消旋17-苯-18,19,20-失三碳前列腺素F2α甲酯及其15-差向异构体的合成

从中间体(4)出发,经醛(5),与鏻叶立德(3)或2-酮-4-苯丁烷磷酸酯(11)钠缩合成(6),再钠硼氢还原得3′α-醇(7A)及其差向异构体(7B),经硅胶柱色谱分开,分别经二异丁基铝氢还原,与溴化5-三苯鏻戊酸之Wittig试剂缩合,得17-苯-18,19,20-失三碳前列腺素F_2α(9A)及其15-差向异构体(9B),再用重氮甲烷甲酯化,分别得相应的17-苯-18,19,20-失三碳前列腺素F_2α甲酯(10A)及其15-差向异构体(10B)。

SYNTHESISOF dI-17-PHENYL-18, 19, 20-TRINORPROSTAGLANDIN F2α METHYL ESTER AND ITS 15-EPIMER

d,1-17,Phenyl-18,19,20-trinorprostaglandin (PG) F_2α methyl ester (10A) and its 15-epimer (10B) were synthesized in an attempt to develop new PG congeners with better bioselectivities and higher potency in terminating pregnancy. Wittig-Horner reaction of aldehyde (6) with the ylide (3) of 4-phenyl-2-oxo-n-butyl-triphenylphosphonium bromide gave 42% yield of 1' 2'-unsaturated 3'-ketone (6). Reduction of (6) with sodium borohydride in absolute methanol at —3℃ yielded a mixture of epimers, 3'α-alcohol (7A) and 3' β-alcohol (7B), which were separated by column chromatography on silica gel with diethyl ether as eluent to yield 42% (TA) and 36% (7B) respectively. Treatment of (7A) with an excess of di-isobutylaluminium hydride in ethylene glycol dimethylether and diethyl ether under nitrogen at —78℃ afforded the intermediate lactol (SA) as colorless semisolid in 80% yield. Subjected to Wittig condensation with a 5-fold excess of Wittig reagent generated in situ from 4-carboxybutyl triphenylphosphonium bromide and dimsyl sodium in dimethylsulfoxide, (8A)was transformed to d, 1-17-phenyl-18, 19, 20-trinor PGF_2α (9A)in yields of about 77%. Methylation of (gA) with ethereal diazomethane yielded the corresponding methyl ester (10A). By similar transformations,d,1-15-epi-17-phenyl-18, 19, 20-trinor PGF_2α methyl ester (10B) was obtained through intermediates (SB) and (9B).Preliminary bioassays showed that (9A) exhibited activities more potent than that of d,1-15-methyl PGF_2α methyl ester in terminating early pregnancy in mice.