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O. Baszczynski et al. / Bioorg. Med. Chem. 19 (2011) 2114–2124
2123
(dd, 1H, J(gem) = 12.9, J(H–C–P) = 9.3, C4b), 3.69 (dd, 1H, J(gem) = 12.9, J
4.4.11. (R)-2,6-Diamino-N6,N6-dimethyl-9-[3-fluoro-2-(phos-
(H–C–P) = 9.2, C4a), 4.03 (dm, 1H, J(2-F) = 23.0, C2), 4.12 (br s, 2H,
CH2-(1)-R1), 4.23 (dd, 1H, J(gem) = 14.7, J(1b-2) = 6.8, C1b), 4.31 (dd,
1H, J(gem) = 14.6, J(1a-2) = 4.6, C1a), 4.48 (ddd, 1H, J(gem) = 10.5,
phonomethoxy)propyl]purine (27a)
Procedure D and method A afforded 213 mg (52%) of 27a as
white solid; [a]
D +12.6 (c 0.3, H2O); MS (ESI) m/z 349 [M+H]+. Anal.
J(3b-2) = 4.0, J(3b-F) = 46.5, C3b), 4.66 (ddd, 1H, J(gem) = 10.5, J(3a-2)
=
Calcd (C11H18FN6O4P): C, 37.94; H, 5.21; F, 5.45; N, 24.13; P, 8.89.
Found: C, 37.72; H, 5.44; F, 5.38; N, 23.94.
3.5, J(3a-F) = 47.2, C3a), 5.17 (dq, 1H, 3J(cis) = 10.4, J(gem) = 3J(trans) = 1.5,
3
CH(trans)-(3)-R1), 5.24 (dq, 1H, J(cis) = J(gem) = 1.5, 3J(trans) = 17.3,
CH(cis)-(3)-R1), 6.00 (ddt, 1H, 3J(cis) = 10.4, J(CH–CH2) = 4.9,
3J(trans) = 17.3, CH-(2)-R1), 7.83 (s, 1H, Pu8); 13C NMR (D2O): d
43.16 (CH2-(1)-R1), 43.68 (d, J(1-F) = 7.6, C1), 67.54 (d,
J(C–P) = 155.3, C4), 78.56 (dd, J(2-F) = 18.7, J(2-P) = 11.3, C2), 82.81 (d,
J(3-F) = 167.9, C3), 113.27 (Pu5), 116.07 (CH2-(3)-R1), 135.00
(CH-(2)-R1), 140.69 (Pu8), 150.53 (Pu4), 155.44 (Pu6); MS (ESI)
m/z 384 [M+Na]+. Anal. Calcd (C12H16FN6Na2O4P): C, 35.65; H,
3.99; F, 4.70; N, 20.79 P, 7.66. Found: C, 35.38; H, 4.28; F, 4.71;
N, 20.66.
4.4.12. (S)-2,6-Diamino-N6,N6-dimethyl-9-[3-fluoro-2-(phos-
phonomethoxy)propyl]purine (27b)
Procedure D and method B afforded 122 mg (26%, sodium salt)
of 27b as white solid; [
a]
D ꢁ9.7 (c 0.3, H2O); 1H NMR (D2O+NaOD):
d 3.29 (br s, 6H, CH3-R1), 3.47 (dd, 1H, J(gem) = 12.3, J(H–C–P) = 9.1,
C4b), 3.52 (dd, 1H, J(gem) = 12.3, J(H–C–P) = 9.3, C4a), 3.99 (dm, 1H,
J(2-F) = 24.3, C2), 4.28 (m, 2H, C1), 4.44 (ddd, 1H, J(gem) = 10.5,
J(3b-2) = 3.6, J(3b-F) = 46.5, C3b), 4.66 (ddd, 1H, J(gem) = 10.5,
J(3a-2) = 3.5, J(3a-F) = 47.4, C3a), 7.85 (s, 1H, Pu8); 13C NMR
(D2O+NaOD): d 38.98 (CH3-R1), 43.40 (d, J(1-F) = 7.1, C1), 68.98 (d,
J(C-P) = 150.2, C4), 78.11 (dd, J(2-F) = 18.4, J(2-P) = 10.8, C2), 82.87 (d,
J(3-F) = 167.3, C3), 113.77 (Pu5), 139.68 (Pu8), 152.13 (Pu4),
155.58 (Pu6), 160.08 (Pu2); MS (ESI) m/z 416 [M+Na]+. Anal. Calcd
(C11H16FN6Na2O4P): C, 33.68; H, 4.11; F, 4.84; N, 21.43 P, 7.90.
Found: C, 33.56; H, 4.38; F, 4.72; N, 21.28.
4.4.7. (R)-2,6-Diamino-N6-(N,N-dimethylaminoethyl)-9-[3-
fluoro-2-(phosphonomethoxy)propyl]purine (25a)
Procedure D and method A afforded 109 mg (24%, monohy-
drate) of 25a as white solid; [a] +8.4 (c 0.2, H2O); MS (ESI) m/z
D
390 [MꢁH]ꢁ. Anal. Calcd (C13H23FN7O4PꢀH2O): C, 38.14; H, 6.16;
F, 4.64; N, 23.95 P, 7.57. Found: C, 38.02; H, 5.89; F, 4.87; N, 23.76.
4.4.13. (R)-2,6-Diamino-N6,N6-diethyl-9-[3-fluoro-2-(phos-
phonomethoxy)propyl]purine (28a)
4.4.8. (S)-2,6-Diamino-N6-(N,N-dimethylaminoethyl)-9-[3-
fluoro-2-(phosphonomethoxy)propyl]purine (25b)
Procedure D and method B afforded 220 mg (44%, sodium salt)
Procedure D and method B afforded 94 mg (18%, sodium salt) of
of 28a as white solid; [a] +21.9 (c 0.4, H2O); MS (ESI) m/z 377
D
25b as white solid; [
a
]
D ꢁ6.8 (c 0.2, H2O); 1H NMR (D2O): d 2.96 (s,
[M+H]+. Anal. Calcd (C13H20FN6Na2O4P): C, 37.15; H, 4.80; F, 4.52;
N, 20.00; P, 7.37. Found: C, 37.42; H, 5.55; F, 4.25; N, 19.72.
6H, CH3-R1), 3.43 (t, 2H, J(CH2–CH2) = 5.9, CH2-(2)-R1), 3.51 (dd, 1H,
J(gem) = 12.7, J(H–C–P) = 9.4, C4b), 3.64 (dd, 1H, J(gem) = 12.7,
J(H–C–P) = 9.2, C4a), 3.90 (m, 2H, CH2-(1)-R1), 4.02 (dm, 1H,
J(2-F) = 23.6, C2), 4.21 (dd, 1H, J(gem) = 14.6, J(1b-2) = 6.9, C1b), 4.28
(dd, 1H, J(gem) = 14.6, J(1a-2) = 4.5, C1a), 4.49 (ddd, 1H, J(gem) = 10.5,
J(3b-2) = 3.8, J(3b-F) = 46.5, C3b), 4.67 (ddd, 1H, J(gem) = 10.5,
J(3a-2) = 3.6, J(3a-F) = 47.3, C3a), 7.86 (s, 1H, Pu8); 13C NMR (D2O): d
36.23 (CH3-R1), 43.68 (C1), 43.71 (CH3-R1), 57.95 (CH2-(2)-R1),
67.96 (d, J(C-P) = 153.5, C4), 78.28 (dd, J(2-F) = 18.6, J(2-P) = 11.2, C2),
82.76 (d, J(3-F) = 167.9, C3), 113.37 (Pu5), 140.87 (Pu8), 151.04
(Pu4), 155.42 (Pu6), 160.38 (Pu2); MS (FAB) m/z 392 [M+H]+. Anal.
Calcd (C13H21FN7Na2O4P): C, 35.87; H, 4.86; F, 4.36; N, 22.52 P,
7.12. Found: C, 35.60; H, 5.04; F, 4.34; N, 22.37.
4.4.14. (S)-2,6-Diamino-N6,N6-diethyl-9-[3-fluoro-2-(phos-
phonomethoxy)propyl]purine (28b)
Procedure D and method A afforded 372 mg (84%) of 28b as
white solid; [
a
]
ꢁ18.4 (c 0.4, H2O); 1H NMR (D2O+NaOD): d 1.19
D
(m, 6H, CH3-R1), 3.57 (dd, 1H, J(gem) = 12.8, J(H–C–P) = 9.2, C4b), 3.70
(m, 1H, C4a), 3.77 (br s, 4H, CH2-R1), 4.02 (dm, 1H, J(2-F) = 22.9,
C2), 4.24 (dd, 1 H, J(gem) = 14.9, J(1b-2) = 6.6, C1b), 4.32 (dd, 1H,
J(gem) = 15.0, J(1a-2) = 4.0, C1a), 4.47 (ddd, 1H, J(gem) = 10.7, J(3b-2)
=
3.8, J(3b-F) = 46.5, C3b), 4.64 (ddd, 1H, J(gem) = 10.7, J(3a-2) = 3.5,
J(3b-F) = 47.2, C3a), 7.78 (s, 1H, Pu8); 13C NMR (D2O+NaOD): d
13.34 (CH3-R1), 43.66 (CH2-R1), 43.97 (br s, C1), 67.52 (d,
J(C-P) = 157.7, C4), 78.64 (dd, J(2-F) = 18.9, J(2-P) = 11.2, C2), 82.76 (d,
J(3-F) = 168.3, C3), 113.20 (Pu5), 139.72 (Pu8), 150.68 (Pu4),
153.71 (Pu6), 158.81 (Pu2); MS (ESI) m/z 377 [M+H]+. Anal. Calcd
(C13H22FN6O4P): C, 41.49; H, 5.89; F, 5.05; N, 22.33 P, 8.23. Found:
C, 41.14; H, 5.70; F; 4.87; N, 22.16.
4.4.9. (R)-2,6-Diamino-N6-(2-methoxyethyl)-9-[3-fluoro-2-
(phosphonomethoxy)propyl]purine (26a)
Procedure D and method A afforded 249 mg (56%, monohy-
drate) of 26a as white solid; [a] +6.2 (c 0.2, H2O); MS (ESI) m/z
D
377 [MꢁH]ꢁ. Anal. Calcd (C13H23FN7O4P.H2O): C, 38.10; H,
5.33; F, 5.02; N, 22.22 P, 8.19. Found: C, 37.89; H, 5.45; F, 5.00;
N, 22.09.
4.4.15. (R)-2-Amino-9-[3-fluoro-2-(phosphonomethoxy)-
propyl]-6-(pyrrolidin-1-yl)purine (29a)
Procedure D and method A afforded 238 mg (54%) of 29a as
4.4.10. (S)-2,6-Diamino-N6-(2-methoxyethyl)-9-[3-fluoro-2-
(phosphonomethoxy)propyl]purine (26b)
white solid; [
a]
D +10.9 (c 0.3, H2O); MS (ESI) m/z 373 [MꢁH]ꢁ. Anal.
Calcd (C13H20FN6O4P): C, 41.71; H, 5.39; F, 5.08; N, 22.45; P, 8.27.
Found: C, 41.64; H, 5.46; F, 4.87; N, 22.29.
Procedure D and method B afforded 182 mg (37%, sodium salt)
of 26b as white solid; [
a]
D
ꢁ5.4 (c 0.2, H2O); 1H NMR (D2O): d 3.4
(s, 3H, CH3-R1), 3.56 (dd, 1H, J(gem) = 12.8, J(H–C–P) = 9.4, C4b), 3.71 m
(dd, 5H, CH2-(1, 2)-R1, C4a), 4.03 (dm, J(2-F) = 23.2, C2), 4.24 (dd, 1H,
J(gem) = 14.8, J(1b-2) = 6.8, C1b), 4.32 (dd, 1H, J(gem) = 14.7, J(1a-2) = 4.6,
C1a), 4.48 (ddd, 1H, J(gem) = 10.5, J(3b-2) = 3.9, J(3b-F) = 46.4, C3b), 4.65
(ddd, 1H, J(gem) = 10.5, J(3a-2) = 3.5, J(3a-F) = 47.2, C3a), 7.84 (s, Pu8);
13C NMR (D2O): d 40.32 (CH2-(1)-R1), 43.68 (d, J(1-F) = 7.6, C1),
58.68 (CH3-R1), 67.51 (d, J(C-P) = 155.5, C4), 71.34 (CH2-(2)-R1),
78.60 (dd, J(2-F) = 18.7, J(2-P) = 11.2, C2), 82.80 (d, J(3-F) = 167.9, C3),
113.48 (Pu5), 140.73 (Pu8), 150.50 (Pu4), 155.78 (Pu6), 160.38
(Pu2); MS (ESI) m/z 446 [M+Na]+. Anal. Calcd (C12H18FN6Na2O5P):
C, 34.13; H, 4.30; F, 4.50; N, 19.90 P, 7.43. Found: C, 33.89; H,
4.56; F, 4.53; N, 19.86.
4.4.16. (S)-2-Amino-9-[3-fluoro-2-(phosphonomethoxy)-
propyl]-6-(pyrrolidin-1-yl)purine (29b)
Procedure D and method B afforded 249 mg (50%, sodium salt)
of 29b as white solid; [
a]
D ꢁ9.4 (c 0.3, H2O);1H NMR (D2O): d 1.93
and 2.00 (br s, 2 ꢂ 2H, CH2-(3, 4)-R1-R2), 3.44 (br s, 2H, CH2-(2b,5b)-
R1-R2), 3.52 (dd, 1H, J(gem) = 12.8, J(H–C–P) = 9.3, C4b), 3.65 (dd, 1H,
J(gem) = 12.8, J(H–C–P) = 9.3, C4a), 3.77 (br s, 2H, CH2-(2a, 5a)-R1-R2),
3.99 (dm, 1H, J(2-F) = 23.3, C2), 4.21 (dd, 1H, J(gem) = 14.8,
J(1b-2) = 6.9, C1b), 4.28 (dd, 1H, J(gem) = 14.8, J(1a-2) = 4.5, C1a), 4.47
(ddd, 1H, J(gem) = 10.6, J(3b-2) = 3.9, J(3b-F) = 46.5, C3b), 4.66 (ddd,
1H, J(gem) = 10.6, J(3a-2) = 3.5, J(3a-F) = 47.2, C3a), 7.75 (s, 1H, Pu8);
13C NMR (D2O): d 24.38 and 26.17 (br s, CH2-(3, 4)-R1-R2), 43.72