Resesrch On The Synthesis Method Of Xaliproden Hydrochloride

Xaliproden hydrochloride (1-[2-(2-naphthy)ethy]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride), is a kind of typical drug consisting of three fluorine. Xaliproden hydrochloride is mainly used to treat Amyotrophic Lateral Sclerosis(ALS), Phasa Ⅲ clinical has finished and gained the rare medicine qualification. In addition to treat ALS, the drug can also be used to treat Alzheimer’s disease(AD), which is at phase Ⅲ clinical now. The drug can be potentially used in treatment of oher neighboring neurological diseases. Xaliproden hydrochloride is a new oral drug that does not produce immunosuppression effect.On the basis of analyzing numbers of internal and international relative literatures, we have optimized and improved the synthetic process of Xaliproden hydrochloride in order to achieve the lowest cost, the highest yield and simplify operation. In this paper, we have studied two efficient synthetic methods of Xaliproden hydrochloride(14) with2-naphthlcetic acid(1) and4-paperidone monohydrate hydrochloride(5) as staring materials.(1) Chlorination-protecttion method1-[2-(2-naphthalenyl)ethyl]-4-piperidine ketone(8) was synthesized via5-step reactions from starting material by reduction, chlorination, nucleophilic addition reaction, nucleophile substitution reaction, deprotection, and Xaliproden hydrochloride(14) was synthesized from (8) by nucleophilic addition reaction, elimination and so on. The synthetic procedure was optimized and the target coupmoud was prepared via7-step reactions in total yield of28.3%. The entire processing condition was simple and low cost. (2) Iodization-docking method1-[2-(2-naphthalenyl)ethyl]-4-piperidine ketone(8) was synthesized via3-step reactions from starting material by reduction, iodization, nucleophile substitution reaction, and Xaliproden hydrochloride was synthesized from (8) by nucleophilic addition reaction, elimination and so on. The synthetic procedure was optimized and the target coupmoud was prepared via5-step reactions in total yield of52.6%. The whole process was warm in moderation and the yield was high.In consideration of the raw material cost, yield, experimental operation and degree of harm to the environment, Iodization-docking method is suitable for industrial production.The intermediates and the desired product that we have synthesized were characterized by LC-MS,GC-MS, IR and1H NMR. The research on the synthesis of xaliproden hydrochloride, has practical applications, and is a available for industrialized production. At the same time, The intermediate1-[2-(2-naphthalenyl)ethyl]-4-ketone was not reported before, and it has important significance in the theory and applied research.