J C-F
) 12 Hz, C-8a), 151.14 (d, C-2), 149.44 (dd, J C-F ) 19 Hz, C-5),
117.63 (d, J C-F ) 3 Hz, C-4a), 104.27 (dd, J C-F ) 37 Hz, C-8).
Anal. (C7H4FN3O) C, H, N.
J
) 4.5 Hz, 3 H, 4-NHCH3), 2.86 (d, J ) 4.7 Hz, 3 H,
7-NHCH3); HREIMS m/ z calcd for C9H11N5 189.1014 (M+),
found 189.1011.
4-[(3-Br om op h en yl)a m in o]-7-(d im eth yla m in o)p yr id o-
[4,3-d ]p yr im id in e (5g). Similar reaction of 5e (101 mg, 0.32
mmol), Et3N (4.4 mL, 32 mmol), and dimethylamine hydro-
chloride (2.58 g, 32 mmol) in 2-propanol (30 mL) in a pressure
vessel at 100 °C (oil bath) for 4 h gave 4-[(3-bromophenyl)-
amino]-7-(dimethylamino)pyrido[4,3-d]pyrimidine (5g) (102
mg, 94%): mp (MeOH/CHCl3) 240-241.5 °C; 1H NMR [(CD3)2-
SO] δ 9.93 (s, 1 H, NH), 9.42 (s, 1 H, H-5), 8.48 (s, 1 H, H-2),
8.19 (s, 1 H, H-2′), 7.85 (d, J ) 7.7 Hz, 1 H, H-6′), 7.35 (t, J )
7.9 Hz, 1 H, H-5′), 7.30 (br d, J ) 7.8 Hz, 1 H, H-4′), 6.53 (s,
1 H, H-8), 3.16 (s, 6 H, 7-N(CH3)2); 13C NMR δ 160.36 (s, C-7),
157.98 (d, C-2), 157.74 (s, C-4), 154.78 (s, C-8a), 147.75 (d, C-5),
140.73 (s, C-1′), 130.38 (d, C-5′), 126.04, 124.27 (2 d, C-2′,4′),
121.17 (s, C-3′), 120.79 (d, C-6′), 103.24 (s, C-4a), 95.75 (d, C-8),
37.66 (q, 2 C, N(CH3)2). Anal. (C15H14BrN5) C, H, N.
4-[(3-Br om op h en yl)a m in o]-7-m eth oxyp yr id o[4,3-d ]p y-
r im id in e (5h ). A solution of 5e (100 mg, 0.31 mmol) in 1 M
NaOMe in MeOH (30 mL) was stirred under reflux for 42 h.
The resulting mixture was concentrated under vacuum, diluted
with water, and neutralized with dilute HCl to give 4-[(3-
bromophenyl)amino]-7-methoxypyrido[4,3-d]pyrimidine (5h )
(92 mg, 89%): mp (MeOH/H2O) 276-279 °C; 1H NMR [(CD3)2-
SO] δ 10.22 (s, 1 H, NH), 9.57 (s, 1 H, H-5), 8.63 (s, 1 H, H-2),
8.19 (s, 1 H, H-2′), 7.86 (br d, J ) 7.9 Hz, 1 H, H-6′), 7.39 (t,
J ) 7.9 Hz, 1 H, H-5′), 7.35 (br dd, J ) 7.9, 1.5 Hz, 1 H, H-4′),
6.96 (s, 1 H, H-8), 4.00 (s, 3 H, 7-OCH3); 13C NMR δ 165.93 (s,
C-7), 158.45 (d, C-2), 157.89 (s, C-4), 155.76 (s, C-8a), 147.79
(d, C-5), 140.21 (s, C-1′), 130.48 (d, C-5′), 126.68, 124.76 (2 d,
C-2′,4′), 121.24 (s+d, 2 C, C-3′,6′), 107.56 (s, C-4a), 101.27 (d,
C-8), 54.38 (q, OCH3). Anal. (C14H11BrN4O) C, H, N.
P yr id o[3,4-d ]p yr im id in es: 4-[(P h en ylm eth yl)a m in o]-
p yr id o[3,4-d ]p yr im id in e (6a ) a n d 4-[(3-Br om op h en yl)-
a m in o]p yr id o[3,4-d ]p yr im id in e (7a ). A mixture of pyrido-
[3,4-d]pyrimidin-4(3H)-one21 (366 mg, 2.49 mmol) and P2S5 (1.1
g, 2.5 mmol) in pyridine (4 mL) was heated under reflux for 4
h under N2 to give a black tar, which was dissolved in water.
The resultant solid was collected by filtration, washed with
water, and dried in a vacuum oven to yield the known18 pyrido-
[3,4-d]pyrimidine-4(3H)-thione (370 mg, 91%) as a yellow solid
which was used directly (lit.18 mp 325 °C): 1H NMR [(CD3)2-
SO] δ 14.48 (br s, 1 H, NH), 9.13 (s, 1 H, H-8), 8.70 (d, J ) 5.4
Hz, 1 H, H-6), 8.29 (s, 1 H, H-2), 8.27 (d, J ) 5.4 Hz, 1 H,
H-5). A mixture of this (370 mg, 2.26 mmol), Et3N (0.6 mL,
4.5 mmol), DMSO (2 mL), and MeI (0.24 mL, 3.96 mmol) was
stirred under N2 at 25 °C for 12 h and then poured into water.
The resulting solid was filtered and dried in a vacuum oven
to yield the known18 4-(methylthio)pyrido[3,4-d]pyrimidine
(222 mg, 55%) as a brown solid which was used directly (lit.18
mp 132 °C): 1H NMR [(CD3)2SO] δ 9.51 (s, 1 H, H-8), 9.18 (s,
1 H, H-2), 8.79 (d, J ) 5.8 Hz, 1 H, H-6), 7.97 (d, J ) 5.8 Hz,
1 H, H-5), 2.73 (s, 3 H, SCH3). Reaction of the methylthio
compound with benzylamine at 100 °C for 2 h, followed by
purification of the mixture on preparative silica gel TLC, gave
4-[(phenylmethyl)amino]pyrido[3,4-d]pyrimidine (6a ) (21 mg,
20%): mp 136-144 °C (lit.31 mp 150-154 °C); 1H NMR [(CD3)2-
SO] δ 9.21 (t, J ) 5.8 Hz, 1 H, NH), 9.19 (s, 1 H, H-8), 8.63 (d,
J ) 5.8 Hz, 1 H, H-6), 8.58 (s, 1 H, H-2), 8.20 (d, J ) 5.8 Hz,
1 H, H-5), 7.41-7.30 (m, 4 H, H-2′,3′,5′,6′), 7.26 (t, J ) 7.1 Hz,
1 H, H-4′), 4.81 (d, J ) 5.8 Hz, 2 H, CH2). Anal. (C14H12N4‚0.5
H2O) C, H.
A suspension of 23 (2.91 g, 17.6 mmol) in SOCl2 (100 mL)
containing 2 drops of DMF was stirred under reflux for 8 h
and then concentrated under reduced pressure to give crude
4-chloro-7-fluoropyrido[4,3-d]pyrimidine (24) as an oil. This
was ice-cooled, and a solution of 3-bromoaniline (5 mL, 45.9
mmol) in CH2Cl2 (50 mL) was added, followed by dry 2-pro-
panol (50 mL), and the mixture was stirred at 20 °C for 16 h.
Addition of aqueous NaHCO3 gave a precipitate which was
collected and washed with water and CH2Cl2 to give 4-[(3-
bromophenyl)amino]-7-fluoropyrido[4,3-d]pyrimidine (5e) (5.05
g, 90%): mp (2-propanol/water) 219-221.5 °C; 1H NMR
[(CD3)2SO] δ 10.38 (br s, 1 H, NH), 9.59 (s, 1 H, H-5), 8.72 (s,
1 H, H-2), 8.17 (s, 1 H, H-2′), 7.85 (m, 1 H, H-6′), 7.38 (m, 3 H,
H-4′,5′,8); 13C NMR δ 164.76 (d, J C-F ) 237 Hz, C-7), 159.07
(d, C-2), 157.81 (s, C-4), 157.20 (d, J C-F ) 13 Hz, C-8a), 148.41
(dd, J C-F ) 19 Hz, C-5), 139.78 (s, C-1′), 130.44 (d, C-5′), 127.01,
124.86 (2 d, C-2′,4′), 121.30 (d, C-6′), 121.19 (s, C-3′), 110.51
(d, J C-F ) 3 Hz, C-4a), 103.00 (dd, J C-F ) 36 Hz, C-8). Anal.
(C13H8BrFN4) C, H, N.
4-[(3-Br om oph en yl)am in o]-7-(m eth ylam in o)pyr ido[4,3-
d ]p yr im id in e (5f). A mixture of 5e (74 mg, 0.23 mmol), Et3N
(7 mL, 50 mmol), and methylamine hydrochloride (3.0 g, 44
mmol) in 2-propanol (30 mL) was stirred in a pressure vessel
at 95 °C (oil bath) for 5 h. The resulting mixture was
concentrated under reduced pressure, basified with aqueous
Na2CO3, diluted with water, and extracted with EtOAc (3 ×
100 mL). Chromatography of this extract on silica gel, eluting
with MeOH/CH2Cl2 (3:97), gave 4-[(3-bromophenyl)amino]-7-
(methylamino)pyrido[4,3-d]pyrimidine (5f) (50 mg, 65%): mp
(MeOH/CH2Cl2/petroleum ether) 288-290 °C; 1H NMR [(CD3)2-
SO] δ 9.93 (s, 1 H, NH), 9.37 (s, 1 H, H-5), 8.47 (s, 1 H, H-2),
8.18 (s, 1 H, H-2′), 7.84 (d, J ) 7.8 Hz, 1 H, H-6′), 7.34 (t, J )
7.9 Hz, 1 H, H-5′), 7.30 (br d, J ) 8.1 Hz, 1 H, H-4′), 7.19 (q,
J ) 4.7 Hz, 1 H, 7-NHCH3), 6.35 (s, 1 H, H-8), 2.85 (d, J ) 4.8
Hz, 3 H, 7-NHCH3); 13C NMR δ 161.55 (s, C-7), 157.81 (d, C-2),
157.68 (s, C-4), 154.58 (s, C-8a), 148.43 (d, C-5), 140.78 (s, C-1′),
130.37 (d, C-5′), 126.02, 124.29 (2 d, C-2′,4′), 121.15 (s, C-3′),
120.80 (d, C-6′), 103.61 (s, C-4a), 94.70 (br d, C-8), 28.40 (q,
NCH3). Anal. (C14H12BrN5) C, H, N.
When the above reaction was carried out at 100 °C for 14
h, a mixture of products was obtained (Scheme 3). Chroma-
tography on silica gel and elution with 1-2% MeOH/CH2Cl2
gave firstly N4-(3-bromophenyl)-3-methyl-7-(methylamino)-
pyrido[4,3-d]pyrimidin-4(3H)-imine (12) (23 mg, 21%): mp
(MeOH/CH2Cl2/petroleum ether) 263-264 °C; 1H NMR [(CD3)2-
SO] δ 8.14 (s, 1 H, H-2), 7.79 (s, 1 H, H-5), 7.30 (J ) 8.0 Hz,
1 H, ArH), 7.20 (ddd, J ) 7.9, 1.8, 0.8 Hz, 1 H, ArH), 7.03 (br
q, J ) 4.9 Hz, 1 H, 7-NHCH3), 7.01 (t, J ) 1.9 Hz, 1 H, ArH),
6.82 (ddd, J ) 7.8, 1.8, 0.9 Hz, 1 H, ArH), 6.25 (s, 1 H, H-8),
3.40 (s, 3 H, NCH3), 2.73 (d, J ) 4.9 Hz, 3 H, 7-NHCH3); 13C
NMR δ 160.93 (s, C-7), 153.74 (s, C-8a), 153.16 (s, C-4a), 151.65
(d, C-2), 149.61 (d, C-5), 145.30 (s, C-4), 131.75 (d, C-5′), 124.38
(d, C-2′), 122.62 (s, C-3′), 121.98 (s, C-2′), 118.71 (d, C-6′),
105.06 (s, C-4a), 99.14 (br d, C-8), 36.20 (q, NCH3), 27.89 (q,
7-NHCH3). Anal. (C15H14BrN5‚0.5H2O) C, H, N.
Similar reaction of the methylthio compound with 3-bro-
moaniline, and purification of the product by silica gel chro-
matography, eluting with a gradient of 0-5% MeOH in CHCl3,
gave 4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine (7a )
1
(53% yield): mp (Et2O) 209 °C; H NMR [(CD3)2SO] δ 10.15
(s, 1 H, NH), 9.21 (s, 1 H, H-8), 8.80 (s, 1 H, H-2), 8.76 (d, J )
5.8 Hz, 1 H, H-6), 8.44 (d, J ) 5.6 Hz, 1 H, H-5), 8.25 (s, 1 H,