Quinone-related hexacyclic by-products in the production process of exemestane.
Exemestane, a 3rd-generation aromatase inhibitor, is clinically used in the treatment of breast cancer in postmenopausal women. The key step of the industrial synthetic process, i.e., a dehydrogenation to introduce the Δ1-unsaturation, is normally performed with quinones such as p-chloranil or DDQ. We observed the formation of two different hexacyclic by-products, depending on the quinone used in the oxidation step. These compounds arise from an initial [4+2] cycloaddition between the precursor 6-methylenandrost-4-ene-3,17-dione and the quinone reagent, followed by a twofold dehydrohalogenation (with p-chloranil) or dehydrogenation (with DDQ). The structures of these unprecedented hexacyclic adducts were determined by a combination of mass spectrometry, NMR techniques and crystallographic analysis.
Università del Piemonte Orientale "A. Avogadro", Dipartimento di Scienze del Farmaco, Largo Donegani 2, I-28100 Novara, Italy. Electronic address: giovannibattista.giovenzana@uniupo.it.
Giovanni Battista
GB
Giovenzana
Università degli Studi dell'Insubria, Dipartimento di Scienza e Alta Tecnologia, Via Valleggio 11, I-22100 Como, Italy.
Norberto
N
Masciocchi
Università del Piemonte Orientale "A. Avogadro", Dipartimento di Scienze del Farmaco, Largo Donegani 2, I-28100 Novara, Italy.
Roberto
R
Negri
Università degli Studi dell'Insubria, Dipartimento di Scienza e Alta Tecnologia, Via Valleggio 11, I-22100 Como, Italy.
Giovanni
G
Palmisano
Università degli Studi dell'Insubria, Dipartimento di Scienza e Alta Tecnologia, Via Valleggio 11, I-22100 Como, Italy.
Andrea
A
Penoni
Università degli Studi di Pavia, Dipartimento di Chimica, Via Taramelli 12, I-27100 Pavia, Italy.
Lucio
L
Toma
D000730:Androstadienes / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D014961:X-Ray Diffraction
D000730:Androstadienes; D016227:Benzoquinones; C004532:quinone; C056516:exemestane
Cycloaddition; DDQ; Exemestane; p-Chloranil