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5.13.5. 9-[2-(1-Phosphonobutan-2-yloxy)ethyl]-2-amino-6-
bromopurine (30b)
(C-4); 145.88 (C-2); 141.12 (C-8); 124.11 (C-5); 69.70 d,
J(P,C) = 2.7 (C-30); 68.66 (C-20); 43.65 (C-10); 39.97 d,
J(P,C) = 134.0 (C-40); 19.98 d, J(P,C) = 3.8 (C-50); 12.55 d,
J(P,C) = 7.6 (C-60). MS (ESI): m/z = 315 [MꢁH]ꢁ. Anal. Calcd for
C11H17N4O5Pꢀ1/2H2O: C, 40.62; H, 5.58; N, 17.23. Found: C, 40.50;
H, 5.42; N, 16.85.
Starting from diester 26b, yield 60%. 1H NMR (DMSO-d6): 8.10 s,
1H (H-8); 6.91 br s, 2H (NH2); 4.17 t, 2H, J(10,20) = 5.4 (H-10); 3.80
dt, 1H, J(20a,10) = 4.9, Jg = 10.5 (H-20a); 3.65 dt, 1H, J(20b,10) = 6.0,
Jg = 10.5 (H-20b); 3.47 m, 1H (H-30); 1.80 ddd, 1H, J(40a,30) = 4.6,
Jg = 14.9, J(40a,P) = 19.8 (H-40a); 1.62 ddd, 1H, J(40b,30) = 7.9,
Jg = 14.9, J(40b,P) = 17.7 (H-40b); 1.62 m, 1H (H-50a); 1.38 sept, 1H,
J(50b,30) = J(50b,60) = 7.1, Jg = 14.2 (H-50b); 0.65 t, 3H, J(60,50) = 7.3
(H-60). 13C NMR (DMSO-d6): 159.74 (C-2); 153.03 (C-4); 143.64
(C-8); 142.01 (C-6); 125.88 (C-5); 76.39 (C-30); 65.67 (C-20);
43.47 (C-10); 32.17 d, J(P,C) = 132.6 (C-40); 27.18ꢁd, J(P,C) = 5.7 (C-
50); 9.00 (C-60). MS (ESI): m/z = 392–394 [MꢁH] . Anal. Calcd for
C11H17BrN5O4Pꢀ1/3MeOH: C, 33.89; H, 4.70; N, 17.19. Found: C,
33.96; H, 4.71; N, 17.46.
5.14.3. 9-[2-(3-Phenyl-2-
phosphonopropoxy)ethyl]hypoxanthine (19c)
Starting from bromo derivative 17c, white solid, yield 60%. 1H
NMR (DMSO-d6): 12.29 br s, 1H (OH); 8.03 s, 1H and 8.01 s, 1H
(H-2, H-8); 7.14 m, 3H and 6.97 m, 2H (Ar); 4.25 br t, 2H,
J(10,20) = 4.8 and 5.6 (H-10); 3.62 ddd, 1H, and 3.58 ddd,
J(20,10) = 4.8 and 5.6, Jg = 10.3 (H-20); 3.40 m, 2H (H-30); 2.87 td,
1H, J(50a,40) = 4.8, J(50,P) = Jg = 13.8 (H-50a); 2.61 ddd, 1H,
J(50b,40) = 9.1, J(50,P) = 9.4, Jg = 13.8 (H-50b); 2,00 m, 1H (H-40). 13C
NMR (DMSO-d6): 156.82 (C-6); 148.48 (C-4); 145.59 (C-2);
140.98 (C-8); 140.31 d, J(P,C) = 11.8 (Ar); 129.02, 2C (Ar); 128.12,
2C (Ar); 125.93 (Ar); 123.89 (C-5); 68.54 br s (C-30); 68.43 (C-20);
43.35 (C-10); 41.11 d, J(P,C) = 13ꢁ4.6 (C-40); 32.17 d, J(P,C) = 2.0 (C-
50). MS (ESI): m/z = 377 [MꢁH] . Anal. Calcd for C16H19N4O5Pꢀ3/
4H2O: C, 49.04; H, 5.27; N, 14.30. Found: C, 49.12; H, 5.07; N, 13.91.
5.13.6. 9-[2-(3-Phenyl-1-phosphonopropan-2-yloxy)ethyl]-2-
amino-6-bromopurine (30c)
Starting from diester 26c, yield 53%. 1H NMR (DMSO-d6): 7.95 s,
1H (H-8); 7.09 m, 3H and 6.97 m, 2H (Ar); 6.88 br s, 2H (NH2); 4.14
ddd, 1H, J(10,20) = 4.0 and 7.4, Jg = 14.3 (H-10a); 4.06 br dt, 1H,
J(10,20) = 4.4, Jg = 14.3 (H-10b); 3.78 br dt, 1H, J(20,10) = 4.8, Jg = 10.5
(H-20a); 3.57 ddd, 1H, J(20,10) = 7.4 and 4.0, Jg = 10.5 (H-20b);
3.75 m, 1H (H-30); 2.91 dd, 1H, J(50a,30) = 4.1, Jg = 14.0 (H-50a);
2.64 dd, 1H, J(50b,30) = 7.2, Jg = 14.0 (H-50b); 1.81 ddd, 1H,
J(40a,30) = 5.2, Jg = 14.9, J(40a,P) = 19.2 (H-40a); 1.66 ddd, 1H,
J(40b,30) = 7.4, Jg = 14.9, J(40b,P) = 17.4 (H-40b). 13C NMR (DMSO-
d6): 159.74 (C-2); 153.00 (C-4); 143.60 (C-8); 142.08 (C-6);
138.55 (Ar); 129.51, 2C (Ar); 128.05, 2C (Ar); 126.05 (Ar); 126.02
(C-5); 76.56 (C-30); 66.17 (C-20); 43.51 (C-10); 40.71 d, J(P,C) = 7.3
(C-50); 32.82 d, J(P,C) = 133.0 (C-40). MS (ESI): m/z = 454–456
[MꢁH]ꢁ. Anal. Calcd for C16H19BrN5O4Pꢀ1/2MeOH: C, 41.96; H,
4.48; N, 14.83. Found: C, 42.05; H, 4.28; N, 14.58.
5.14.4. 9-[2-(1-Phosphonopropan-2-yloxy)ethyl]hypoxanthine
(31a)
Starting from bromo derivative 29a, colorless foam, yield 90%.
1H NMR (DMSO-d6): 12.27 br s, 1H (NH); 8.05 s, 1H and 8.03 s,
1H (H-2 and H-8); 4.25 t, 2H, J(10,20) = 5.4 (H-10); 3.72 t, 2H,
J(20,10) = 5.4 (H-20); 3.64 m, 1H (H-30); 1.86 ddd, 1H, J(40a,30) = 4.1,
Jg = 14.7, J(40a,P) = 19.8 (H-40a); 1.58 ddd, 1H, J(40b,30) = 8.8,
Jg = 14.7, J(40b,P) = 17.4 (H-40b); 1.13 d, 3H, J(50,30) = 6.1 (H-50). 13C
NMR (DMSO-d6): 156.63 (C-6); 148.32 (C-4); 145.38 (C-2);
140.69 (C-8); 123.71 (C-5); 71.41 (C-30); 65.47 (C-20); 43.51 (C-
10); 35.26 d, J(P,C) = 132.3 (C-40); 20.84 d, J(P,C) = 4.7 (C-50). MS
(ESI): m/z = 301 [MꢁH]ꢁ. Anal. Calcd for C10H15N4O5Pꢀ2/3H2O: C,
38.22; H, 5.24; N, 17.83. Found: C, 38.34; H, 5.15; N, 17.52.
5.14. Synthesis of 9-[2-(phosphonoalkoxy)ethyl]hypoxanthines
19 and 31—general procedure
The 6-bromo derivative 17 or 29 (1 mmol) was dissolved in tri-
fluoroacetic acid (75%, 16 ml) and stirred overnight. The solvent
was evaporated and the residue codistilled with water (3x).After
preparative HPLC and codistillation with methanol pure products
were obtained.
5.14.5. 9-[2-(1-Phosphonobutan-2-yloxy)ethyl]hypoxanthine
(31b)
Starting from bromo derivative 29b, colorless foam, yield 84%.
1H NMR (DMSO-d6): 12.32 br s, 1H (NH); 8.11 s, 1H and 8.04 s,
1H (H-2 and H-8); 4.28 t, 2H, J(10,20) = 5.3 (H-10); 3.82 dt, 1H,
J(20a,10) = 4.8, Jg = 10.5 (H-20a); 3.67 dt, 1H, J(20b,10) = 5.6, Jg = 10.5
(H-20b); 3.46 m, 1H (H-30); 1.79 ddd, 1H, J(40a,30) = 4.7, Jg = 14.9,
J(40a,P) = 19.6 (H-40a); 1.60 ddd, 1H, J(40b,30) = 7.9, Jg = 14.9,
J(40b,P) = 17.6 (H-40b); 1.60 m, 1H, J(50a,30) = 4.0, J(50a,60) = 7.3,
Jg = 14.2 (H-50a); 1.37 sept, 1H, J(50b,30) = J(50b,60) = 7.2, Jg = 14.2
(H-50b); 0.65 t, 3H, J(60,50) = 7.3 (H-60). 13C NMR (DMSO-d6):
156.69 (C-6); 148.49 (C-4); 145.70 (C-2); 140.91 (C-8); 123.61
(C-5); 76.39 (C-30); 66.06 (C-20); 43.91 (C-10); 32.16 d,
J(P,C) = 132.4 (C-40); 27.23 d, J(P,C) = 5.8 (C-50); 8.99 (C-60). MS
(ESI): m/z = 315 [MꢁH]ꢁ. Anal. Calcd for C11H17N4O5Pꢀ3/4H2O: C,
40.06; H, 5.65; N, 16.99. Found: C, 40.06; H, 5.50; N, 16.73.
5.14.1. 9-[2-(2-Phosphonopropoxy)ethyl]hypoxanthine (19a)
Starting from bromo derivative 17a, colorless foam, yield 67%.
1H NMR (DMSO-d6): 12.8 br s, 1H (OH); 8.05 s, 1H and 8.03 s, 1H
(H-2, H-8); 4.29 m, 2H (H-10); 3.77 ddd, 1H, J(20a,10) = 4.6 and 6.0,
Jg = 10.8 (H-20a); 3.67 ddd, 1H, J(20b,10) = 4.8 and 5.8, Jg = 10.8 (H-
20b); 3.64 ddd, 1H, J(30a,40) = 3.9, J(30a,P) = 7.0, Jg = 9.7 (H-30a);
3.24 td, 1H, J(30b,P) = 5.8, J(30b,40) = Jg = 9.8 (H-30b); 1.82 m, 1H,
J(40,30) = 3.9 and 10.0, J(40,P) = J(40,50) = 7.1 (H-40); 0.93 dd, 3H,
J(50,40) = 7.1, J(50,P) = 17.3 (H-50). 13C NMR (DMSO-d6): 156.91 (C-
6); 148.65 (C-4); 145.68 (C-2); 140.93 (C-8); 124.01 (C-5); 71.10
d, J(P,C) = 3.6 (C-30); 68.33 (C-20); 43.41 (C-10); 31.12 d,
J(P,C) = 135.6 (C-40); 11.91 d, J(P,C) = 5.1 (C-50). MS (ESI): m/
z = 301 [MꢁH]ꢁ. Anal. Calcd for C10H15N4O5Pꢀ1/2MeOH: C, 39.69;
H, 5.23; N, 17.63. Found: C, 39.62; H, 5.32; N, 17.27.
5.14.6. 9-[2-(3-Phenyl-1-phosphonopropan-2-
yloxy)ethyl]hypoxanthine (31c)
Starting from bromo derivative 29c, colorless foam, yield 54%. 1H
NMR (DMSO-d6): 12.25 br s, 1H (OH); 7.99 s, 1H and 7.91 s, 1H (H-2
and H-8); 7.12 m, 3H and 7.00 m, 2H (Ar); 4.22 ddd, 1H, J(10,20) = 4.4
and 7.0, Jg = 14.4 (H-10a); 4.16 dt, 1H, J(10,20) = 4.5, Jg = 14.4 (H-10b);
3.80 br dt, 1H, J(20,10) = 4.5, Jg = 10.4 (H-20a); 3.59 ddd, 1H,
J(20,10) = 7.0 and 4.5, Jg = 10.4 (H-20b); 3.75 m, 1H (H-30); 2.91 dd,
1H, J(50a,30) = 4.1, Jg = 13.9 (H-50a); 2.65 dd, 1H, J(50b,30) = 7.1,
Jg = 13.9 (H-50b); 1.79 ddd, 1H, J(40a,30) = 5.2, Jg = 14.9,
J(40a,P) = 19.1 (H-40a); 1.65 ddd, 1H, J(40b,30) = 7.5,Jg = 14.9,
J(40b,P) = 17.5 (H-40b). 13C NMR (DMSO-d6): 156.58 (C-6); 148.18
5.14.2. 9-[2-(2-Phosphonobutoxy)ethyl]hypoxanthine (19b)
Starting from bromo derivative 17b, colorless foam, yield 68%.
1H NMR (DMSO-d6): 12.26 br s (OH); 8.06 s, 1H and 8.03 s, 1H
(H-2, H-8); 4.30 t, 2H, J(10,20) = 5.3 (H-10); 3.75 dt, 1H, and 3.70
dt, 1H, J(20,10) = 5.3, Jg = 10.6 (H-20); 3.63 ddd, 1H, J(30a,40) = 3.9,
Jg = 9.7, J(30a,P) = 10.2 (H-30a); 3.40 ddd, 1H, J(30b,40) = 8.9, Jg = 9.7,
J(30b,P) = 6.7 (H-30b); 1.65 m, 1H (H-40); 1.45 m, 2H (H-50); 0.80 t,
3H, J(60,50) = 7.5 (H-60). 13C NMR (DMSO-d6): 157.07 (C-6); 148.83