N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, sertraline imine (3), is an intermediate for the
synthesis of Zoloft, sertraline hydrochloride (1). A cleaner,
simpler, and more efficient alternative to the Schiff base-mediated formation of sertraline imine has been developed and
is presented in this paper. The condensation reaction between
4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalone, sertraline tetralone (2), and monomethylamine was carried out in
ethanol, without the need for classical dehydrating agent, such
as TiCl4, or more novel approaches, such as molecular sieves,
both of which produce hazardous byproducts and solid wastes.
The low solubility of the imine 3 in this type of solvent is
exploited, such that the reaction equilibrium favorably enhances
the imine formation. Furthermore, an improved and highly
selective catalytic reduction of 3 with Pd/CaCO3 catalyst in
ethanol as the reaction solvent, followed by the resolution of
the racemic cis isomer (6) with d-(−)-mandelic acid results in
a more efficient telescoped commercial process to (1S-cis)-4-(3,4-dichlorophenol)-1,2,3,4-tetrahydro-N-methyl-1-naphthalen-amine mandelate, sertraline mandelate (4). This new process
has been implemented commercially and eliminates the use of
hazardous material such as TiCl4, significantly reduces undesirable byproducts, reduces the number of intermediate isolations,
and improves the overall process yield and productivity on
industrial scale.