Norsertraline

The SSRIs are eliminated mainly through hepatic metabolism. Their half-lives are about 1 day for fluvoxamine, paroxetine, and sertraline (2-5), 1.5 days for citalopram (6), and 2-3 days for fluoxetine (7). Norfluoxetine, the main metabolite of fluoxetine, is a potent and selective serotonin re-uptake inhibitor, and since this metabolite also has a very long half-hfe (7-15 days) it contributes significantly to the clinical effect. Norsertraline, the desmethylated metabolite of sertraline, is also an inhibitor of serotonin re-uptake, but... 

The substrate scope of the DKR protocol above was extended to include a wide range of primary amines [89]. Functional groups tolerated include fluorine, bromine, nitrile, nitrate, and trifluoromethyl. Aliphatic amines and more sterically hindered substrates were also obtained in high yields and ee values. The method was found applicable with both isopropenyl acetate and dibenzyl carbonate as acyl donors. For 18 different substrates, the corresponding enantiomericafly pure products were obtained in high to excellent yields (70-95%) and with high to excellent ee values (93 to >99%). The chemoenzymatic DKR protocol was also applied to the synthesis of norsertraline, from readily available 1,2,3,4-tetrahydro-l-naphthyl-amine. Norsertraline is cmrently in clinical trials for the treatment of central nervous system (CNS) disorders. 

DKR of racemic amines for the synthesis of norsertraline and (/ )-rasagiline mesylate. 

Thalen, L. K., Zhao, D. B., Sortais, J. B., Paetzold, J., et al. (2009). A chemoenzymatic approach to enantiomerically pure amines using dynamic kinetic resolution Application to the synthesis of norsertraline. Chem. Eur.., 15,3403-3410. 

This highly efficient DKR methodology was applied to the synthesis of the selective serotonin reuptake inhibitor, norsertraline (Scheme 1.4), which is used to treat depression. For the application of enzymatic dynamic kinetic resolution in stereoselective synthesis, see chapter 57. 

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