708
S. Gauthier et al. / Tetrahedron 56 (2000) 703–709
organic phase was washed with brine (20 mL), dried
(MgSO4), and concentrated. The residual solid was recrys-
tallized from ethanol to give (E)-droloxifene (1) (216 mg,
61%) with a Ͼ100:1 E/Z ratio as a white solid: mp 162–
References
1. (a) Marschner, N.; Kreienberg, R.; Balas, R.; Brandtner, M.;
Schlingensiepen, R.; Schumann, S.; Buttner, S.; Staab, H. J.;
Rauschning, W. Onkologie 1994, 17 (Suppl. 1), 32. (b) Rauschn-
ing, W.; Pritchard, K. I. Breast Cancer Res. Treat. 1994, 31, 83. (c)
Hegg, R. In Proceedings of the 16th International Cancer
Congress, Free Paper Posters; Rao, R. S., Ed.; Monduzzi Editore:
Bologna, Italy, 1994; Vol. 2, pp 1511–1514. (d) Bruning, P. F. Eur.
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2. (a) Ke, H. Z.; Thompson, D. D. WO 9731640 A1 970904, Pfizer
Inc. (b) Maclean, D. B.; Thompson, D. D. EP 792639 A1 970903,
Pfizer Inc. (c) Maclean, D. B.; Thompson, D. D. EP 791356 A1
970827, Pfizer Inc.
1
163ЊC; IR (KBr) 2928, 1582, 1505, 1451, 1288 cmϪ1; H
NMR (CD3OD) d 0.89 (t, J7.5 Hz, 3H), 2.28 (s, 6H), 2.46
(q, J7.2 Hz, 2H), 2.48 (t, J5.5 Hz, 2H), 3.95 (t,
J5.6 Hz, 2H), 6.57 (d, J8.8 Hz, 2H), 6.67–6.78 (m,
4H), 7.10–7.15 (m, 7H); 13C NMR (CDCl3) d 13.5, 28.9,
45.4, 58.0, 65.0, 113.2, 113.8, 116.6, 120.8, 125.8, 127.7,
128.9, 129.6, 131.7, 135.4, 138.1, 140.9, 142.4, 145.1,
156.5, 156.6. HRMS calcd for C26H29NO2: 387.2202.
Found: 387.2198. Anal. calcd for C26H29NO2·0.11H2O: C,
80.14; H, 7.51; N, 3.59. Found: C, 80.29; H, 7.43, N, 3.42.
3. (a) Ke, H. Z.; Crawford, D. T.; Qi, H.; Pirie, C. M.; Simmons,
H. A.; Chidsey-Frink, K. L.; Chen, H. K.; Jee, W. S. S.; Thompson,
D. D. Bone 1999, 24, 41. (b) Ke, H. Z.; Chen, H. K.; Simmons,
H. A.; Qi, H.; Crawford, D. T.; Pirie, C. M.; Chidsey-Frink, K. L.;
Ma, Y. F.; Jee, W. S. S.; Thompson, D. D. Bone 1997, 20, 31. (c)
Ke, H. Z.; Chen, H. K.; Qi, H.; Pirie, C. M.; Simmons, H. A.; Ma,
Y. F.; Jee, W. S. S.; Thompson, D. D. Bone 1995, 17, 491. (d)
Chen, H. K.; Ke, H. Z.; Lin, C. H.; Ma, Y. F.; Qi, H.; Crawford,
D. T.; Price, C. M.; Simmons, H. A.; Jee, W. S. S.; Thompson, D.
D. Bone 1995, 17 (Suppl. 4), 175s. (e) Chen, H. K.; Ke, H. Z.; Jee,
W. S. S.; Ma, Y. F.; Pirie, C. M.; Simmons, H. A.; Thompson,
D. D. J. Bone Miner. Res. 1995, 10, 1256. (f) Ke, H. Z.; Simmons,
H. A.; Pirie, C. M.; Crawford, D. T.; Thompson, D. D. Endo-
crinology 1995, 136, 2435. (g) Niikura, K.; Nakajima, Y.; Nishio,
M.; Nakayama, O.; Kojo, H.; Notsu, Y. Jpn. J. Pharmacol. 1992,
58 (Suppl. 1), 361. (h) Niikura, K.; Nakajima, Y.; Notsu, Y.; Ono,
R.; Nakayama, O. EP 509317 A2 921021, Klinge Pharma GmbH.
4. (a) Thompson, D. D. US 5852059 A 981222, Pfizer Inc. (b)
Fontana, S. A. US 5455275 A 951003, Eli Lilly and company.
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981027. (b) Aiello, R. J. EP 842659 A1 980520, Pfizer Inc. (c)
MacLean, D. B.; Thompson, D. D. US 5726207 A 980310 (d)
Grainger, D. J.; Metcalfe, J. C.; Kunz, L. L.; Kemp, P. R.; Schroff,
R. W.; Weissberg, P. L. WO 9640098 A2 961219, PCT Int. (e)
Denecke, R. DE 4320898 A1 950105. (f) Denecke, R. DE 4401554
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40-[2-(N,N-Dimethylamino)ethoxy]-3-(trimethylacetoxy)-
benzophenone (15). The same procedure for compound 12
was used, starting from benzophenone 10 (2.53 g,
0.848 mmol). Flash chromatography (EtOAc–methanol
19:1) gave amine 15 as a light yellow solid (1.49 g, 61%):
mp 60–62ЊC; IR (CHCl3) 1747, 1652, 1600 cmϪ1; 1H NMR
(CDCl3) d 1.35 (s, 9H), 2.35 (s, 6H); 2.77 (t, J5.6 Hz, 2H),
4.14 (t, J5.6 Hz, 2H), 6.97 (d, J8.5 Hz, 2H), 7.24 (d,
J7.3 Hz, 1H), 7.57 (m, 2H), 7.45 (m, 1H), 7.80 (d,
J8.5 Hz, 2H); 13C NMR (CDCl3) d 27.1, 39.1, 45.9,
58.0, 66.2, 114.2, 122.7, 125.7, 126.9, 129.1, 129.8, 132.5,
139.5, 150.9, 162.6, 176.8, 194.3. HRMS calcd for
C22H27NO4: 369.1940. Found: 369.1934.
40-[2-(N,N-Dimethylamino)ethoxy]-3-hydroxybenzo-
phenone (16). A solution of amine 15 (743 mg, 2.01 mmol)
in EtOH (5 mL) was treated with 2 N KOH (1.5 mL,
3.0 mmol) and stirred for 5 h. The reaction mixture was
brought to pH 8–9 with 10% HCl, concentrated, and
extracted with CH2Cl2 (3×30 mL). The combined organic
phase was washed with saturated NaHCO3 (2×10 mL) and
brine (10 mL), dried (Na2SO4), and concentrated to afford
without further purification the amine 16 (494 mg, 86%) as
a white solid: mp 96–98ЊC; IR (CHCl3) 2912, 1650,
1
1597 cmϪ1; H NMR (CD3OD) d 2.37 (s, 6H), 2.81 (t,
J5.7 Hz, 2H), 4.12 (t, J5.7 Hz, 2H), 6.84 (d, J8.7 Hz,
2H), 7.20 (d, J7.5 Hz, 2H), 7.22 (s, 1H), 7.35 (m, 1H),
7.67 (d, J8.7 Hz, 2H); 13C NMR (CD3OD) d 45.8, 58.8,
66.9, 115.2, 117.2, 120.4, 121.9, 130.4, 131.3, 133.6, 140.7,
158.7, 164.0, 197.4. HRMS calcd for C17H19NO3: 285.1365.
Found: 285.1370. Anal. calcd for C17H19NO3·0.044H2O: C,
71.34; H, 6.67; N, 4.89. Found: C, 71.29; H, 6.79; N, 4.88.
6. Maclean, D. B., Thompson, D. D., EP 792638 A1 970903,
Pfizer Inc.
7. (a) Kraska, A. R. EP 897720 A1 990224, Pfizer Inc. (b)
MacNeil, S. GB 2273873 A1 940706, University of Sheffield,
UK.
8. (a) Ruenitz, P. C.; Bagley, J. R.; Mokler, C. M. J. Med. Chem.
1982, 25, 1056. (b) Schickaneder, H.; Loeser, R.; Grill, H. EP
54168 A1 820623, Klinge Pharma GmbH. (c) Forster, A. B.;
Jarman, M.; Leung, O.-T.; McCague, R.; Leclercq, G.;
Devleeschouwer, N. J. Med. Chem. 1985, 28, 1491. (d) Loeser,
R.; Grill, H.; Schickaneder, H.; Seibel, K. DE 3425413 A1 860116,
Klinge Pharma GmbH. (e) Woschina, A.; Grill, H. EP 313799 A2
890503, Klinge Pharma GmbH. (f) Grill, H.; Woschina, A. WO
9518786 A1 950713, Klinge Pharma GmbH.
McMurry reaction between amine (16) and propio-
phenone. The same procedure for compound 11 was used,
starting from benzophenone 16 (287 mg, 1.01 mmol) and
propiophenone (402 mg, 2.99 mmol). Flash chromato-
graphy (CH2Cl2–methanol 9:1) afforded compound 1
(230 mg, 60%) as an inseparable 2:1 mixture of E/Z
1
isomers. (Z)-Droloxifene: H NMR (CD3OD) d 2.33 (s,
9. Major improvement was achieved concerning the purity of (E)-
droloxifene 1 in Ref. 8f.
10. Gauthier, S.; Mailhot, J.; Labrie, F. J. Org. Chem. 1996, 61,
3890.
6H), 2.75 (t, J5.5 Hz, 2H), 4.08 (t, J5.5 Hz, 2H), 6.34
(m, 2H), 6.90 (m, 2H).
11. Blicke, F. F.; Weinkauff, O. J. J. Org. Chem. 1932, 54, 1446.
12. Examples of meta-phenolic and para-phenolic regioselective
substitution in 3,4-dihydroxybenzene derivatives: (a) Astles, P. C.;
Brown, T. J.; Cox, P.; Halley, F.; Lockey, P. M.; McCarthy, C.;
McLay, I. M.; Majid, T. N.; Morley, A. D.; Porter, B.; Ratcliffe,
Acknowledgements
This work was supported by Endorecherche.