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Organic & Biomolecular Chemistry
extraction, column chromatography and distillation. The
Cross‐Coupling Reactions, Wiley‐VCH, New
DOI: 10.1039/C8OB02977F
excess organolithium reagent (protonated after reaction
quenching, 12-H) and the formed lithium bromide pose
no difficulty in the separation from the product (Figure
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). Acid-base extraction or column chromatography were
both suitable means to achieve purification.
4
) E. B. Pinxterhuis, M. Giannerini, V. Hornillos, B. L.
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N
O
N
O
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H
N
O
LiBr
1
2-H
13
Z-Tamoxifen
E-Tamoxifen
Figure 4: (Z)-Tamoxifen and side products.
5
The remaining impurity of dehalogenated starting
material 13 exhibits near identical behavior compared to
the product, but flash chromatography was able to yield
the pure (E/Z)-Tamoxifen mixture. If desired, RP-
preparative HPLC in water/ acetonitrile/TFA separates
effectively the (E) from the (Z) isomer of the product.
In conclusion, the carbolithiation of diphenylacetylene
and the consecutive cross coupling with the appropriate
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4
-bromo-dimethylamine-ethylether (6) yields (Z)-
Tamoxifen with good (Z/E) selectivity (10:1) and with
yields up to 65%. The reaction mixture was purified by
flash chromatography to obtain the pure (E/Z)-Tamoxifen
mixture. Further optimization could lead to a lowering of
the catalyst loading and suppressing the lithium halogen
exchange or E-Z isomerisation that lead to the undesired
side products which have proven to be a challenge in the
purification of this pharmaceutical. The method
distinguishes itself from previously reported syntheses by
its high atom economy, reaction mass efficiency, non-
toxic waste production, step count and ease of reaction
setup. The organolithium cross coupling is also an
attractive strategy for the coupling of less reactive
2
016, 22, 3991–3995; m) D. Heijnen, F. Tosi, C. Vila, M.
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studies might further enhance the efficiency towards
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Conflict of Interest
9
1
659–9669.
There are no conflicts of interest to declare.
0) E. Shirakawa, D. Ikeda, T. Ozawa, S. Watanabe, T.
Hayashi, Chem. Commun., 2009, 1885–1887.
Acknowledgements
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1) a) R. A. Sheldon, Chem. Commun,. 2008, 3352–
365; b) B. H. Lipshutz, N. A. Isley, J. C. Fennewald, E.
B.L.F. acknowledges financial support from The
Netherlands Organisation for Scientific Research, the
European Research Council (ERC Advanced Grant
D. Slack, Angew. Chem. Int. Ed., 2013, 52, 10952–10958.
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27897), the Royal Netherland Academy of Arts and
Sciences (KNAW), and the Ministry of Education,
Culture and Science (Gravitation program 024.601035).
Guide to Determining and Evaluating Process
Greenness, Springer 2015.
1
3). C. Avendano, C. Menendez, Medicinal Chemistry of
Anticancer Drugs, Elsevier Science 2015.
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