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Efficient preparation of a key intermediate in the exemestane synthesis

Łukasz S. Kaczmarek 1Marcin Cybulski 1Marek Kubiszewski 1Andrzej Leś 1,2

1. Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland
2. Faculty of Chemistry, University of Warsaw, Pasteura 1, Warszawa 02-093, Poland


One-third of breast cancers is hormone-dependent and uses estrogen to proliferate. The major source of estrogens in post-menopausal women is enzymatic conversion of circulating androgens. Therefore, the inhibition of enzyme activity causes tumor regression. One of the Type I aromatase inhibitors is exemestane (6-methyleneandrosta-1,4-dione), the only orally active irreversible steroidal aromatase inhibitor, effectively used in postmenopausal women with advanced breast cancer.

In general, there are two different routes to obtain exemestane. The first exploits 6-methylation of androstenedione or boldenone followed by oxidation of the appropriate intermediate. The above mentioned processes are unfavorable because of toxic and environmentally unsafe reagents as well as harsh reaction conditions. The second method proposed by a German group starts from androsta-1,4-diene-3,17-dione (ADD) and appears to be an advantageous alternative. The crucial point of synthesis is the formation of 1α,3-di(1-pyrrolidino)androsta-3,5-diene-17-one (DPA) followed by transformation into 6-(hydroxymethyl)androsta-1,4-dien-3,17-dione.

In order to develop the technology of exemestane in a pilot scale the both reaction were examined. The sampling of reaction parameter space such as reaction time, temperature, the amount of acid catalyst and some details of the work-up procedure in the course of several experiments led us to formulation of a reasonable conditions for ADD transformation to DPA. The use of the adequate amount of the acid catalyst at room temperature and the NMR monitoring of the reaction mixture is essential for this process. The developed method produces a high yield intermediate on a level of purity which is suitable for the last step of exemestane synthesis. Taking into consideration our observation about the instability of DPA during the studies on various work-up procedures, a hypothetical transformation routes of ADD to DPA were analyzed. The suggested reaction pathways were calculated with the theoretical B3LYP/6-31G(d,p)quantum mechanical method. The theoretical molecular structures were verified with 1H and 13C NMR spectra.


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Submitted: 2012-03-21 14:11
Revised:   2012-04-03 12:52