Limaprost alfadex, Limaprost alpha-cyclodextrin, OP-1206.alpha-CD, Ono-1206.alpha-CD, Prorenal, Opalmon

合成路线:The reaction of sec-butyl crotonate (I) with butylmagnesium bromide (II) by means of Cu2Cl2 in refluxing ether gives sec-butyl 3-methylheptanoate (III),wich is condensed with dimethyl methylphosphonate (IV) by means of butyllithium in THF at -70 C to afford dimethyl 2-oxo-4-methylphosphonate (V).The Wittig condensation of (V) with 1alpha-acetoxy-2alpha-(6-methoxycarbonylhexyl)-3beta-formyl-4alpha(tetrahydropyranyloxy)cyclopentane (VI) by means of NaH inTHF yields methyl 9alpha-acetoxy-11alpha-(tetrahydropyranyloxy)-15-oxo-17,20-dimethylprost-trans-13-enoate (VII),which is reduced with NaBH4 in methanol to the 15-hydroxy compound (VIII).Selective hydrolysis of (VIII) with p-toluenesufonic acid in methanol gives the 11,15-dihydroxy derivate (IX),which is then treated with dihydropyran and p-toluenesulfonic acid in methylene chloride to afford the bis-tetrahydropyranyloxy compound (X).The reactin of (X) with diphenydiselenide (XI) by means of butyllithium and diisopropylamine in THF at -70?affords the 2-phenylseleno compound (XII),which by treatment with H2O2 and NaHCO3 in ethyl acetate - THF is converted into methyl 9alpha-hidroxy-11alpha,15lpha-bis(tetrahydropyranyloxy)-17S,20-dimethylprosta-trans-2,trans-13-dienoate (XIII).The hydrolysis of (XIII) with KOH in ethanol gives the corresponding free acid (XIV),which is oxidized with CrO3 - H2SO4 - MnSO4 in water - ether to afford 9-oxo-11alpha,15alpha-bis(tetrahydropyranyloxy)-17S,20-dimethylprosta-trans-2,trans-13-dienoic acid (XV).Finally this compound is deprotected by treatment with hot aqueous acetic acid.

参考文献标题:
文献作者:Hayashi,M.; Kori,S.Kori,S.; Ohyama,I.; Iguchi,S.; Okada,T.(Ono Pharmaceutical Co.,Ltd.)
参考来源:GB 1545213


合成路线:The reaction of sec-butyl crotonate (I) with butylmagnesium bromide (II) by means of Cu2Cl2 in refluxing ether gives sec-butyl 3-methylheptanoate (III),wich is condensed with dimethyl methylphosphonate (IV) by means of butyllithium in THF at -70 C to afford dimethyl 2-oxo-4-methylphosphonate (V).The Wittig condensation of (V) with 1alpha-acetoxy-2alpha-(6-methoxycarbonylhexyl)-3beta-formyl-4alpha(tetrahydropyranyloxy)cyclopentane (VI) by means of NaH inTHF yields methyl 9alpha-acetoxy-11alpha-(tetrahydropyranyloxy)-15-oxo-17,20-dimethylprost-trans-13-enoate (VII),which is reduced with NaBH4 in methanol to the 15-hydroxy compound (VIII).Selective hydrolysis of (VIII) with p-toluenesufonic acid in methanol gives the 11,15-dihydroxy derivate (IX),which is then treated with dihydropyran and p-toluenesulfonic acid in methylene chloride to afford the bis-tetrahydropyranyloxy compound (X).The reactin of (X) with diphenydiselenide (XI) by means of butyllithium and diisopropylamine in THF at -70?affords the 2-phenylseleno compound (XII),which by treatment with H2O2 and NaHCO3 in ethyl acetate - THF is converted into methyl 9alpha-hidroxy-11alpha,15lpha-bis(tetrahydropyranyloxy)-17S,20-dimethylprosta-trans-2,trans-13-dienoate (XIII).The hydrolysis of (XIII) with KOH in ethanol gives the corresponding free acid (XIV),which is oxidized with CrO3 - H2SO4 - MnSO4 in water - ether to afford 9-oxo-11alpha,15alpha-bis(tetrahydropyranyloxy)-17S,20-dimethylprosta-trans-2,trans-13-dienoic acid (XV).Finally this compound is deprotected by treatment with hot aqueous acetic acid.
参考文献标题:
文献作者:Hayashi,M.; Iguchi,S.; Okada,T.(Ono Pharmaceutical Co.,Ltd.)
参考来源:DE 3002677DE 3002677; FR 2447375; GB 2041368; JP 80100360


产品链接: CAS No. 88852-12-4››

产品链接: CAS No.74397-12-9››