【药物名称】FMPA
化学结构式(Chemical Structure):
参考文献No.28092
标题:Novel progesterone cpd. and use thereof
作者:Hibino, S.; Sugino, E.; Kohno, T.; Fujimori, S.; Ichihara, Y.; Sato, Y.; Nemoto, H. (Meiji Milk Products Co., Ltd.)
来源:EP 0754701; US 5693629; WO 9526974
合成路线图解说明:

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No.409759
标题:Synthesis of a new potent anti-angiogenic agent, 17alpha-acetoxy-9alpha-fluoro-6alpha-methylprogesterone (9alpha-fluoromedroxyprogesterone acetate [FMPA])
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.
来源:Chem Pharm Bull 1997,45(2),421
合成路线图解说明:

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.

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