S. Hikishima et al. / Bioorg. Med. Chem. 14 (2006) 1660–1670
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4.18. 4-(Diethoxyphosphoryl)-4,4-difluoro-3-methylbuta-
noic acid (22)
(CD3OD) d 161.5, 155.2, 151.4, 144.5, 124.8, 123.4 (dt,
JCP = 213.5 Hz, JCF = 262.0 Hz), 66.0 (2C, d,
JCP = 7.1 Hz), 44.6, 39.4–38.9 (m), 27.9, 27.1, 16.7 (2C,
d, JCP = 5.2 Hz), 12.5; 31P NMR (CDCl3) d 7.16 (t,
JPF = 109.8 Hz); 19F NMR (CDCl3) d ꢀ50.9 (1F, ddd,
JFF = 300 Hz, JFP = 109.8 Hz, JFH = 14.3 Hz), ꢀ52.8
(1F, ddd, JFF = 300 Hz, JFP = 109.8 Hz, JFH = 18.8 Hz);
IR (film) 3327, 1614, 1558, 1263, 1024 cmꢀ1. ESIMS m/z
426 (MH+). HRMS(ESI) calcd for C15H24N5O3F2PCl
(MH+): 426.1273. Found: 426.1271.
Prepared from 21 in 94% yield as an oil in an analogous
manner for preparation of 15. 1H NMR (CDCl3) d 4.33–
4.25 (4H, m), 2.95 (1H, dd, J = 3.8 Hz, J = 16.4 Hz),
2.84–2.74 (1H, m), 2.32 (1H, dd, J = 9.7, 16.5 Hz),
1.39 (6H, t, J = 7.1 Hz), 1.22 (3H, d, J = 6.9 Hz); 13C
NMR (CDCl3) d 177.6, 121.8 (dt, JCP = 215.6 Hz,
JCF = 263.0 Hz), 65.6 (d, JCP = 7.3 Hz), 65.6 (d,
JCP = 7.4 Hz), 35.6–35.0 (m), 34.3, 16.2 (2C, d,
JCP = 5.4 Hz), 13.0; 31P NMR (CDCl3) d 6.64 (t,
JPF = 109.1 Hz); 19F NMR (CDCl3) d ꢀ50.5 ꢁ ꢀ54.5
(2F, m). IR (neat) 1732, 1253, 1024 cmꢀ1. ESIMS m/z
275 (MH+). Anal. Calcd for C9H17F2O5P: C, 39.42; H,
6.25. Found: C, 39.47; H, 6.17.
4.22. Diethyl 5-(6-chloro-9H-purin-9-yl)-1,1-difluoro-2-
methylpentylphosphonate (25b)
Prepared from 24 in 86% yield as an oil in an analo-
gous manner for preparation of 18a. 1H NMR
(CDCl3) d 8.74 (1H, s), 4.41–4.21 (6H, m), 2.27–2.04
(2H, m), 2.00–1.82 (2H, m), 1.45–1.41 (1H, m), 1.36
(6H, t, J = 7.2 Hz), 1.13 (3H, d, J = 7.0 Hz); 13C
NMR (CDCl3) d 152.7 (2C), 146.0, 132.3, 129.3,
122.7 (dt, JCP = 211.1 Hz, JCF = 263.2 Hz), 64.9 (d,
JCP = 6.2 Hz), 64.7 (d, JCP = 6.3 Hz), 44.6, 38.2–37.7
(m), 27.3, 26.2, 16.3 (d, JCP = 5.4 Hz); 31P NMR
(CDCl3) d 7.04 (t, JPF = 110.2 Hz); 19F NMR (CDCl3)
d ꢀ50.4 ꢁ ꢀ52.1 (2F, m); IR (film) 1592, 1558, 1267,
1027 cmꢀ1. ESIMS m/z 411 (MH+). HRMS (ESI)
calcd for C15H23N4O3F2PCl (MH+): 411.1164. Found:
411.1163.
4.19. 5-(Diethoxyphosphoryl)-5,5-difluoro-4-methylpen-
tanoic acid (23)
Prepared from 22 in 58% yield as an oil in an analogous
manner for preparation of 16. 1H NMR (CDCl3) d 4.31–
4.26 (4H, m), 2.52–2.46 (1H, m), 2.43–2.46 (1H, m),
2.43–2.35 (1H, m), 2.35–2.15 (2H, m), 1.69–1.64 (1H,
m), 1.38 (6H, t, J = 7.1 Hz), 1.15 (3H, d, J = 7.0 Hz);
13C NMR (CDCl3) d 178.0, 122.9 (dt, JCP = 212.5 Hz,
JCF = 263.0 Hz), 64.6 (d, JCP = 6.3 Hz), 64.4 (d,
JCP = 6.4 Hz), 37.8–37.2 (m), 31.3, 24.1, 16.3 (d,
JCP = 5.5 Hz, 2C), 31P NMR (CDCl3) d 7.12 (t,
JPF = 109.4 Hz); 19F NMR (CDCl3) d ꢀ50.8 (1F, ddd,
JFF = 301.1 Hz, JFP = 109.4 Hz, JFH = 15.1 Hz), ꢀ52.3
(1F, ddd, J = 301.1 Hz, JFP = 109.4 Hz, JFH = 18.4 Hz);
IR (film) 1731, 1254, 1025 cmꢀ1. ESIMS m/z 289
(MH+). Anal. Calcd for C10H19F2O5P: C, 41.67; H,
6.64. Found: C, 41.75; H, 6.70.
4.23. 5-(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-1,1-
difluoro-2-methylpentylphosphonic acid (26a)
Prepared as an amorphous powder from 25a in 82%
yield in an analogous manner for preparation of 8a.
1H NMR (CDCl3) d 9.09 (1H,s), 4.29–4.26 (2H, m),
3.80–2.08 (2H, m), 2.03–1.81 (2H, m), 1.47–1.36 (1H,
m), 1.18 (3H, d, J = 7.0 Hz); 13C NMR (CD3OD) d
156.9, 154.8, 151.4, 138.1, 123.2 (dt, JCP = 207.1 Hz,
JCF = 260.9 Hz), 108.6, 46.5, 39.0–38.4 (m), 27.5, 27.0,
12.8; 31P NMR (CD3OD) d 5.04 (t, JPF = 108.3 Hz);
19F NMR (CD3OD) d ꢀ51.8 ꢁ ꢀ53.9 (2F, m); IR
(KBr) 3124, 1684 cmꢀ1. ESIMS m/z 352 (NH+). HRMS
(ESI) calcd for C11H17N5O4F2P (MH+): 352.0986.
Found: 352.0966.
4.20. Diethyl 1,1-difluoro-5-hydroxy-2-meth-
ylpentylphosphonate (24)
Prepared from 23 in 34% yield as an oil in an analogous
manner for preparation of 17. 1H NMR (CDCl3) d 4.31–
4.23 (4H, m), 3.65 (2H, t, J = 6.3 Hz), 2.24–2.18 (1H,
m), 1.93–1.70 (3H, m), 1.55–1.48 (1H, m), 1.38 (6H, t,
J = 7.1 Hz), 1.13 (3H, d, J = 7.0 Hz); 13C NMR (CDCl3)
d 123.0 (dt, JCP = 211.5 Hz, JCF = 262.8 Hz), 64.7 (d,
JCP = 6.6 Hz), 64.5 (d, JCP = 6.5 Hz), 62.2, 38.3–37.7
(m), 29.8, 25.2, 16.2 (d, JCP = 5.4 Hz), 19F NMR
4.24. 1,1-Difluoro-2-methyl-5-(6-oxo-1,6-dihydro-9H-
purin-9-yl)pentylphosphonic acid (26b)
(CDCl3)
d
ꢀ51.0 (1F, ddd, JFF = 298.5 Hz,
JFP = 110.9 Hz, JFH = 16.2 Hz), ꢀ52.6 (1F, ddd,
JFF = 298.5 Hz, JFP = 110.9 Hz, JFH = 17.7 Hz); IR
(film) 3462, 1265, 1028 cmꢀ1. ESIMS m/z 297 (MNa+).
Anal. Calcd for C10H21F2O4P: C, 43.80; H, 7.72. Found:
C, 43.94; H, 7.64.
Prepared as an amorphous powder from 25b in 85%
yield in an analogous manner for preparation of 8a.
1H NMR (CD3OD) d 9.24 (1H, s), 8.28 (1H, s),
4.44 (2H, t, J = 7.0 Hz), 2.27–1.95 (2H, m), 1.93–1.89
(2H, m), 1.46–1.42 (1H, m), 1.17 (3H, d, J = 6.9 Hz);
13C NMR (CD3OD) d 155.1, 149.8, 149.0, 140.9,
123.5 (dt, JCP = 206.1 Hz, JCF = 260.5 Hz), 118.2,
47.0, 39.1–38.6 (m), 27.9, 27.3, 12.7; 31P NMR
4.21. Diethyl 5-(2-amino-6-chloro-9H-purin-9-yl)-1,1-
difluoro-2-methylpentylphosphonate (25a)
(CD3OD)
(CD3OD)
d
d
4.97 (t, JPF = 106.7 Hz); 19F NMR
ꢀ51.9 (1F, ddd, JFF = 297.0 Hz,
Prepared from 24 in 61% yield as an oil in an analogous
manner for preparation of 18a. 1H NMR (CDCl3) d 7.88
(1H, s), 5.16 (2H, br s, NH2), 4.28–4.20 (4H, m), 4.14–
4.03 (2H, m), 2.35–2.28 (1H, m), 2.03–1.99 (2H, m),
1.89–1.80 (2H, m), 1.36 (3H, t, J = 7.1 Hz), 1.35 (3H,
t, J = 7.1 Hz), 1.12 (3H, d, J = 7.0 Hz); 13C NMR
JFP = 106.7 Hz, JFH = 15.8 Hz), ꢀ53.6 (1F, ddd,
JFF = 297.0 Hz, JFP = 106.7 Hz, JFH = 15.8 Hz); IR
(KBr) 1716, 1569, 1542, 1172 cmꢀ1. ESIMS m/z 337
(MH+). HRMS (ESI) calcd for C11H16N4O4F2P
(MH+): 337.0877. Found: 337.0863.