3266 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 17
Dvorˇa´kova´ et al.
was deionized on Dowex 50 × 8 (H+ form, 100 mL). The
obtained crude product was purified by chromatography on a
column of Dowex 1 × 2 (acetate form, 100 mL). The product
was eluted with a linear gradient of acetic acid (0 - 0.5 mol/L,
1 L each). Crystallization from 80% ethanol afforded the pure
phosphonate.
(dd, 1H, J (1′b,2′) ) 4.6, J g ) 14.9, 1′b-CH2), 4.03 (m, 1H, 2′-
CH), 3.70 (dd, 1H, J (P,CH) ) 9.3, J g ) 12.0, PCH2), 3.45 (dd,
1H, J (P,CH) ) 9.5, J g ) 12.0, PCH2), 2.50 (d, 2H, J (3′,2′) )
5.9, 3′-CH2), 2.36 (s, 6H, N(CH3)); FABMS m/z MH+ 331.3.
Anal. (C11H19N6O4P) C, H, N, P.
1-(3-(Dim eth yla m in o)-2-(p h osp h on om eth oxy)p r op yl)-
cytosin e (8c): yield 0.41 g (24%); mp >250 °C; k ) 1.0 (0.05
M TEAB); EUp 0.46; 1H NMR (D2O + NaOD) δ 7.61 (d, 1H,
J (5,6) ) 7.3, H-6), 6.03 (d, 1H, J (5,6) ) 7.3, H-5), 4.05 (dd,
1H, J (1′a,2′) ) 3.9, J g ) 14.7, 1′a-CH2), 4.00 (dd, 1H, J (1′b,2′)
) 5.6, J g ) 14.7, 1′b-CH2), 4.20 (m, 1H, 2′-CH), 3.86 (dd, 1H,
J (P,CH) ) 8.5, J g ) 13.2, PCH2), 3.50 (dd, 1H, J (P,CH) ) 9.0,
J g ) 13.2, PCH2), 3.28 (dd, 1H, J (3′a,2′) ) 2.4, J g ) 13.4, 3′a-
CH2), 3.20 (dd, 1H, J (3′b,2′) ) 10.7 J g ) 13.4, 3′b-CH2); 2.92
(s, 6H, N(CH3)2); FABMS m/z MH+ 307.1. Anal. (C10H19N4O5P)
C, H, N, P.
9-(3-Am in o-2-(ph osph on om eth oxy)pr opyl)aden in e (2a):
yield 1.1 g (34%); mp >250 °C; k ) 1.9 (0.05 M TEAB); EUp
1
0.44; H NMR (D2O + NaOD) δ 8.27 and 8.15 (2 × H, 2 × s,
H-2, H-8), 4.42 (dd, 1H, J (1′a,2′) ) 4.8, J g ) 14.7, 1′a-CH2),
4.32 (dd, 1H, J (1′b,2′) ) 5.2, J g ) 14.7, 1′b-CH2), 3.77 (m, 1H,
OCH), 3.57 (dd, 1H, J (P,CH) ) 9.5, J g ) 12.2, PCH2), 3.50 (dd,
1H, J (P,CH) ) 9.5, J g ) 12.2, PCH2), 2.70 (dd, 1H, J (3′a,2′) )
4.0, J g ) 13.7, 3′a-CH2), 2.49 (dd, 1H, J (3′b,2′) ) 7.3, J g ) 13.7,
3′b-CH2); FABMS m/z MH+ 303; UV spectrum (λmax (ꢀ)) at pH
2 259.0 (10 600), at pH 7 261.0 (12 000), at pH 12 261.0
(12 000). Anal. (C9H15N6O4P‚H2O) C, H, N, P.
9-(3-Mor p h olin o-2-(p h osp h on om et h oxy)p r op yl)a d e-
n in e (9a ): yield 1.1 g (35%); mp 197-200 °C; k ) 2.7 (4%
acetonitrile/0.05 M TEAB); EUp 0.64; 1H NMR (D2O + NaOD)
δ 8.21 and 8.14 (2 × s, 2 × 1H, H-2, H-8), 4.47 (dd, 1H, J (1′a,2′)
9-(3-Am in o-2-(p h osp h on om et h oxy)p r op yl)-2,6-d ia m i-
n op u r in e (2b): yield 0.43 g (13%); mp 243-245 °C; k ) 2.3
1
(0.05 M TEAB); EUp 0.42; H NMR (D2O + NaOD) δ 7.91 (s,
1H, H-8), 4.32 (dd, 1H, J (1′a,2′) ) 4.6, J g ) 15.1, 1′a-CH2),
4.24 (dd, 1H, J (1′b,2′) ) 5.6, J g ) 15.1, 1′b-CH2), 4.09 (m, 1H,
2′-CH), 3.72 (dd, 1H, J (P,CH) ) 8.1, J g ) 12.7, PCH2), 3.32
(dd, 1H, J (P,CH) ) 8.5, J g ) 12.7, P-CH2); 3.22 (dd, 1H,
J (3′a,2′) ) 2.9, J g ) 13.4, 3′a-CH2), 2.86 (dd, 1H, J (3′b,2′) )
9.5, J g ) 13.4, 3′b-CH2); FABMS m/z MH+ 318.4; UV spectrum
(λmax (ꢀ)) at pH 2 290.0 (10 000), 252.0 (10 400); at pH 7 281.0
(9700), 255.0 (8400), at pH 12: 281.0 (9700), 255.0 (8100).
Anal. (C9H16N7O4P‚H2O) C, H, N, P.
) 3.2, J g ) 14.0, 1′a-CH2), 4.34 (dd, 1H, J (1b′,2′) ) 5.6, J g )
14.0, 1′b-CH2), 4.32 (m, 1H, 2′-CH), 3.94 (m, 4H, OCH2), 3.73
(dd, 1H, J (P,CH) ) 8.3, J g ) 12.9, P-CH2), 3.31 (dd, 1H,
J (P,CH) ) 7.3, J g ) 12.9, PCH2), 3.18 and 3.06 (2 × m, 2 ×
2H, NCH2), 3.06 (m, 1H, 3′a-CH2), 2.92 (dd, 1H, J (3′a,2′) )
10.0, J g ) 13.7, 3′b-CH2); FABMS m/z MH+ 373.2; UV
spectrum (λmax (ꢀ)), at pH 2 259.0 (11 900), at pH 7 261.0
(12 300), at pH 12 262.0 (12 700). Anal. (C13H21N6O5P) C, H,
N, P.
1-(3-Am in o-2-(p h osp h on om e t h oxy)p r op yl)cyt osin e
(2c): yield 0.33 g (11%); mp 240 °C (with decomposition); k )
9-(2-(P h osp h on om eth oxy)-3-(tr im eth yla m m on io)p r o-
p yl)a d en in e (10a ): yield 0.34 g (10%); mp 270-273 °C; k )
1
1
2.1 (0.05 M TEAB); EUp 0.54; H NMR (D2O + NaOD) δ 7.65
0.5 (0.05 M TEAB), EUp 0.28; H NMR (D2O + NaOD) δ 8.35
(d, 1H, J (5,6) ) 7.5, H-6), 6.03 (d, 1H, J (5,6) ) 7.5, H-5), 4.05
(dd, 1H, J (1′a,2′) ) 3.9, J g ) 13.7, 1′a-CH2), 3.94 (dd, 1H,
J (1′b,2′) ) 5.9, J g ) 13.7, 1′b-CH2), 4.00 (m, 1H, 2′-CH), 3.73
(dd, 1H, J (P,CH) ) 8.1, J g ) 12.7, PCH2), 3.26 (dd, 1H, J (P,CH)
and 8.25 (2 × s, 2 × 1 H, H-2, H-8), 4.64 (dd, 1H, J (1′a,2′) )
4.4, J g ) 14.9, 1′a-CH2), 4.53 (m, 1H, 2′-CH), 4.48 (dd, 1H,
J (1′b,2′) ) 3.2, J g ) 14.9, 1′b-CH2), 3.84 (dd, 1H, J (P,CH) )
9.3, J g ) 12.2, PCH2), 3.60 (dd, 1H, J (P,CH) ) 9.8, J g ) 12.2,
PCH2), 3.42 (dd, 1H, J (3′a,2′) ) 1.5, J g ) 14.2, 3′a-CH2), 3.24
(dd, 1H, J (3′b,2′) ) 9.8 J g ) 14.2, 3′b-CH2), 3.19 (s, 9H, N+-
(CH3)3); FABMS m/z MH+ 345.2; UV spectrum (λmax (ꢀ)) at pH
2 258.0 (11 700), at pH 7 261.0 (11 800), at pH 12 261.0
(11900). Anal. (C12H22N6O4P) C, H, N, P.
) 8.8, J g ) 12.7, PCH2); 3.22 (dd, 1H, J (3′a,2′) ) 2.7, J g
)
13.4, 3′a-CH2), 2.95 (dd, 1H, J (3′b,2′) ) 9.3 J g ) 13.4, 3′b-CH2);
FABMS m/z MH+ 279.2; UV spectrum (λmax (ꢀ)), at pH 2 282.0
(13 500), at pH 7 273.0 (10 100), at pH 12 275.0 (9900). Anal.
(C8H15N4O5P‚H2O) C, H, N, P.
9-[3-((o-Ca r b oxyb en zoyl)a m in o)-2-(p h osp h on om et h -
oxy)p r op yl]a d en in e (7a ) a n d 9-[3-((o-ca r boxyben zoyl)-
a m in o)-2-(p h osp h on om et h oxy)p r op yl]-2,6-d ia m in op u -
r in e (7b). Compounds 7a and 7b were obtained after elution
of amino derivatives 2a and 2b from the column of Dowex 1
× 2 (acetate form) by continued washing with acetic acid (1
M) and processed analogously.
7a : yield 0.34 g; mp >250 °C; k ) 5.1 (0.05 M TEAB/10 min,
grad. 10% acetonitrile/10 min); EUp 0.70; 1H NMR (D2O +
NaOD) δ 8.34 and 8.18 (2 × s, 2 × 1H, H-2, H-8), 7.30-7.65
(m, 4H, arom), 4.49 (2 × dd, 2H, J (1′a,2′) ) 4.6, J (1′b,2′) )
5.1, J g ) 14.9, 1′-CH2), 4.04 (m, 1H, OCH); 3.47-3.70 (m, 4H,
PCH2, 3′-CH2); 13C NMR (D2O) δ 177.1 and 174.05 (CdO),
156.57 (C-6), 153.53 (C-2), 150.28 (C-4), 144.83 (C-8), 138.82,
135.41, 131.37, 130.35, 129.02, and 128.28 (arom C), 119.29
(C-5), 78.70 (d, J (P,C) ) 12.2, C-2′), 69.24 (d, J (P,C) ) 149.5,
P-C), 45.68 (C-1′), 41.00 (C-3′). Anal. (C17H19N6O7P) C, H, N,
P.
9-(2-(P h osp h on om eth oxy)-3-(tr im eth yla m m on io)p r o-
p yl)-2,6-d ia m in op u r in e (10b): yield 0.37 g (8%); mp >250
°C, k ) 0.7 (0.05 M TEAB), EUp 0.39; 1H NMR (D2O + NaOD)
δ 8.00 (s, 1H, H-8), 4.43 (dd, 1H, J (1′a,2′) ) 4.9, J g ) 15.1,
1′a-CH2), 4.30 (dd, 1H, J (1′b,2′) ) 2.9, J g ) 15.1, 1′b-CH2), 4.48
(m, 1H, 2′-CH), 3.81 (dd, 1H, J (P,CH) ) 9.2, J g ) 12.2, PCH2),
3.58 (dd, 1H, J (P,CH) ) 9.8, J g ) 12.2, PCH2), 3.40 (dd, 1H,
J (3′a,2′) ) 1.5, J g ) 13.9, 3′a-CH2), 3.28 (dd, 1H, J (3′b,2′) )
9.5, J g ) 13.9, 3′b-CH2), 3.19 (s, 9H, N+(CH3)3); UV spectrum
(λmax (ꢀ)) at pH 2 281.0 (9400), 255.0 (7900), at pH 7 280.0
(9800), 256.0 (8300), at pH 12 2861.0 (9700), 256.0 (8200).
Anal. (C12H22N6O4P) C, H, N, P.
1-(2-(P h osp h on om eth oxy)-3-(tr im eth yla m m on io)p r o-
p yl)cytosin e (10c): yield 0.6 g (6%); mp >250 °C; k ) 2.4
(0.05 M TEAB); EUp 0.4; 1H NMR (D2O + NaOD) δ 7.63 (d,
1H, J (5,6) ) 7.3, H-6), 6.04 (d, 1H, J (5,6) ) 7.3, H-5), 4.37
(brpent, 1H, 2′-CH), 4.13 (dd, 1H, J (1′a,2′) ) 4.6, J g ) 14.7,
1′a-CH2), 4.03 (dd, 1H, J (1′b,2′) ) 4.6, J g ) 14.7, 1′b-CH2), 3.82
(dd, 1H, J (P,CH) ) 9.8, J g ) 12.7, PCH2), 3.69 (dd, 1H, J (P,CH)
) 10.7, J g ) 12.7, PCH2), 3.52 (d, 2H, J (3′,2′) ) 5.9, 3′-CH2),
3.23 (s, 9H, N+(CH3)3); FABMS m/z MH+ 321.2; UV spectrum
(λmax (ꢀ)) at pH 2 281.0 (13 900), at pH 7 273.0 (10 400), at pH
12 273.0 (10700). Anal. (C11H21N4O5P‚2H2O) C, H, N, P.
9-(2-(P h osp h on om eth oxy)-3-(tr im eth yla m m on io)p r o-
p yl)gu a n in e (10e): yield 0.3 g (18%); mp >250 °C; k ) 0.6
7b: yield 0.2 g; mp >250 °C; k ) 6.4 (0.05 M TEAB/10 min,
grad. 10% acetonitrile/10 min); EUp 0.70; 1H NMR (D2O +
NaOD) δ 8.03 (s, 1H, H-8), 7.34-7.61 (m, 4H, arom), 4.36 (dd,
1H, J (1′a,2′) ) 4.9, J g ) 14.9, 1′a-CH2), 4.31 (dd, 1H, J (1′b,2′)
) 5.6, J g ) 14.9, 1′b-CH2), 4.01 (brpent, 1H, 2′-CH), 3.60 (dd,
1H, J (P,CH) ) 9.8, J g ) 11.7, PCH2), 3.54 (dd, 1H, J (P,CH) )
9.3, J g ) 11.7, PCH2), 3.58 (dd, 1H, J (3′a,2′) ) 4.0, J g ) 14.2,
3′a-CH2), 3.52 (dd, 1H, J (3′b,2′) ) 4.9, J g ) 14.2, 3′b-CH2), 13
C
1
(0.05 M TEAB); EUp0.50; H NMR (D2O + NaOD) δ 7.86 (s,
NMR (D2O) δ 177.09 and 174.04 (CdO), 161.12 (C-2), 157.22
(C-6), 152.46 (C-4), 142.48 (C-8), 138.82, 135.47, 131.37, 130.37,
129.03 and 128.32 (arom C), 113.87 (C-5), 78.70 (d, J (P,C) )
12.2, C-2′), 69.21 (d, J (P,C) ) 151.1, P-C), 45.25 (C-1′), 41.00
(C-3′). Anal. (C17H20N7O7P) C, H, N, P.
1H, H-8), 4.45 (m, 1H, 2′-CH), 4.37 (dd, 1H, J (1′a,2′) ) 4.9, J g
) 15.1, 1′a-CH2), 4.29 (dd, 1H, J (1′b,2′) ) 3.4, J g ) 15.1, 1′b-
CH2), 3.82 (dd, 1H, J (P,CH) ) 9.5, J g ) 11.7, PCH2), 3.58 (dd,
1H, J (P,CH) ) 10.5, J g ) 11.5, P-CH2), 3.39 (brd, 1H, J (3′a,2′)
) 0.5, J g ) 13.9, 3′a-CH2), 3.31 (dd, 1H, J (3′b,2′) ) 9.3, J g
)
9-(3-(Dim eth yla m in o)-2-(p h osp h on om eth oxy)p r op yl)-
13.9, 3′b-CH2), 3.19 (s, 9H, N+(CH3)3); FABMS m/z MH+ 361.3;
UV spectrum (λmax (ꢀ)) at pH 2 254.0 (7700), at pH 7 252.0
(9100), at pH 12 269.0 (7400). Anal. (C12H22N6O5P‚2H2O) C,
H, N, P.
1
a d en in e (8a ): yield 0.34 g (11%); mp >250 °C; EUp 0.53; H
NMR (D2O + NaOD) δ 8.34 and 8.21 (2 × s, 2 × 1 H, H-2 and
H-8), 4.49 (dd, 1H, J (1′a,2′) ) 4.1, J g ) 14.9, 1′a-CH2), 4.35