Study On The Synthesis Of Antithrombotic Agent Vorapaxar Sulfate And Intermediates

Vorapaxar Sulfate is a derivative from natural products and an antithrombotic drug for the treatment of coronary artery disease(CAD), which was approved in United States on the May of 2014.In this thesis, a scalable process of synthesizing Vorapaxar Sulfate was developed via a 7-steps route starting from(E)-(R,Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl-3-(5-nitrocyclohex-1-en-1-yl)acrylate(2) and diethyl((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate(8). Intermediate 2 was synthesized via 3-steps reactions from(E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid(27) and(R)-4-hydroxy-N,N-diphenylpent-2-ynamide(29).The synthesis processes of intermediates 27, 29, 2 and 8 were carefully studied and the main synthetic route had been explored, which support a solid base to the application of new drug registration to CFDA of Vorapaxar Sulfate.The specific works on this thesis are as follows:1. Synthesis of intermediate 2727 was synthesized from nitromethane and acraldehyde(32) through nucleophilic addition, acetalization, hydrolization, aldol condensation and Knoevenagel reaction. The chemical purity of 27 was up to 99.1%, total yield of this synthetic route was about 21.0%.2. The synthesis of intermediate 29(R)-butyl-3-yn-2-ol(41) was successfully synthesized from butyl-3-yn-2-ol(51) by chemical resolution with 4 steps. Total yield of this synthetic route is about 28.4%, the GC purity of 41 is up to 91.6%. 29 was successfully prepared via 7 steps starting from 41 by silylanization, Li-H exchange,and nucleophilic substitution. Total yield of this synthetic route is about 18.5%. During the preparation of 29, pipe-reactor was substituted by tank reactor, the cost was cut down and the yield was stable.3. The synthesis of intermediate 22 was successfully synthesized from compounds 27 and 29, the order of lindlar reduction and esterification was carefully studied, via nucleophilic substitution, lindlar reduction, and esterification, total yield of the process was 72.0%.The reaction condition of lindlar reduction was strictly followed by the patent. This reaction was substituted by hydrogenation under normal pressure. The purity of 2 was increased by the screening of catalyst, reaction temperature and time. Total yield of 3 steps was higher than results that were reported by the patent.4. The synthesis of intermediate 8The key intermediate 8 was synthesized via 7 steps starting from 44. The chemical purities of 8 was up to 99.6%, total yield of this synthetic route was about 6.1%.5. The main route exploration of Vorapaxar SulfateEthyl-(9-(diphenylcarbamoyl)-1-methyl-3-oxododecahydronaphtho [2,3-c]furan-6-yl)carbomate(5-7) was synthesized by intramolecular Diels-Alder reaction, reduction, nucleophilic substitution starting from(E)-(Z)-5-(diphenylamino)-5-oxopent-3-en-2-yl 3-(5-nitrocyclohex-1-en-1-yl)acrylate(2-7). The reaction condition was optimized, the double bond was reduced by new method, the side reaction of amide bound fracture was avoided by the adjustment of alkaline solution.Synthesis and processes optimizations of Vorapaxar Sulfate and its key intermediates 2, 8, 27 and 29 had been completed, the main route was explored and the primary HPLC analysis and quality control method were set up in this thesis. The quality of intermediates was stable starting from cheap materials by the optimized process which has the potential to be industrialized on large scale.