R-59274, CS-570

Chemical Name: 17(R)-Methyl-20-isopropylidenecarbacyclin sodium salt
项目整合开发状态: Clinical
项目研究机构: Sankyo (Originator)
合成路线:The decarboxylative hydrolysis ot 2beta,4alpha-di(methoxycarbonyl)-3alpha-(3-phenylpropyl)cyclopentanone (I) with HCl in refluxing acetic acid gives 3alpha-(3-phenylpropyl)cyclopentanone-4alpha-carboxylic acid methyl ester (II),which by successive reactions with oxalyl chloride in refluxing benzene,with diazomethane in ether,and with silver benzoate and triethylamine in methanol,is converted to 3alpha-(3-phenylpropyl)cyclopentanone-4alpha-acetic acid methyl ester (III).The dehydrogenation of (III) by reaction with N-bromosuccinimide and sodium selenobenzene in benzene and THF affords 3alpha-(3-phenyl-2-propenyl)cyclopentanone-4alpha-acetic acid methyl ester (IV),which is oxidized with sodium methaperiodate and Jones reagent,and methylated with diazomethane to give cyclopentanone 3alpha,4alpha-di(acetic acid) dimethyl ester (V).The reaction of (V) with ethyl eneglycol and p-toluenesulfonic acid yields the corresponding ketal (VI),which is submitted to a cyclization with sodium methoxide in hot methanol - DMSO to afford 7,7-ethylenedioxybicyclo[3.3.0] octan-3-one-4beta-carboxylic acid methyl ester (VII).The reduction of (VII) with NaBH4 in methanol gives the corresponding hydroxyester (VIII),which is protected with dihydropyran and p-toluenesulfonic acid to the corresponding tetrahydropyranyloxy compound (IX).The reduction of (IX) with LiAlH4 in ether affords the methanol derivative (X),which is oxidized with CrO3 - pyridine to the aldehyde (XI).The Wittig condensation of (XI) with dimethyl 2-oxo-4R,8-dimethyl-7-nonenylphosphonate (XII) by means of NaH in THF affords the dienic ketone (XIII).

合成路线:Ketone (XIII) is reduced with NaBH4 to the dienic alcohol (XIV).The hydrolysis of (XIV) with HCl in aqueous acetone gives the dihydroxyketone (XV),which is treated with dihydropyran and p-toluenesulfonic acid to afford the bistetrahydropyranyloxy derivative (XVI).The Wittig condensation of ketone (XVI) with 4-(methoxycarbonylbutyl)triphenylphosphonium bromide (XVII) by means of NaH in DMSO affords the protected carbacyclin (XVIII),which is deprotected with acetic acid in THF water yielding 17R-methyl-20-isopropylidenecarbacyclin methyl ester (XIX).Finally,this compound is saponified with KOH in aqueous methanol.