Synthesis of Antiviral Nucleoside Phosphoramidates and Thiophosphoramidates 625
NMR (400 MHz, CDCl3): δ 9.37 (s, 1H, indole NH), 8.69, 8.65 (s, 1H, NH-3),
7.55, 7.53 (s, 1H, H-6), 7.34 (d, J = 8.1 Hz, 1H, indole H-4), 7.23–7.13 (m,
2H, indole H-7, indole H-2), 7.10 (m, 1H, indole H-6), 7.04 (s, 1H, indole
H-5), 6.87, 6.74 (d, J P,H = 665 Hz, 1H, PH), 6.01, 5.95 (t, J = 6.4 Hz, 1H,
H-1ꢁ), 4.39–4.21 (m, 1H, H-3ꢁ), 4.20–3.97 (m, 2H, H-5ꢁ), 3.96–3.70 (m, 6H,
H-4ꢁ, NH, H-α, OCH3), 3.35–3.11 (m, 2H, indole CH2), 2.36–2.12 (m, 2H,
H-2ꢁ), 1.83, 1.80 (s, 3H, CH3-5) ppm; 13C NMR (100 MHz, CDCl3): δ 173.5,
164.0, 150.3, 136.3, 136.1, 135.9, 127.4, 123.6, 122.4, 119.9, 119.8, 118.5,
111.7, 111.6, 111.4, 111.3, 109.8, 109.7, 86.2, 85.4, 82.3, 62.4, 60.1, 60.0,
54.2, 52.8, 37.2, 30.3, 30.1, 12.6, 12.5 ppm; 31P NMR (162 MHz, CDCl3):
δ 12.58, 11.81 ppm; IR (KBr): νmax 3446, 2374, 2109, 1657, 1274, 1108,
968, 738, 558 cm−1; HRMS (ESI+): m/z Calcd. for C22H27N7O7P [M+H]+
532.1704; found 532.1715.
3ꢁ-Deoxy-3ꢁ-azidothymidin-5ꢁ-yl-L-leucyl-H-phosphonamidate (13). Start-
ing from AZT (267 mg, 1.0 mmol) and l-leucine methyl ester hydrochloride
(182 mg, 1.0 mmol), the diastereomeric mixture of compound 13 was syn-
thesized according to the general procedure. Flash column chromatography
1
afforded 13 (321 mg, 70%) as white foam; H NMR (400 MHz, CDCl3): δ
9.71 (s, 1H, NH-3), 7.35, 7.32 (s, 1H, H-6), 7.06, 7.04 (d, J P,H = 663 Hz, 1H,
PH), 6.16, 6.05 (t, J = 6.4 Hz, 1H, H-1ꢁ), 4.44–4.35 (m, 1H, H-3ꢁ), 4.34–4.10
(m, 2H, H-5ꢁ), 4.02–3.87 (m, 2H, H-4ꢁ, NH), 3.85–3.74 (m, 1H, H-α), 3.72
(s, 3H, OCH3), 2.47–2.31 (m, 2H, H-2ꢁ), 1.90 (s, 3H, CH3-5), 1.82–1.66
(m, 1H, CHCH2(CH3)2), 1.65–1.45 (m, 2H, CHCH2(CH3)2), 0.92 (d, J =
6.5 Hz, 6H, CHCH2(CH3)2) ppm; 13C NMR (100 MHz, CDCl3): δ 174.5,
163.9, 150.4, 136.1, 135.7, 111.6, 111.5, 86.0, 85.2, 82.4, 62.7, 62.5, 60.2,
60.1, 52.6, 51.9, 43.4, 37.3, 37.2, 24.7, 24.6, 22.9, 21.6, 12.5 ppm; 31P NMR
(162 MHz, CDCl3): δ 13.01, 12.32 ppm; IR (KBr): νmax 3434, 2107, 1639,
1405, 1206, 1111, 612 cm−1; HRMS (ESI+): m/z Calcd. for C17H28N6O7P
[M+H]+ 459.1752; found 459.1763.
3ꢁ-Deoxy-3ꢁ-azidothymidin-5ꢁ-yl-L-valyl-H-phosphonamidate (14). Start-
ing from AZT (267 mg, 1.0 mmol) and l-valine methyl ester hydrochloride
(168 mg, 1.0 mmol), the diastereomeric mixture of compound 14 was syn-
thesized according to the general procedure. Flash column chromatography
1
afforded 14 (289 mg, 72%) as white foam; H NMR (400 MHz, CDCl3): δ
9.46 (s, 1H, NH-3), 7.35, 7.30 (s, 1H, H-6), 7.07, 7.03 (d, J P,H = 663 Hz, 1H,
PH), 6.16, 6.04 (t, J = 6.1 Hz, 1H, H-1ꢁ), 4.40 (m, 1H, H-3ꢁ), 4.37–4.10 (m,
2H, H-5ꢁ), 3.99 (s, 1H, H-4ꢁ), 3.92–3.78 (m, 1H, H-α), 3.74 (s, 3H, OCH3),
2.42 (m, 2H, H-2ꢁ), 2.15 (m, 1H, CH(CH3)2), 1.91 (s, 3H, CH3-5), 0.98
(d, J = 4.8 Hz, 3H, CH(CH3)2), 0.91–0.80 (m, 3H, CH(CH3)2) ppm; 13C
NMR (100 MHz, CDCl3): δ 173.5, 163.8, 150.4, 136.1, 135.7, 111.6, 111.5,
86.1, 85.3, 82.4, 62.6, 60.2, 60.1, 58.7, 52.6, 37.4, 37.3, 32.0, 31.8, 19.4, 19.3,
17.2, 17.0, 12.6 ppm; 31P NMR (162 MHz, CDCl3): δ 12.75, 11.97 ppm; IR
(KBr): νmax 3857, 3733, 3182, 2966, 2826, 2423, 2110, 1469, 1273, 1107, 773,