Study On The Synthetic Process Of Maropitant Citrate

Maropitant citrate,a new antiemetic durg,is an antagonist that acts on Type 1neurokinin（NK₁）receptors,acting on central nervous system by inhibiting the key neurotransmitter P that is associated with vomiting,prevention and treatment of acute vomiting.As a special drug for the treatment of vomiting,Maropitant citrate has the advantages of rapid absorption,wide distribution,short peak time,high bioavailability,long elimination half-life,long efficacy and high safety.In this paper,the synthesis of Maropitant citrate was studied.Through the study and optimization of the synthetic process,a synthetic route suitable for industrial production was determined.By analyzing and comparing related literatures about the synthesis of Maropitant citrate,the optimum synthesis conditions were determined and the high quality of Maropitant citrate was obtained.The route has the advantages of simple operation,low production cost and can realize industrialized production.The corresponding imines were prepared by nucleophilic addition reaction of（2S,3S）-2-diphenylquinine-3-amine with 5-tert-butyl-2-methoxybenzaldehyde.The crude product was reduced by Na BH（OAc）₃ and purified by L-camphorsulfonic acid,and then forming salt with citric acid to prepare Maropitant citrate.The total yield was 59.67%.The preparation of（2S,3S）-2-diphenylmethylquinine-3-amine was based on 3-quino-ne hydrochloride as raw material and underwent aldol condensation reaction with benza-ldehyde.And then react with phenylmagnesium bromide catalyzed by Cu Br·（CH₃）₂S to prepare 2-benzylmethylquinone and treat with L-tartaric acid for configuration transformation to obtain（S）-benzylquinone.Then（S）-diphenylquinidine benzimine was prepared with benzylamine in the presence of isopropyl titanate.The key raw material（2S,3S）-2-diphenylmethyl quinine-3-amine for the synthesis of Maropitant citrate was prepare-d by catalytic hydrogenation of（S）-diphenylquinine benzylamine and thermodynamic resolution of L-camphorsulfonic acid,and then catalytic hydrogenation deprotection again.The total yield of the key raw materials for the synthesis of Maropitant citrate was33.53%.The structures of the intermediates and the target compounds were confirmed by¹H-NMR and HPLC.