摘要
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 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.
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 △^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.
基金
Project(50573019) support by the National Natural Science Foundation of China
