Study On The Chiral Synthesis Of The Anti-alzheimer Disease Medicine Encenicline Hydrochloride

Alzheimer disease,referred to as AD,is a neurodegenerative disease with a hidden onset.Its incidence in the elderly is gradually increasing.It has been the fifth death factor of America,and has a bad influence on the quality of life of patients and also burdens the ralations and society with problems.The etiology of Alzheimer disease is unknown.The cholinergic hypothesis is the most prevalent.The cholinergic pharmaceutics can improve the cognitive function by increasing the amount of acetylcholine through several ways.Thus they can be used to treat Alzheimer disease.Encenicline hydrochloride,R-7-chloro-N-(quinuclidin-3-yl)benzo[b]thi-ophene-2-carboxamide hydrochloride,is a novel and selective a7 nicotinic receptor agonist(nAChRs).It penetrates the blood-brain barrier and then acts as a co-agonist with acetylcholine(ACh)to enhance cognition in patients.Encenicline hydrochloride is a very potential drug no matter in monotherapy or combination therapy of Alzheimer disease.Objective:To establish the preparation and analysis methods for Encenicline hydrochloride.Methods:The synthetic route of Encenicline hydrochloride is settled by accessing to the relevant literatures and experiment design.We took 3-quinuclidinone hydrochloride(2)as the starting material reacting with the NaOH(aq)to give the free 3-quinuclidinone(3).N-(R-l-phenylethyl)-3-quinu-clidinimine(4)was synthesized by the condensation reaction of compound 3 and the chiral auxiliary S-1-phenethylamine.The compound 4 was reduced by sodium borohydride by the asymmetric reaction to give diastereoisomer 3S-3-[R-(1-phenyl)ethylamino]-quinuclidine dihydrochloride(5).The key intermediate R-3-aminoquinuclidine dihydrochloride(6)was synthesized by the hydrogenation of the compound 5 in the presence of 10%Pd/C catalyst.2,3-Dichlorobenzaldehyde(7)was used as another starting material reacting with 2-mercaptoacetic acid by the nucleophilic substitution reaction to give the key intermediate 7-chlorobenzo[b]thiophene-2-carboxylic acid(8).7-Chlorobenzo[b]thiophene-2-carbonyl chloride(9)was synthesized by comp-ound 8 and SOCl2.Finally,the targeted compound Encenicline hydrochloride was achieved from the compound R-6 and 9 by an ammonolysis reaction.The overall yield was 53.1%starting with the compound 2.The methods of mass spectrometry,nuclear magnetic resonance and melting point measurement were used to conform the intermediates and the targeted product Encenicline hydrochloride.Two HPLC methods were inspected and established respectively for the determination of the optical purity and chemical purity of Encenicline hydrochloride.Results:The targeted compound Encenicline hydrochloride was successfully synthesized in an optically pure form,which is an off-white solid.Through optimizing some of the synthetic methods,their yields were improved.The overall yield was 53.1%starting with the compound 2.Some of the intermediates and the targeted product Encenicline hydrochloride were conformed by the mass spectrometry,nuclear magnetic resonance and melting point measurement.Two HPLC methods were settled respectively for the determination of the Encenicline hydrochloride:the ee is 100%and the chemical purity is 99.972%.Conclusions:Encenicline hydrochloride was successfully prepared in optically pure forms from the inexpensive starting materials,including 3-quinuclidinone hydrochloride and 2,3-dichlorobenzaldehyde by seven steps.The operations of the methods were convenient and easily controlled,the generation cycle was short,the cost was low and the overall yield is high.Over the process,environmental unfriendly reagents were avoided.Two HPLC methods were established respectively for the determination of the optical purity and chemical purity of Encenicline hydrochloride.The system suitability and sensitivity of the method is high,which made it a proper method to analyze Encenicline hydrochloride.The results indicated that the purity of Encenicline hydrochloride is high enough to be used as a pharmaceutical ingredient.