An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142)

Abstract

Triple monoamine reuptake inhibitors have been implicated in the development of a new generation of antidepressants with higher efficacy than the currently existing therapies. In this paper, we have developed an alternative efficient synthetic route for triple monoamine reuptake inhibitor D-142 in 18.5% overall yield in 11 steps starting from diphenylmethane. D-142 was developed by us recently. The key step of the present synthetic strategy is the preferential formation of a bromohydrin from olefin via a cis-bromoinum intermediate, which introduced significant efficiency in the overall synthesis. Furthermore, we have developed an efficient way to recycle the optically active intermediate diol back to the desired chiral epoxide.

Development of potent dopamine–norepinephrine uptake inhibitors (DNRIs) based on a (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template

“…[39, 40] Reductive amination of amines 1, 3 , and 5 (Schemes 1, 2, and 3, respectively) with appropriate aldehydes in presence of sodium triacetoxyborohydride or sodiumcyanoborohydride and catalytic amount of acetic acid in 1,2-dichloroethane afforded final target compounds 2a, 4a–4i, 6a–6h in appreciable yields.…”

“…39–43 Thus, our drug development work led to discovery of novel TRIs which interacted with all three transporters. In this manuscript, we report a structure-activity relationship (SAR) study describing modifications of the TRI profile of our compounds resulting in potent SSRI- and DNRI-type transporter inhibitors.…”

Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Synthesis, biological characterization, and development of a pharmacophore model

“…Briefly, the epoxide ring in ( R )- 2-benzhydryloxirane ( 28 ) 36 was regioselectively opened with vinyl magnesium bromide and a catalytic amount of copper (I) iodide resulting in ( S )-alcohol intermediate 29 in 75% yield. The alcohol intermediate was then subjected to trans -vinylation using ethyl vinyl ether and a catalytic amounts of mercury (II) trifluoroacetate.…”

“…Further, optimization resulted in the discovery of a unique di- and tri-substituted pyran template, several derivatives of which (Figure 1) inhibited the uptake of all three monoamine transporters. 33–36 Dual acting inhibitors as blockers of both 5-HT and NE transporters (SNRIs) or NE and dopamine transporters (DNRIs) have also been identified. Two of our lead TUIs D-142 and D-161 have shown to possess antidepressant activity and were found to be efficacious in animal models of depression.…”

Structural Exploration of (3S,6S)‐6‐Benzhydryl‐N‐benzyltetrahydro‐2H‐pyran‐3‐amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants

“…The stereochemistry of the trans-epoxide was comprehensively determined in our recent publication. [28] The trans-epoxide 28 was regioselectively converted into the corresponding azide 29, which upon hydrogenation in the presence of 10 % Pd/C in methanol, afforded the key intermediate amine 30 in quantitative yield. Reductive amination of amine 30 with various aldehydes provided the target compounds 31 a-b.…”