Synthesis of 3,7‐Disubstituted Imipramines by Palladium‐Catalysed Amination/Cyclisation and Evaluation of Their Inhibition of Monoamine Transporters

Abstract

We describe a novel approach for the synthesis of a series of 3,7-difunctionalised symmetric and unsymmetrical analogues of the tricyclic antidepressant (TCA) imipramine, which uses a key palladium-catalysed amination/cyclisation of an ester-functionalised dibromide. Of the ester, methyl, hydroxymethyl and methoxymethyl disubstituted compounds prepared, 3,7-dimethyl-imipramine was found to be the most potent against the human serotonin transporter (hSERT). The inhibitory potency of 3,7-dimethyl imipramine was found to be at least as high as the parent imipramine. This novel TCA also exhibits an increased selectivity (relative to imipramine) in binding to hSERT versus the human norepinephrine transporter (hNET). Even higher selectivity could be obtained with 3,7-dihydroxymethyl imipramine, which was found to be 167-fold more selective for hSERT over hNET, representative of a 120-fold gain in selectivity relative to the parent imipramine. These results further validate our previous model for the binding of imipramine and high-affinity analogues of imipramine to the central binding site of hSERT.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…Building on Jørgensen’s method for the synthesis of phenothiazines ( 1 , Scheme 1 a), 58 Jensen and co-workers prepared a series of 3,7-disubstituted analogues of the tricyclic antidepressant imipramine (R = H) ( 6 , Scheme 2 a). 60 The dibenzazepines were generated in a one-pot procedure from bisaryl bromides 5 . The two N-arylation steps were enabled by a first-generation L17 palladium precatalyst with a weak base in t- BuOH.…”

Palladium‐Catalyzed Reaction of Aryl Iodides with ortho‐Bromoanilines and Norbornene/Norbornadiene: Unexpected Formation of Dibenzoazepine Derivatives

“…[5] Various methods to synthesize these compounds have been reported in the literature. [6] Nevertheless, the development of new and efficient procedures for the selective synthesis of these seven-membered rings continues to represent an important and challenging goal. The methodology proposed herein is based on the ordered assembly of three simple and readily available components under mild catalytic conditions.…”

Nondirecting Group sp3 C−H Activation for Synthesis of Bibenzyls via Homo‐coupling as Catalyzed by Reduced Graphene Oxide Supported PtPd@Pt Porous Nanospheres

“…To date, imipramine is regarded as the “gold‐standard” antidepressant on account of its efficacy to lift the most severe depressive episodes, which is still insurmountable . Recently, numerous methods for obtaining the imipramine were developed, but most of them need dibenzo[b,f]‐azepines as the starting material and are difficult to control the reaction because many side reactions would take place during the cyclisation process . Herein, the product 2 v and 2 w can be efficiently obtained with good yield in this catalytic system and then transformed to the desired imipramines using the previously reported method (Scheme ) .…”