Studies On Synthetic Route And Isomer Analysis Method For Sertraline Hydrochloride

Depression is a common dysthymic disorder with a feature of persistent low mood or sadness, resulting in loss of interest in daily activities, low in spirits, and loss of appetite. Depression is characterized by high morbidity, high recurrence, high disability and high medical cost,and has huge negative impact on society. Sertraline hydrochloride, a selective 5-hydroxy tryptamine re-uptake inhibitor, has been widely used for the treatment of depression and obsessive-compulsive disorder. It can boost physical activity and effectively alleviate depression. Therefore, it has substantial theoretical and practical value to develop novel synthetic and analytical method for sertraline hydrochloride. This thesis is mainly focused on the following studies.1. A synthetic route to sertraline hydrochloride was described. The starting material α-naphthol was reacted with 1,2-dichloride benzene by using aluminum chloride as catalyst. The formed ketone was condensed with methyl amine followed by reduction with sodium borohydride to afford racemic sertraline. Following chemical resolution, optically-puresertraline hydrochloride was afforded with an overall yield of 32%, a final purity and enantiomeric excess(ee) of greater than 99%. Effects of different reagents, catalytic system, reaction time and raw ratio on the yield of sertraline were evaluated. The optimized synthetic route reduced the use of expensive raw materials and toxic reagents, and was easier to handle and more suitable for commercial large-scale production.2. A separation and analytical method for(1R, 4S)-sertraline hydrochloride and its(1R, 4R)-,(1S, 4R), and(1R, 4S)-isomers were described. High-performance liquid chromatography(HPLC) was used to separate and quantitate sertraline hydrochloride and its three isomers. The stationary and mobile phase were amylose-tri(3,5-dimethylphenyl carbamate)(AD-H) and n-hexane-ethanol-diethylamine(80:20:0.2),respectively. The flow rate for the analysis was 0.6mL/min, elution was monitored at 223 nm, and the column temperature was set at 25℃.This new method can separate the three isomers and is superior to the EP and USP method in terms of simplicity, scientificity and accuracy.Overall, this thesis described a new synthetic route and quality control strategy for sertraline hydrochloride, and provided solid foundation for its further industrialization.