7590
A. Marcos-Escribano et al. / Tetrahedron 65 (2009) 7587–7590
20
to afford 10 (0.23 g, 85%). [
a
]
D
þ92.7 (c 21.35, CHCl3); IR (CHCl3)
n
References and notes
(cmꢁ1): 918, 1041, 1255, 1379, 1658, 1735, 2858, 2942; 1H NMR
1. Brodie, A. M. H. Pharmacology 1985, 34, 3213–3219.
2. Santen, R. J. Breast Cancer Res. Treat. 1986, 7, S23–S35.
3. Brodie, A. M. H.; Coombes, R. C.; Dowsett, M. J. Steroid Biochem. 1987, 27,
899–903.
4. Bossche, H. V. J. Steroid Biochem. Mol. Biol. 1992, 43, 1003–1021.
5. Brodie, A. Trends Endocrinol. Metab. 2002, 13, 61–65.
6. Geisler, J.; Lonning, E. Clin. Cancer Res. 2005, 11, 2809–2821.
7. Jordan, V. C.; Brodie, A. M. H. Steroids 2007, 72, 7–25.
8. Brueggemeier, R. W.; Hackett, J. C.; Dı´az-Cruz, E. S. Endocr. Rev. 2005, 26,
331–345.
(CDCl3),
d (ppm): 0.85 (s, 3H), 1.14 (s, 3H), 2.04 (s, 3H), 1.0–2.6 (m,
13H), 4.62 (t, J¼8.0 Hz, 1H), 4.94 (s, 1H), 5.01 (s, 1H), 6.14 (d,
J¼2.0 Hz, 1H), 6.28 (dd, J1¼10.0 Hz, J2¼2.0 Hz, 1H), 7.06 (d,
J¼10.0 Hz,1H); 13C NMR (CDCl3),
d (ppm): 12.0,19.6, 21.0, 22.2, 23.4,
27.3, 35.5, 36.4, 39.9, 42.6, 43.6, 49.8, 50.2, 82.1, 111.9, 122.5, 127.6,
145.7, 154.3, 167.6, 170.9, 186.5; HRMS-EI (MþNa) calcd for
C22H28O3Na 363.1931, found 363.1921.
9. Santen, R. J. Steroids 1977, 50, 575–593.
10. Buzdar, A. Anti-Cancer Drugs 2000, 11, 609–616.
4.4. 6-Methylenandrost-1,4-diene-3,17-dione (1). Exemestane
11. Brueggemeier, R. W. Breast Cancer Res. Treat. 2002, 74, 177–185.
12. Di Salle, E.; Ornati, G.; Giudici, D.; Lassus, M.; Evans, T. R. J.; Coomes, R. C.
J. Steroid Biochem. Mol. Biol. 1992, 43, 137–143.
13. Kirk, D. N.; Petrow, V. Patent U.S, 3,112,305, 1963; Chem. Abstr. 1964, 60,
9336h.
14. Dube´, J. Patent U.S. 3,274,176, 1966; Chem. Abstr.1965, 62, 9204f.
15. Buzzetti, F.; Barbugian, N.; Lombardi, P.; Di Salle, E. Patent GB 2177700A, 1987;
Chem. Abstr. 1988, 108, 221966v.
16. Bucourt, R.; Dube, J. Bull. Soc. Chim. Fr. 1978, II, 33–36.
17. Wagner, H.; Ponsold, K.; Schumann, G. Patent DD 258820, 1986; Chem. Abstr.
1989, 111, 7672q.
18. Wagner, H.; Ponsold, K.; Schumann, G. Patent DD 264220, 1987; Chem. Abstr.
1989, 111, 78501v.
19. Longo, A.; Lombardi, P. Patent EP 0307134, 1989; Chem. Abstr. 1989, 111,
134643f.
20. Longo, A.; Lombardi, P. Patent EP 0326340, 1989; Chem. Abstr. 1990, 112,
36257j.
21. Buzzetti, F.; Salle, E. D.; Longo, A.; Briatico, G. Steroids 1993, 58, 527–532.
22. Levina, I. S. Russ. Chem. Rev. 1998, 67, 975–998.
4.4.1. Synthesis of exemestane (1) from 9
A two neck round bottom flask equipped with an Argon inlet, an
addition funnel, magnetic stirrer, and a septum inlet was charged
with 9 (0.11 g, 0.4 mmol) solved in methanol and cooled to ꢁ20 ꢀC.
Jones reagent was poured dropwise into the reaction vessel to the
point of a persistent orange colour. The excess of the reagent was
destroyed with isopropyl alcohol, and the reaction mixture was
poured into brine at 0 ꢀC. The steroid was extracted with EtAcO and
washed with saturated NaHCO3. The organic phase was dried
20
(Na2SO4) and evaporated to afford 1 (0.11 g,100%). Mp: 196 ꢀC; [
a]
D
þ280.6 (c 13.79, CHCl3); IR (CHCl3),
n
(cmꢁ1): 729, 813, 909, 1027,
(ppm): 0.94 (s, 3H),
1277, 1453, 1647, 1734, 2941; 1H NMR (CDCl3),
d
1.17 (s, 3H), 1.2–2.7 (m, 13H), 5.00 (s, 1H), 5.06 (s, 1H), 6.17 (d,
J¼2.0 Hz, 1H), 6.25 (dd, J1¼10.0 Hz, J2¼2.0 Hz, 1H), 7.08 (d,
23. Shao, Y.; Li, W.; You, Q. Zhongguo Yiyao Gongye Zazhi 2001, 32, 345–346; Chem.
Abstr. 2002, 136, 232434z.
24. Krook, M.; Hewitt, B. D. Patent WO 2001/04342A1, 2001; Chem. Abstr. 2001, 134,
99682u.
25. Lombardi, P. Biochim. Biophys. Acta 2002, 1587, 326–337.
26. Go¨rlitzer, K.; Bonnekessel, Ch.; Jones, P. G.; Kaufmann, G. Pharmazie 2002, 57,
808–810.
J¼10.0 Hz, 1H); 13C NMR (CDCl3),
d (ppm): 13.3, 19.2, 21.4, 21.6, 30.7,
34.9, 35.1, 38.8, 43.2, 47.2, 49.5, 50.3, 112.0, 122.2, 127.3, 144.8, 153.7,
167.0, 185.9, 219.0; HRMS-EI (MþNa) calcd for C20H24O2Na:
319.1668, found 319.1650.
27. Huang, H.; Song, X.; Gu, T. Patent CN 1415624A, 2003; Chem. Abstr. 2005, 143,
133584m.
4.4.2. Synthesis of exemestane (1) from 8
Compound 8 (1.06 g, 3.54 mmol) was dehydrogenated as de-
scribed above (compound 9 from 6) for 45 min. The residue was
cromatographed on silica gel and eluted with 1:1 hexane/ethyl
acetate to achieve 1 (0.85 g, 81%) pure.
28. Gao, X.; Liu, K. Patent CN 1453288A, 2003; Chem. Abstr. 2005, 142, 392563t.
29. Zhu, Q.; Pan, J. Patent CN 1491957A, 2004; Chem. Abstr. 2005, 143, 26772z.
30. Kunnen, K.; Stehle, N.; Weis, S. W.; Pascone, J. M.; Pariza, R. J.; Van Ornum, S. G.
Patent WO 2005/070951A1, 2005; Chem. Abstr. 2005, 143, 173027p.
31. Go¨rlitzer, K.; Bonnekessel, Ch.; Jones, P. G.; Palusczak, A.; Hartmann, R. W.
Pharmazie 2006, 61, 575–581.
32. Fontana, E.; Pignatti, A.; Giribone, D.; Di Salle, E. Steroids 2008, 73, 760–764.
33. Annen, K.; Hofmeister, H.; Laurent, H.; Wiechert, R. Synthesis 1982, 34–40.
34. Turner, A. B.; Ringold, H. J. J. Chem. Soc. C 1967, 1720–1730.
35. Pradhan, S. K.; Ringold, H. J. Org. Chem. 1964, 29, 601–604.
36. (a) Ryu, I.; Murai, S.; Hatayama, Y.; Sonoda, N. Tetrahedron Lett. 1978, 37, 3455–
3458; (b) Bhattacharya, A.; DiMichele, L. M.; Dolling, U.-H.; Grabowski, J. J.;
Grenda, V. J. J. Org. Chem. 1989, 54, 6118–6120.
Acknowledgements
´
We are grateful to Crystal Pharma SA (Parque Tecnologico de
Boecillo, Valladolid, Spain) for a research contract to A.M.E. and
financial support.
37. Bhattacharya, A.; DiMichele, L. M.; Dolling, U.-H.; Douglas, A. W.; Grabowski, J. J.
J. Am. Chem. Soc. 1988, 110, 3318–3319.
38. Williams, J. M.; Marchesini, G.; Reamer, R. A.; Dolling, U.-H.; Grabowski, J. J.
J. Org. Chem. 1995, 60, 5337–5340.
39. Jiang, Z.-X.; Ye, J.-Q.; Jiang, L.; Zhao, Y.-S. Steroids 2005, 70, 690–693.
40. Walker, D.; Hiebert, J. D. J. Org. Chem. 1966, 31, 153–195.
Supplementary data
Supplementary data associated with this article can be found in