Corey Inner Fat Glycol Synthesis Process Improvement And Its Application In The Synthesis Of Other Drugs

Prostaglandin is an important class of multiple bioactive endogenous natural products. Theyhave certain effects on the respiratory system, gastrointestinal tract, cardiovascular system andplatelet aggregation. They also have anti-virus, hypnotic, anti-inflammatory and anti-tumoractivities. As a natural endogenous product, the toxicity of PGs in the human body is relativelysmall and small doses of them can introduce a variety of physiological effects. Therefore, theyhave attracted an enormous amount of interest in the the areas of chemistry, medicine, pharmacyand biology. Chemical synthesis of them is very significant as the natural sources ofprostaglandins are rare. As commonly used intermediates for the synthesis of various types ofPGs, Corey lactone diol and its derivatives also have important research value. In this paper, wepay much attention on the synthesis of Corey lactone diol, and we also investigate the synthesisof lubiprostone and latanoprost. The paper mainly includes:1. Using dicyclopentadiene as the starting material, Corey lactone diol,(1S,5R,6S,7R)-7-hydroxy-6-hydroxymethyl-2-oxabicyclo[3.3.0]octan-3-one, was synthesized by a series ofreactions of depolymerization, cyclization, dechlorination, enantiomeric separation, oxidation,Prins reaction and hydrolysis. The total yield of the entire synthetic route reaches up to12.1%.2. With2,5-norbornadiene as the starting material, Corey lactone diol was producedthrough Prins reaction, Jones oxidation, addition, oxidation, hydrolysis, enantiomeric separation,esterification and reduction. The total yield of this synthetic route is only3.65%. If thecompound6-carboxy-7-hydroxy-2-oxabicyclo[3.3.0]octan-3-ketone (14) was prepared fromthe compounds12with one-pot cooking method, the total yield of the synthetic route can beincreased to6.42%. 3. Two of pharmaceutical intermediates,(1S,5R,6R,7R)-6-(1-en-3-oxooctyl)-7-ben-zyloxymethoxy-2-oxabicyclo[3.3.0]oct-3-one (23) and (1S,5R,6R,7R)-6-(1-en-4,4-difluoro-3-oxooctyl)-7–benzyloxymethoxy-2-oxabicyclo[3.3.0]octan-3-one (24), were synthesized fromCorey lactone diol as the starting compound via five steps by TBDMSCl protecting the primaryhydroxyl group, benzyl chloromethyl ether protecting the secondary hydroxyl, deprotection ofTBDMS, oxidation of primary hydroxyl and Wittig reaction. The total yield of compound24is22%and that of compound23is46.6%. 4. Using (1S,5R,6R,7R)-6-methoxyformyl-7-hydroxy-2-oxabicyclo[3.3.0]oct-3-ketone (16a)or (1S,5R,6R,7R)-6-carbethoxy-7-hydroxy-2-oxabicyclo[3.3.0]oct-3-ketone (16b) as startingmaterials, two intermediates for the synthesis of Latanoprost,(1S,5R,6R,7R)-3-hydroxy-6-(3-methoxymethoxy-4-benzylbutyl)-7-methoxymethoxy-2-oxabicyclo[3.3.0]octan-3-one (32a) and (1S,5R,6R,7R)-3-hydroxy-6-(3-tert-butyl dimethyl silicon oxy-4-benzylbutyl)-7-methoxymethoxy-2-oxabicyclo[3.3.0]oct-3-one (32b) were obtained by a seriesreactions of hydroxyl protection, reduction, oxidation, Wittig reaction, carbonyl reduction, olefinreduction, hydroxyl protection and carbonyl reduction. The total yields for the synthesis ofcompound32a and32b is6.82%and7.68%(from compounds16a).