Synthesis and characterization of mibolerone

Abstract

A simple and effective route for the synthesis of mibolerone was described starting from the estr-5(10)-en-3,17-dione in four steps with the overall yield of 47.0%. Thus, two methods for key intermediate methylnorandrost were investigated: one(method A) starting from estr-4-en-3,17-dione underwent 3-keto group protected with ethyl orthoformate to give 3-ethoxy-3,5-dien-estr-17-one, the other(method B) from estr-5(10)-en-3,17-dione and protected 3-keto group to give 3,3-dimethoxy-estr-5(10)-7-one in a mild acidic condition. Then, two intermediates were subsequently reacted with methyllithium followed by a mild hydrolytic procedure and gave methylnorandrost with total yield 25.0% and 86.0%, respectively. In the preparation of 6-dehydrogenation product of methylnorandrost, two procedures(method C and method D) were investigated: one was the protected 17α-methyl-17β-hydroxy Δ^3,5-enol ethers estrendiene brominated and the resulting 6-bromo-19-methylnortestosterone was then immediately dehydrohaloenated to give 6-dehydro-19-methylnortestosterone, the total yield only reaches 36.0%; the other was directly dehydrogenated with chloranil and the yield reaches 75.6% under the optimum conditions: in refluxing tetrahydrofuran, the molar ratio of methylnorandrost to chloranil is 0.66 and reaction time of 5 h. The titled compound and intermediates were characterized by ¹H and ¹³C NMR, IRMS and elemental analysis.

Keywords

mibolerone / methylnorandrost / steroids / synthesis / hepatic androgen receptor

References

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