LETTER
Synthesis of Aryl Phosphoramidate Derivatives of AZT/d4T
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and 1 mmol of NCS, respectively, 4 mmol of Et3N in CH2Cl2 (15
mL) was added dropwise at –5 °C within 1 h, and then the solution
was warmed to r.t. and stirred for another 2 h at r.t. The solvents
were removed by rotary distillation. Then, 5 mL of EtOAc was add-
ed to the residue, and the triethylamine hydrochloride was filtered.
The filtrate was concentrated, and the residue was purified by silica
gel column chromatography using EtOAc–MeOH (40: 1) as eluent.
The corresponding aryl phosphoramidate derivative of AZT/d4T
was obtained as white or yellow foam in moderate to high yield.
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Characterization data of two representative compounds are shown
as follows:
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Compound 4ac
Yield 70%. 31P NMR (121.5 MHz, CDCl3): d = 3.73, 3.41 ppm (a
1
pair of diastereomers, 1:1). H NMR (300 MHz, CDCl3): d = 9.73
(br, 1 H, NH-3), 7.36–7.20 (m, 6 H, H-6 and phenyl), 6.21–6.13 (m,
1 H, H-1¢), 4.35–4.20 (m, 4 H, H-3¢, H-4¢ and H-5¢), 4.10–3.95 (m,
2 H, NH and CH of Ala), 3.71 (d, 3 H, OCH3), 2.39–2.31 (m, 1 H,
H-2¢), 2.24–2.19 (m, 1 H, H-2¢), 1.89 (d, 3 H, CH3-5), 1.37 (m, 3 H,
CH3 of Ala) ppm. 13C NMR (75 MHz, CDCl3): d = 174.0, 164.1,
150.5, 135.5, 129.9, 125.4, 120.1, 111.5, 85.0, 82.4, 65.8, 60.3,
52.7, 50.4, 37.4, 21.0, 12.5 ppm. ESI-MS: m/z = 509.2 [M + H]+.
HRMS: m/z calcd [M+H]+: 509.1550; found: 509.1558.
Compound 5bc
Yield 77%. 31P NMR (121.5 MHz, CDCl3): d = 4.35, 3.70 ppm (a
1
pair of diastereomers, 1:1). H NMR (300 MHz, CDCl3): d = 9.25
(d, 1 H, NH-3), 7.34–7.28 (m, 1 H, H-6), 7.13–7.07 (m, 3 H, H-1¢
and phenyl), 6.84–6.80 (m, 2 H, phenyl), 6.37–6.27 (m, 1 H, H-2¢),
5.89 (t, 1 H, H-3¢), 5.02 (br, 1 H, H-4¢), 4.37–4.29 (m, 2 H, H-5¢),
4.01–3.97 (m, 1 H, NH of Ala), 3.87–3.84 (m, 1 H, CH of Ala), 3.77
(s, 3 H, OCH3), 3.71 (d, 3 H, OCH3), 1.84 (d, 3 H, CH3-5), 1.34 (m,
3 H, CH3 of Ala) ppm. 13C NMR (75 MHz, CDCl3): d = 174.2,
164.0, 156.9, 151.0, 143.9, 135.9, 133.3, 127.5, 121.2, 114.7, 111.4,
89.8, 84.8, 66.8, 55.7, 52.7, 50.2, 21.0, 12.4. ESI-MS: m/z = 496.1
[M + H]+. HRMS: m/z calcd [M + H]+: 496.1485; found: 496.1473.
Acknowledgment
This work was supported by the Excellent Dissertation Foundation
of the Chinese Ministry of Education (No. 200222), the Excellent
Young Teacher Program of MOE, P. R. C., and the National Natural
Science Foundation of China (Grant No. 20472042).
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References
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Synlett 2005, No. 16, 2537–2539 © Thieme Stuttgart · New York