S.R. Houghton et al. / Tetrahedron 66 (2010) 8137e8144
8143
matched authentic, commercial 2 in all respects (HPLC tR, MS). ESI-
MS [MþH] observed m/z¼520.3, calculated m/z¼520.2.
Supplementary data associated with this article can be found in
include MOL files and InChIKeys of the most important com-
pounds described in this article.
4.2. General procedure for the one-pot synthesis of tenofovir
disoproxil (8) from 5
References and notes
A dry round bottom flask equipped with a reflux condenser and
a magnetic stir bar was charged with 5 (8.0107 g, 23.33 mmol,
1.0 equiv) and sodium bromide (5.0505 g, 49.08 mmol, 2.10 equiv)
under Ar atmosphere. N-Methylpyrrolidone (NMP, 23.3 mL) and
TMSCl (11.9 mL, 93.8 mmol, 4.02 equiv) were added to the flask and
the mixture was stirred. The flask was capped and stirred vigor-
ously while heating to 60 ꢀC. The reaction mixture was maintained
at 60 ꢀC for 12 h and monitored by HPLC for complete conversion to
2 (for HPLC conditions see General procedure for the formation of
tenofovir). When complete (less than 2 area % of 5 and 9 com-
bined), the reaction mixture is diluted with EtOAc (35 mL) and
stirred for 5 min. The EtOAc and remaining TMSCl were then re-
moved by vacuum distillation at 60 ꢀC. EtOAc (35 mL) was again
added, stirred for 5 min, and removed by vacuum distillation at
60 ꢀC. Isopropanol (3.6 mL, 47 mmol, 2.0 equiv) was then added to
the reaction mixture and was stirred for 15 min. The mixture was
diluted with EtOAc (35 mL) and the volatile reagents removed by
vacuum distillation at 60 ꢀC. Chloromethyl isopropylcarbonate, 7,
(15.6 mL, 118 mmol, 5.03 equiv) and Et3N (9.8 mL, 70 mmol,
3.0 equiv) were added to the mixture and the reaction mixture is
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HPLC conditions: UV detection
l¼254 nm, Zorbax RX-C18, 3.5
mm,
4.6ꢃ100 mm, flow rate 1.5 mL/min, gradient elution H2O, 0.05% v/v
formic acid/MeCN 0.05% v/v formic acid, 95:5 to 45:55 over 18 min
run time. Typical retention times; 2: tR¼1.13 min, mono isoproxyl
phosphonate ester (assigned by ESI-MS [MþH] m/z¼403.9):
tR¼4.81 min, 8: tR¼10.72 min. The reaction was considered com-
plete when HPLC analysis showed less than 15 area % of the mono
isoproxyl phoshonate ester. The reaction was diluted in EtOAc
(35 mL), stirred for 5 min, and the ethyl acetate and remaining Et3N
are removed by vacuum distillation at 60 ꢀC. The reaction mixture
was diluted in EtOAc (140 mL) and extracted with water (70 mL).
The organic layer was washed with brine (70 mL), dried over
Na2SO4, filtered, and concentrated to dryness in vacuo. The
resulting light brown oil 8 (TD, 11.87 g) was assayed by HPLC to give
a potency corrected yield of 31%. Compound 8 produced following
this protocol matched authentic 8 in all respects (HPLC, MS, 1H
NMR). Compound 2: HPLC tR¼10.72 min; 1H NMR (300 MHz,
CDCl3) d 8.74 (s, 1H, CH), 7.98 (s, 1H, CH), 5.63 (m, 4H, CH2), 4.91 (m,
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34. Allan, A. L.; Gladstone, P. L.; Price, M. L. P.; Hopkins, S. A.; Juarez, J. C.; Donate, F.;
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2006, 49, 7807.
2H, CH(CH3)2), 4.36 (dd, J¼3.0, 14.4 Hz, 1H, CH), 4.14 (dd, J¼7.3,
14.4 Hz, 1H, CH), 3.94 (m, 2H, CHH and CH), 3.71 (dd, J¼9.1, 13.7 Hz,
1H, CHH), 1.30 (d, J¼15 Hz, 12H, CH(CH3)2), 1.27 (s, 3H, CH3), 1.21 (d,
J¼7.4 Hz, 3H, CH3); ESI-MS [MþH] observed m/z¼520.3, calculated
m/z¼520.2.
Acknowledgements
35. Kim, A.; Hong, J. H.; Oh, C. H. Nucleosides Nucleotides Nucleic Acids 2006, 25,
1399.
36. Nesterov, V. V.; Kolodyazhnyi, O. I. Russ. J. Gen. Chem. 2006, 76, 1510.
37. Horejsi, K.; Andrei, G.; De Clercq, E.; Snoeck, R.; Pohl, R.; Holy, A. Bioorg. Med.
Chem. 2006, 14, 8057.
We thank the Clinton Health Access Initiative, Syracuse Uni-
versity, and ProcesScience Inc. for financial support.
38. Oh, C. H.; Hong, J. H. Arch. Pharm. 2006, 339, 507.
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Supplementary data
Experimental procedure and complete data sets for all hy-
drolysis experiments, 1H NMR spectra for compounds 1, 2, 5, and
8 are available. ESI-MS spectra for compounds 2, 5, 8, reaction
intermediate 9, impurities, as well as HPLC traces of a represen-
tative hydrolysis and coupling reaction time course are included.
40. Nesterov, V. V.; Kolodyazhnyi, O. I. Russ. J. Gen. Chem. 2006, 76, 1022.
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Chem. 2006, 49, 5932.
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