Publikationsdatum:
2014-01-18
Beschreibung:
The classical synthesis, followed by purification of the steroidal A -ring Δ 1 -olefin, 5 α -androst-1-en-17-one ( 5 ), from the Δ 1 -3-keto enone, (5 α ,17 β )-3-oxo-5-androst-1-en-17-yl acetate ( 1 ), through a strategy involving the reaction of Δ 1 -3-hydroxy allylic alcohol, 3 β -hydroxy-5 α -androst-1-en-17 β -yl acetate ( 2 ), with SOCl 2 , was revisited in order to prepare and biologically evaluate 5 as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ 2 -olefin 6 as a by-product, which could only be detected on the basis of NMR analysis. Optimization of the purification and detection procedures allowed us to reach 96% purity required for biological assays of compound 5 . The same synthetic strategy was applied, using the Δ 4 -3-keto enone, 3-oxoandrost-4-en-17 β -yl acetate ( 8 ), as starting material, to prepare the potent aromatase inhibitor Δ 4 -olefin, androst-4-en-17-one ( 15 ). Unexpectedly, a different aromatase inhibitor, the Δ 3,5 -diene, androst-3,5-dien-17-one ( 12 ), was formed. To overcome this drawback, another strategy was developed for the preparation of 15 from 8 . The data now presented show the unequal reactivity of the two steroidal A -ring Δ 1 - and Δ 4 -3-hydroxy allylic alcohol intermediates, 3 β -hydroxy-5 α -androst-1-en-17 β -yl acetate ( 2 ) and 3 β -hydroxyandrost-4-en-17 β -yl acetate ( 9 ), towards SOCl 2 , and provides a new strategy for the preparation of the aromatase inhibitor 12 . Additionally, a new pathway to prepare compound 15 was achieved, which avoids the formation of undesirable by-products.
Print ISSN:
0018-019X
Digitale ISSN:
1522-2675
Thema:
Chemie und Pharmazie
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