Studies On The Process Of The Key Intermediates Of Ledipavir

Ledipasvir is a kind of drug for the treatment of hepatitis C with an excellent therapeutic effect and small by-effects.(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-benzimidazole-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxyl ic acid tert-butyl ester is a key intermediate for the synthesis of Ledipasvir with three chiral centers.At present,chiral synthesis was used to construct its chiral center,but the yield and stereoselectivity of the target product were low because of the byproducts.Therefore,studying and optimizing the synthetic process of this key intermediate is greatly important to the production of Ledipasvir.In this paper,ethyl benzoate and R-(+)-phenylethylamine were used as raw materials through condensation reaction,aza-Diels-Alder reaction,hydrolysis reaction and cyclization to give(1R,3S,4S)-3-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-benzimidazole-2-yl]-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester.We studied the effects on the yield and stereoselectivity of the aza-Diels-Alder reaction by texting the reaction temperature,solvent and Lewis acid,and found a new aryl boron difluoride Lewis acid.With the new Lewis acid in hand,we optimized the reaction conditions to afford a yield up to 70%.The selectivity of the aimed product was up to 90.2%.The best reaction conditions were determined by the detailed optimization of hydrogenation reaction,hydrolysis reaction,condensation reaction,cyclization reaction and substitution reaction.The total yield of Ledipasvir reached 39%,which was 8% higher than that reported in the literature.Compared with the original process,this synthetic route has some advantages of low production costs,simple process conditions,fewer by-products,easy to industrial production,etc.