S. H. Szajnman et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4685–4690
4689
18. Ling, Y.; Sahota, G.; Odeh, S.; Chan, J. M. W.; Araujo, F.
G.; Moreno, S. N. J.; Oldfield, E. J. Med. Chem. 2005, 48,
3130.
19. Szajnman, S. H.; Bailey, B. N.; Docampo, R.; Rodriguez,
J. B. Bioorg. Med. Chem. Lett. 2001, 11, 789.
20. Szajnman, S. H.; Montalvetti, A.; Wang, Y.; Docampo,
R.; Rodriguez, J. B. Bioorg. Med. Chem. Lett. 2003, 13,
3231.
21. Garzoni, L. R.; Waghabi, M. C.; Baptista, M. M.; de
Castro, S. L.; Meirelles, M. N. L.; Britto, C. C.; Docampo,
R.; Oldfield, E.; Urbina, J. A. Int. J. Antimicrob. Agents
2004, 23, 286.
22. Rodan, G. A.; Martin, T. J. Science 2000, 289, 1508.
23. Reszka, A. A.; Rodan, G. A. Curr. Rheumatol. Rep. 2003,
5, 65.
to afford 1.67 g (70% yield) of pure compound 7 as a white
solid: mp 250–251 °C; 1H NMR (D2O)
0.82 (t,
d
J = 7.6 Hz, 3H, H-3), 1.65 (tq, J = 13.5, 7.4 Hz, 2H, H-
2); 13C NMR (D2O) d 10.43 (t, J = 6.7 Hz, C-2), 29.39 (C-
3), 57.51 (t, J = 127.6 Hz, C-1); 31P NMR (D2O) d 20.89.
Anal. Calcd for C3H11O6P2N: C, 16.45; H, 5.06; N, 6.39.
Found: C, 16.50; H, 5.00; N, 6.33. Compound 8: A
mixture of butyronitrile (1.26 mL, 11.3 mmol), H3PO3
(1.86 g, 22.7 mmol), and anhydrous benzenesulfonic acid
(10 g) was stirred at 65 °C for 10 min under argon
atmosphere: Then, PCl3 (1.14 mL, 11.3 mmol) was added
dropwise with vigorous stirring. The reaction was stirred
at 70 °C for 6 h. Water (40 mL) was added and the
mixture was stirred at room temperature for 1 h. Ethanol
(20 mL) was added and the resulting product was filtered
and crystallized from (c) HCl–ethanol to afford 1.77 g
(53% yield) of pure compound 8 as a white solid: mp 255–
24. Rogers, M. J.; Gordon, S.; Benford, H. L.; Coxon, F. P.;
Luckman, S. P.; Monkkonen, J.; Frith, J. C. Cancer 2000,
88(Suppl.), 2961.
1
257 °C; H NMR (D2O) d 0.77 (t, J = 7.3 Hz, 3H, H-4),
25. Dunford, J. E.; Thompson, K.; Coxon, F. P.; Luckman, S.
P.; Hahn, F. M.; Poulter, C. D.; Ebetino, F. H.; Rogers,
M. J. J. Pharmacol. Exp. Ther. 2001, 296, 235.
26. Reszka, A. A.; Rodan, G. A. Mini Rev. Med. Chem. 2004,
4, 711.
27. Rogers, M. J. Curr. Pharm. Des. 2003, 9, 2643.
28. Yokoyama, K.; Trobridge, P.; Buckner, F. S.; Scholten, J.;
Stuart, K. D.; Van Voorhis, W. C.; Gelb, M. H. Mol.
Biochem. Parasitol. 1998, 94, 87.
29. Zhang, F. L.; Casey, P. J. Annu. Rev. Biochem. 1996, 65,
241.
30. Leonard, D. M. J. Med. Chem. 1997, 40, 2971.
31. Martin, M. B.; Arnold, W.; Heath, H. T., III; Urbina, J.
A.; Oldfield, E. Biochem. Biophys. Res. Commun. 1999,
263, 754.
32. Montalvetti, A.; Bailey, B. N.; Martin, M. B.; Severin, G.
W.; Oldfield, E.; Docampo, R. J. Biol. Chem. 2001, 276,
33930.
33. Tarshis, L. C.; Proteau, P. J.; Kellogg, B. A.; Sacchettini,
J. C.; Poulter, C. D. Proc. Natl. Acad. Sci. U.S.A. 1996,
93, 15018.
34. Hosfield, D. J.; Zhang, Y.; Dougan, D. R.; Broun, A.;
Tari, L. W.; Swanson, R. V.; Finn, J. J. Biol. Chem. 2003,
278, 18401.
1.29–1.49 (m, 2H, H-3), 1.73–1.95 (m, 2H, H-2); 13C NMR
(D2O) d 12.28 (C-4), 15.50 (t, J = 5.4 Hz, C-2), 31.25 (C-3),
55.26 (t, J = 127.7 Hz, C-1); 31P NMR (D2O) d 20.94.
Anal. Calcd for C4H13O6P2N: C, 20.61; H, 5.62; N, 6.01.
Found: C, 20.70; H, 5.64; N, 6.05. Compound 9: A
mixture of valeronitrile (1.26 mL, 11.3 mmol), H3PO3
(1.86 g, 22.7 mmol), and anhydrous benzenesulfonic acid
(10 g) was stirred at 65 °C for 10 min under argon
atmosphere. Then, PCl3 (1.14 mL, 11.3 mmol) was added
dropwise and the reaction mixture was stirred at 85 °C for
16 h. The reaction was allowed to cool to room temper-
ature. Water (40 mL) was added and the mixture was
stirred for 10 min more. Ethanol (20 mL) was added, and
the resulting product was filtered and crystallized from (c)
HCl–ethanol to afford 720 mg (25% yield) of pure com-
pound 9 as a white solid: mp 245–247 °C; 1H NMR (KOD
40% (w/w) in D2O) d 0.77 (t, J = 7.4 Hz, 3H, H-5), 1.08–
1.15 (m, 2H, H-4), 1.26–1.32 (m, 2H, H-3), 1.47–1.55 (m,
2H, H-2); 13C NMR (40% KOD (w/w) in D2O) d 14.39 (C-
5), 24.24 (C-4), 27.53 (t, J = 5.4 Hz, C-2), 36.90 (C-3),
57.26 (t, J = 128.2 Hz, C-1); 31P NMR (KOD 40% (w/w)
in D2O) d 20.82 (s); Anal. Calcd for C5H15O6P2N: C,
24.30; H, 6.12; N, 5.67. Found: C, 24.42; H, 6.13; N, 5.67.
Compound 10: A mixture of hexanenitrile (1.25 mL,
10 mmol), H3PO3 (1.68 g, 20 mmol), and anhydrous
benzenesulfonic acid (10 g) was heated at 65 °C under
argon atmosphere. Then, PCl3 (1.0 mL, 10 mmol) was
added dropwise with vigorous stirring. The reaction
mixture was stirred at 90 °C for 16 h. Water (40 mL)
was added and the reaction mixture was stirred a room
temperature for 1 h. Ethanol (20 mL) was added, and the
resulting product was filtered and crystallized from (c)
HCl–ethanol to afford 397 mg (15% yield) of pure com-
pound 10 as a white solid: mp 240–242 °C; 1H NMR (40%
KOD (w/w) in D2O) d 0.64 (t, J = 7.6 Hz, 3H, H-6), 0.98–
1.02 (m, 2H, H-5), 1.05–1.10 (m, 2H, H-4), 1.22–1.28 (m,
2H, H-3), 1.48–1.57 (m, 2H, H-2); 13C NMR (40% KOD
(w/w) in D2O) d 14.50 (C-6), 22.96 (C-5), 25.09 (t,
J = 6.0 Hz, C-2); 33.56 (C-3), 37.11 (C-4), 57.34 (t,
J = 127.6 Hz, C-1); 31P NMR (40% KOD (w/w) in D2O)
d 20.95. Anal. Calcd for C6H17O6P2N: C, 27.59; H, 6.56;
N, 5.36. Found: C, 27.78; H, 6.64; N, 5.41. Compound 11:
A mixture of heptanoamide (800 mg, 6.2 mmol), H3PO3
(508 mg, 6.2 mmol), and anhydrous benzenesulfonic acid
(10 g) was stirred at 70 °C under argon atmosphere for
10 min. Then, PCl3 (1.86 mL, 18.6 mmol) was added
dropwise and the reaction mixture was stirred at 90 °C
for 16 h. The reaction mixture was allowed to cool to
room temperature. Water (40 mL) was added and the
mixture was stirred at room temperature for 2 h. Ethanol
(20 mL) was added, and the resulting mixture was kept at
35. Widler, L.; Jaeggi, K. A.; Glatt, M.; Muller, K.; Bachman,
¨
R.; Bisping, M.; Born, A.-R.; Cortesi, R.; Guiglia, G.;
Jeker, H.; Klein, R.; Ramseier, U.; Schmid, J.; Schreiber,
G.; Seltenmeyer, Y.; Green, J. R. J. Med. Chem. 2002, 45,
3721.
36. Papapoulos, S.; van Beek, E. R.; Lowick, C. W. G. M.;
Labriola, R.; Vecchioli, A. EP 0 753 523 A1.
37. Olive, G.; Le Moigne, F.; Mercier, A.; Tordo, P. Synth.
Commun. 2000, 34, 617.
38. Griffiths, D. V.; Hughes, J. M.; Brown, J. W.; Caesar, J.
C.; Swetnam, S. P.; Cumming, S. A.; Kelly, J. D.
Tetrahedron 1997, 52, 17815.
39. Compound 6: A mixture of H3PO3 (4.1 g, 50 mmol) and
acetonitrile (1.0 mL, 20 mmol) was stirred at 130 °C for
12 h under argon atmosphere. Methanol (10 mL) was
added and the solid was filtered and crystallized from
water–methanol to afford 2.10 g (51% yield) of pure
1
compound 6 as a white solid: mp 266–269 °C; H NMR
(500.13 MHz, D2O) d 1.54 (t, J = 14.2 Hz, H-2); 13C NMR
(125.77 MHz, D2O) d 18.28 (t, J = 3.0 Hz, C-2), 54.39 (t,
J = 131.8 Hz, C-1); 31P NMR (202.45 MHz, D2O) d 13.36.
Anal. Calcd for C2H9O6P2N: C, 11.72; H, 4.42; N, 6.83.
Found: C, 11.63; H, 4.55; N, 6.73. Compound 7: SB13 A
mixture of H3PO3 (3.57 g, 43.5 mmol) and propionitrile
(0.77 mL, 10.8 mmol) was stirred at 135 °C for 12 h under
argon atmosphere. Methanol (10 mL) was added and the
solid was filtered and crystallized from 1.0 N HCl–ethanol