Pyrido[2,1-f]purine-2,4-dione Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3341
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chromatography was performed with silica gel 60 (230-400
mesh, Merck).
MS (EI): m/z 334 (M+, 71). H NMR (CDCl3) δ: 0.95 (t, J )
7.5 Hz, 3H, CH3), 1.69 (m, J ) 7.5 Hz, 2H, CH2CH3), 4.01 (pt,
J ) 7.3 Hz, 2H, NCH2), 5.37 (s, 2H, CH2Ph), 7.06 (pt, J ) 6.1
Hz, H-7), 7.25-7.52 (m, 5H, Ph), 7.52 (pt, J ) 7.0 Hz, H-8),
7.65 (d, J ) 7.0 Hz, 1H, H-9), 9.04 (d, J ) 6.7 Hz, 1H, H-6).
13C NMR (CDCl3) δ: 11.32 (CH3CH2), 21.38 (CH3CH2), 42.83
(NCH2), 46.67 (CH2Ph), 101.90 (C-4a), 113.90 (C-7), 116.41 (C-
9), 127.48 (C-6), 127.79, 128.51, 128.66, 136.37 (Ph), 129.87
(C-8), 147.63 (C-9a), 150.69 (C-10a), 151.39 (C-2), 155.01 (C-
4). Anal. (C19H18N4O2) C, H, N.
All experiments involving water-sensitive compounds were
conducted under scrupulously dry conditions. Acetonitrile and
toluene were dried by refluxing over calcium hydride. Anhy-
drous N,N′-dimethylformamide was purchased from Aldrich.
Gen er a l P r oced u r e for th e Syn th esis of 1-Ben zyl-
1H,3H-p yr id o[2,1-f]p u r in e-2,4-d ion es. N-Bromosuccinimide
(NBS) (445 mg, 2.5 mmol) was added into a suspension of
6-amino-1-benzyluracil (1) (217 mg, 1.0 mmol) in dry CH3CN
(8 mL), and the mixture was heated at 80 °C for 1 h. After the
mixture was cooled to room temperature, the corresponding
pyridine (5-10 mmol) was added, and the resulting mixture
was heated at 80 °C for 6 h. The resulting precipitate, which
contains the target compound, was collected by filtration and
washed with ethyl ether. Evaporation of the filtrate, washing
of the solid obtained with CH2Cl2 (2 × 5 mL), and purification
of this solid by CCTLC on the Chromatotron instrument (CH2-
Cl2/MeOH mixtures) afforded a second portion of the target
compound followed by varying amounts (15-25%) of 6-amino-
1-benzyl-5-bromouracil.
1-Ben zyl-8-m eth oxy-3-pr opyl-1H,3H-pyr ido[2,1-f]pu r in e-
2,4-d ion e (7). Compound 7 was obtained by the reaction of 3
with propyl iodide. Yield: 82%. Mp (CH2Cl2/MeOH): 188-190
°C. MS (EI): m/z 364 (M+, 100). H NMR (CDCl3) δ: 0.97 (t,
1
J ) 7.5 Hz, 3H, CH3), 1.69 (m, J ) 7.7 Hz, 2H, CH2CH3), 3.93
(s, 3H, OCH3), 4.01 (pt, J ) 7.5 Hz, 2H, NCH2), 5.36 (s, 2H,
CH2Ph), 6.75 (dd, J ) 7.2, 2.4 Hz, H-7), 6.99 (d, J ) 2.3 Hz,
H-9), 7.25-7.53 (m, 5H, Ph), 8.83 (d, J ) 7.5 Hz, 1H, H-6).
13C NMR (CDCl3) δ: 11.30 (CH3CH2), 21.44 (CH3CH2), 42.78
(NCH2), 46.66 (CH2Ph), 55.84 (OCH3), 95.39 (C-9), 101.06 (C-
4a), 107.54 (C-7), 127.72, 127.90, 128.49, 128.60, 136.62 (C-6,
Ph), 150.01, 151.49 (C-2, C-9a, C-10a), 154.67 (C-4), 161.56
(C-8). Anal. (C20H20N4O3) C, H, N.
1-Ben zyl-1H,3H-p yr id o[2,1-f]p u r in e-2,4-d ion e (2). Glo-
bal yield: 60%. Mp (CH2Cl2/MeOH): 298-299 °C. MS (EI):
m/z 292 (M+, 59). 1H NMR (DMSO-d6) δ: 5.22 (s, 2H, CH2Ph),
7.10-7.50 (m, 6H, H-7, Ph), 7.66 (m, J ) 7.1, 1.2 Hz, H-8),
7.75 (d, J ) 9.1 Hz, 1H, H-9), 8.94 (d, J ) 6.6 Hz, H-6), 11.35
(br s, 1H, NH). 13C NMR (DMSO-d6) δ: 44.92 (CH2Ph), 101.95
(C-4a), 114.51 (C-7), 116.08 (C-9), 127.11, 127.20, 128.32,
136.71 (C-6, Ph), 130.34 (C-8), 147.08 (C-9a), 150.85 (C-10a),
151.60 (C-2), 154.53 (C-4). Anal. (C16H12N4O2) C, H, N.
1-Ben zyl-8-m eth oxy-1H,3H-p yr id o[2,1-f]p u r in e-2,4-d i-
on e (3). Global yield: 74%. Mp (CH2Cl2/MeOH): 277-278 °C.
1-Ben zyl-8-ter t-bu tyl-3-p r op yl-1H,3H-p yr id o[2,1-f]p u -
r in e-2,4-d ion e (8). Compound 8 was obtained by the reaction
of 4 with propyl iodide and was purified by CCTLC on the
Chromatotron instrument (30:1 ratio of CH2Cl2/MeOH).
Yield: 75%. Mp (CH2Cl2/MeOH): 142-144 °C. MS (EI): m/z
390 (M+, 100). 1H NMR (CDCl3) δ: 0.97 (t, J ) 7.3 Hz, 3H,
CH3), 1.38 [s, 9H, (CH3)3C], 1.70 (m, J ) 7.6 Hz, 2H, CH2CH3),
4.02 (pt, J ) 7.5 Hz, 2H, NCH2), 5.38 (s, 2H, CH2Ph), 7.14
(dd, J ) 7.1, 1.8 Hz, H-7), 7.26-7.54 (m, 5H, Ph), 7.63 (dd, J
) 1.8, 0.9 Hz, H-9), 8.92 (dd, J ) 7.1, 0.9 Hz, 1H, H-6). 13C
NMR (CDCl3) δ: 11.28 (CH3CH2), 21.43 (CH3CH2), 30.51
[(CH3)3C], 35.43 [(CH3)3C], 42.80 (NCH2), 46.67 (CH2Ph),
101.47 (C-4a), 111.76, 112.90 (C-9, C-7), 126.64, 127.71, 128.49,
128.60, 136.61 (C-6, Ph), 148.23 (C-9a), 151.11, 151.53 (C-10a,
C-2), 154.76, 154.92 (C-4, C-8). Anal. (C23H26N4O2) C, H, N.
1
MS (EI): m/z 322 (M+, 100). H NMR (DMSO-d6) δ: 3.88 (s,
3H, OCH3), 5.18 (s, 2H, CH2Ph), 7.01 (dd, J ) 7.5, 2.6 Hz, H-7),
7.10-7.50 (m, 6H, H-9, Ph), 8.70 (d, J ) 7.5 Hz, 1H, H-6), 11.30
(br s, 1H, NH). 13C NMR (DMSO-d6) δ: 44.95 (CH2Ph), 56.23
(OCH3), 95.74 (C-9), 100.38 (C-4a), 107.72 (C-7), 127.20, 127.70,
128.32, 136.92 (C-6, Ph), 149.05 (C-9a), 150.92 (C-10a), 152.41
(C-2), 154.12 (C-4), 161.12 (C-8). Anal. (C17H14N4O3) C, H, N.
1-Ben zyl-8-ter t-bu tyl-1H,3H-p yr id o[2,1-f]p u r in e-2,4-d i-
on e (4). Global yield: 58%. Mp (EtOAc): 258-259 °C. MS
(EI): m/z 348 (M+, 100). 1H NMR (CDCl3) δ: 1.33 [s, 9H,
(CH3)3C], 5.31 (s, 2H, CH2Ph), 7.16 (dd, J ) 7.1, 1.8 Hz, H-7),
7.20-7.65 (m, 5H, Ph), 7.67 (d, J ) 1.8 Hz, H-9), 8.90 (d, J )
7.1 Hz, 1H, H-6), 9.20 (br s, 1H, NH). 13C NMR (CDCl3) δ:
30.47 [(CH3)3C], 35.46 [(CH3)3C], 46.01 (CH2Ph), 100.05 (C-
4a), 111.95 (C-9), 113.22 (C-7), 126.61 (C-6), 127.79, 128.49,
128.65, 136.27 (Ph), 148.60 (C-9a), 151.13 (C10a), 152.80 (C-
2), 154.41 (C-4), 155.17 (C-8). Anal. (C20H20N4O2) C, H, N.
1-Ben zyl-8-p h en yl-1H ,3H -p yr id o[2,1-f]p u r in e-2,4-d i-
on e (5). Global yield: 59%. Mp (EtOAc/MeOH): 282-284 °C.
MS (ES, positive mode): m/z 369 [(M + 1)+], 391 [(M + Na)+].
1H NMR (DMSO-d6) δ: 5.23 (s, 2H, CH2Ph), 7.24-7.90 (m,
11H, Ph, H-7), 8.10 (s, 1H, H-9), 8.95 (d, J ) 7.0 Hz, 1H, H-6),
11.14 (br s, 1H, NH). 13C NMR (DMSO-d6) δ: 44.99 (CH2Ph),
101.11 (C-4a), 112.31 (C-9), 113.34 (C-7), 126.82, 126.98,
127.19, 128.28, 129.08, 136.73 (C-6, Ph), 141.53, 147.53 (C-8,
C-9a), 150.85, 152.19 (C-10a, C-2), 154.45 (C-4). Anal.
(C22H16N4O2) C, H, N.
1-Ben zyl-8-p h en yl-3-p r op yl-1H,3H-p yr id o[2,1-f]p u r in e-
2,4-d ion e (9). Compound 9 was obtained by the reaction of 5
with propyl iodide and was purified by CCTLC on the Chro-
matotron instrument (40:1 ratio of CH2Cl2/MeOH). Yield: 93%.
Mp (CH2Cl2/MeOH): 202-204 °C. MS (ES, positive mode): m/z
411 [(M + 1)+], 433 [(M + Na)+]. H NMR (CDCl3) δ: 0.99 (t,
1
J ) 7.5 Hz, 3H, CH3), 1.74 (m, J ) 7.5 Hz, 2H, CH2CH3), 4.05
(t, J ) 7.5 Hz, 2H, NCH2), 5.42 (s, 2H, CH2Ph), 7.26-7.73 (m,
11H, Ph, H-7), 7.89 (s, 1H, H-9), 9.08 (d, J ) 7.0 Hz, 1H, H-6).
13C NMR (CDCl3) δ: 11.32 (CH2CH3), 21.41 (CH2CH3), 42.86
(NCH2), 46.72 (CH2Ph), 101.62 (C-4a), 113.19 (C-9), 113.42 (C-
7), 126.97, 127.21, 127.80, 128.52, 128.70, 129.19, 129.28,
136.46, 137.73 (C-6, Ph), 142.94, 148.14 (C-9a, C-8), 151.25,
151.42 (C-10a, C-2), 154.91 (C-4). Anal. (C25H22N4O2) C, H, N.
1-Ben zyl-3-et h yl-1H,3H-p yr id o[2,1-f]p u r in e-2,4-d ion e
(10). Compound 10 was obtained by the reaction of 2 with
ethyl iodide and was purified by CCTLC on the Chromatotron
instrument (40:1 ratio of CH2Cl/MeOH). Yield: 34%. Mp (CH2-
Cl2/MeOH): 118-120 °C. MS (ES, positive mode): m/z 321
1
[(M + 1)+], 343 [(M + Na)+]. H NMR (CDCl3) δ: 1.28 (t, J )
7.1 Hz, 3H, CH3), 4.15 (q, J ) 7.1 Hz, 2H, NCH2CH3), 5.40 (s,
2H, CH2Ph), 7.10 (m, J ) 6.9, 1.2 Hz, H-7), 7.23-7.39 (m, 4H,
Ph), 7.55 (t, J ) 7.2 Hz, 2H, Ph, H-8), 7.70 (m, J ) 9.0, 1.2
Hz, 1H, H-9), 9.08 (m, J ) 6.8, 1.2 Hz, 1H, H-6). 13C NMR
(CDCl3) δ: 13.37 (CH3), 36.43 (NCH2), 46.65 (CH2Ph), 101.85
(C-4a), 113.87 (C-7), 116.41 (C-9), 127.47 (C-6), 127.78, 128.49,
128.69, 136.38 (Ph), 129.82 (C-8), 147.61 (C-9a), 150.70, 151.20
(C-10a, C-2), 154.81 (C-4). Anal. (C18H16N4O2) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of N3-Su bsti-
tu ted 1-Ben zyl-1H,3H-p yr id o[2,1-f]p u r in e-2,4-d ion es. A
solution of the corresponding pyridopurinedione (2-5) (0.30
mmol) in dry CH3CN (3 mL) was reacted with DBU (0.05 mL,
0.33 mmol) and the corresponding alkyl, alkenyl, alkynyl, or
benzyl halide (0.45 mmol) at room temperature or at 80 °C.
After 4-6 h, volatiles were removed. The residue was taken
up in CH2Cl2 (50 mL) and washed with 1N HCl (20 mL), water
(20 mL), and brine (20 mL). The organic phase was dried on
anhydrous Na2SO4, filtered, and evaporated. The residue was
purified by CCTLC on the Chromatotron instrument (2:1 ratio
of hexane/EtOAc) except where specified.
1-Ben zyl-3-cyclop r op ylm eth yl-1H,3H-p yr id o[2,1-f]p u -
r in e-2,4-d ion e (11). Compound 11 was obtained by the
reaction of 2 with (bromomethyl)cyclopropane. Yield: 50%. Mp
(CH2Cl2/MeOH): 151-152 °C. MS (ES, positive mode): m/z
347 [(M + 1)+], 369 [(M + Na)+]. H NMR (CDCl3) δ: 0.46-
1
1-Ben zyl-3-p r op yl-1H ,3H -p yr id o[2,1-f]p u r in e-2,4-d i-
on e (6). Compound 6 was obtained by the reaction of 2 with
propyl iodide. Yield: 65%. Mp (CH2Cl2/MeOH): 163-165 °C.
0.50 (m, 4H, CH2), 1.33 (m, 1H, CH), 3.98 (d, J ) 7.1 Hz, 2H,
NCH2), 5.42 (s, 2H, CH2Ph), 7.09 (m, J ) 6.8, 1.2 Hz, H-7),
7.26-7.56 (m, 6H, Ph, H-8), 7.70 (m, J ) 9.0, 1.2 Hz, 1H, H-9),