Improved Industrial Synthesis of Antidepressant Sertraline

Abstract

cis-1S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1naphthalenamine hydrochloride, or sertraline hydrochloride, is a very effective antidepressant. This report presents a novel industrial synthesis of sertraline hydrochloride that is in many respects more advantageous than processes reported thus far. N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-methanamine N-oxide is used as intermediate in our process, which is a stable compound in normal conditions. It can be obtained in a simple reaction from the corresponding tetralone in good yield, using acceptable reagents with regard to environmental and safety respects. Its reduction to the desired cisracemic amine is stereoselective, and thus it provides sertraline hydrochloride with a purity required for pharmaceutical ingredients.

Reductive Cross‐Coupling of Conjugated Arylalkenes and Aryl Bromides with Hydrosilanes by Cooperative Palladium/Copper Catalysis

“…[3] Cross-coupling reactions of aryl halides with 1-arylalkyl metal species represent ac onvenient method to prepare 1,1-diarylalkanes, [4] which are often found in biologically active compounds. [5] 1-Arylalkylmetal reagents such as organoboron and organosilicon compounds are conventionally prepared by the transition metal catalyzed hydrometallation of styrenes. [6] Ther esulting 1-arylalkylmetal reagents are subsequently purified and used for the cross-coupling with aryl halides.…”

EnantioselectiveLCanalysis and determination of selective serotonin reuptake inhibitors

“…The approach of diastereomeric salt formation with ( R )‐MA was also successfully used to separate (Vukics, Fodor, Fischer, Fellegvári, & Lévai, ) racemate [ cis ‐( 1S , 4S )‐, cis ‐( 1R , 4R )‐sertraline], which was obtained in a step to synthesize a biologically active (1 S ,4 S )‐enantiomer of sertraline via catalytic conversion of tetralone; the method of synthesis is patented (Vukics, Fodor, Fischer, Fellegvari, & Lévai, ). The racemate was selectively crystallized and separated to produce the ( R )‐(−)‐MA salt of sertraline that provided sertraline hydrochloride with a purity required for pharmaceutical ingredients.…”

Stereoselective separation of (1S, 4S)‐sertraline from medicinal reaction mixtures by countercurrent chromatography with hydroxypropyl‐β‐cyclodextrin as stereoselective selector

“…The conventional method for separation of cis ‐isomers and trans ‐isomers and enantioseparation of ( 1S, 4S )‐sertraline from cis ‐isomers was diastereoisomeric recrystallization using D‐mandelic acid as stereoselective selector . However, it was difficult to obtain stereoisomeric ( 1S, 4S )‐sertraline with high optical purity.…”