FMPA
Chemical Name: 17alpha-Acetoxy-9alpha-fluoro-6alpha-methylpregn-4-ene-3,20-dione
CAS No. 171611-77-1
项目整合开发状态: Preclinical
项目研究机构: Meiji Dairies (Originator)
合成路线:Monoacetylation of 11b,17a-dihydroxy-4-pregnen-3,20-dione (I) at position 11 with acetic anhydride and pyridine provided acetate (II).Ketalization of both ketonic groups with ethylene glycol was accompanied by doble bond migration to position 5 to give (III),which was then converted to epoxide (IV) on treatment with m-chloroperbenzoic acid.Grignard reaction of epoxide (IV) with methylmagnesium bromide gave the 5a-hydroxy-6b-methylpregnene (V) with concomitant cleavage of the acetyl group.Smooth ketal hydrolysis with potassium bisulfate in aqueous acetone provided diketone (VI) without dehydration of the 11b-hydroxy group,and further treatment with NaOH in aqueous methanol effected crotonization of 5b-hydroxyl to the unsaturated ketone (VII).Reaction with 70% hydrogen fluoride in pyridine provided the 9a-fluorinated compound (VIII),together with some dehydrated product.A new sequence of ketalization with ethylene glycol and further hydrolysis of the resulting ketal (IX) produced epimerization of the 6-methyl group.The resulting compound (X) was finally acetylated by the mixed anhydride method by treatment with acetic acid and trifluoroacetic anhydride.
📌 参考资料/链接：
参考文献标题:Novel progesterone cpd.and use thereof
文献作者:Hibino,S.; Sugino,E.; Kohno,T.; Fujimori,S.; Ichihara,Y.; Sato,Y.; Nemoto,H.(Meiji Milk Products Co.,Ltd.)
参考来源:EP 0754701; US 5693629; WO 9526974
📄 详细内容
合成路线:Monoacetylation of 11b,17a-dihydroxy-4-pregnen-3,20-dione (I) at position 11 with acetic anhydride and pyridine provided acetate (II).Ketalization of both ketonic groups with ethylene glycol was accompanied by doble bond migration to position 5 to give (III),which was then converted to epoxide (IV) on treatment with m-chloroperbenzoic acid.Grignard reaction of epoxide (IV) with methylmagnesium bromide gave the 5a-hydroxy-6b-methylpregnene (V) with concomitant cleavage of the acetyl group.Smooth ketal hydrolysis with potassium bisulfate in aqueous acetone provided diketone (VI) without dehydration of the 11b-hydroxy group,and further treatment with NaOH in aqueous methanol effected crotonization of 5b-hydroxyl to the unsaturated ketone (VII).Reaction with 70% hydrogen fluoride in pyridine provided the 9a-fluorinated compound (VIII),together with some dehydrated product.A new sequence of ketalization with ethylene glycol and further hydrolysis of the resulting ketal (IX) produced epimerization of the 6-methyl group.The resulting compound (X) was finally acetylated by the mixed anhydride method by treatment with acetic acid and trifluoroacetic anhydride.
参考文献标题:Synthesis of a new potent anti-angiogenic agent,17alpha-acetoxy-9alpha-fluoro-6alpha-methylprogesterone (9alpha-fluoromedroxyprogesterone acetate [FMPA])
文献作者:Sugino,E.; Fujimori,S.; Hibino,S.; Choshi,T.; Ichihara,Y.; Sato,Y.; Yamaji,T.; Tsuboi,H.; Murata,N.; Uchida,M.; Shimamura,M.; Oikawa,T.
参考来源:Chem Pharm Bull 1997,45(2),421