Study On The Process For The Preparation Of Ticagrelor

Ticagrelor is highly selective and novel small molecular anticoagulant with particular pharmacological effects and broad market prospects.As the key intermediate,(1S,2R,3S,4R)-2,3-O-isopropylidene-4-aminocyclopentane-1,2,3-triol contains four chiral centers.The reported synthetic methods in the literature generally have some problems,such as low yield,the use of highly toxic substances,industrial production difficulties and so on.So the synthesis of(1S,2R,3S,4R)-2,3-O-isopropylidene-4-aminocyclopentane-1,2,3-triol is mainly studied in this paper.The synthetic route using D-alanine as raw materials was determined and optimized,and the synthesis of ticagrelor was completed.By analyzing the synthetic route of(1S,2R,3S,4R)-2,3-O-isopropylidene-4-aminocyclopentane-1,2,3-triol,we decided to use D-alanine as raw material.We designed a new route for the preparation of hydroxamic acid with D-alanine as raw material,followed by carboxyl esterification and ester hydroxylamine with the 90% yield in two steps;in the oxidation of hydroxamic acid and Diels-Alder addition,we chose Swern oxidized hydroxamic acid and Diels-Alder ring addition "one pot" reaction with the Lewis acid catalyst,and the target product was obtained in 91% yield with 20:1 dr;using cheap and low toxicity of potassium permanganate instead of highly toxic osmium tetroxide,the aimed product was obtained in 85% yield.The total yield was 65%,which was higher than the literature reported,and the intermediates were easy to purify.Based on the optimization of the synthesis of the key intermediates(1S,2R,3S,4R)-2,3-O-isopropylidene-4-aminocyclopentane-1,2,3-triol,the reaction conditions were studied,such as nucleophilic substitution and diazotized ring.Compared with the original process,this synthetic route has following advantages such as using cheap raw material,easy to purify the intermediate,simple reaction conditions,high yield,low cost and so on.