Study On The Synthesis For Key Intermidates Of Vorapaxar

Vorapaxar,a kind of antiplatelet agents,is a new thrombin receptor antagonist.It was developed by Merck company and approved for marketing by America FDA in May 2014,mainly used for patients suffering from a heart attack or clogged leg arteries to reduce further heart attack,stroke,cardiovascular death risk.Vorapaxar is currently the world's most advanced thrombin receptor antagonists,but the clinical trials found it carries some risks of bleeding.Therefore,there is still much space to optimize Vorapaxar in simplification of chemical structure,improvement of antithrombotic efficacy and reduction or elimination of the side effects of bleeding.Vorapaxar is complex with seven chiral centers and synthetic route of up to ten steps to cause high cost for optimization of it.Whereas compound A15 is a key intermediate of Vorapaxar,it has a significance to optimize synthetic routes of compound A15 for Vorapaxar.Based on study on reported synthetic routes of Vorapaxar with our novel design,three synthetic routes were attempted to synthesize the target compound in this paper.Acrolein and R-3-butyn-2-ol were used as raw material via hydroxy protection and deprotection,terminal alkyne C-C coupling,Michael addition reaction,aldol condensation,esterification,Lindlar catalytic hydrogenation,Diels-Alder reaction,hydrogenation and a series of reactions to make the target compound.The main difference is the protecting group which was used to construct carbonyl in the terminal of alkyne,and protecting group is directly related to both yield of subsequent reaction and isomer separation.Finally,the target compounds were synthesized by synthetic route a(benzyloxycarbonyl).By contrast,synthetic route b(t-butoxycarbonyl)as a new synthetic route showed the yield of each step is relatively high but the isomers cannot be separated.The yield of scheme c(diphenylamine formyl)reported from patent is relatively high but the reduction of nitro group and olefinic bond were unsatisfied.Ultimately,the target compound A15 was made by synthetic route a with total yield 5.4%.Meanwhile,the paper also explored and optimized both reaction and work-up conditions with different substrates.The yield for synthesis of compound A9 was improved from 30%to 75%after optimizing both reaction and work-up conditions.All chemical structure of intermediates were confirmed by 1H-NMR and MS.The structure of target compound was confirmed by 1H NMR,13C NMR,DEPT,COSY,HSQC,HMBC,NOESY,MS.