Synthesis of Atomoxetine

A nice application in pharmaceutical s)mthesis has been reported. Thus, from the reduction of pentoxifylline a new methylxanthine could be obtained, and a high ee of 98% was observed for this transformation [126, 127]. Since the baker s yeast reduction of 3-oxo-3-phenylpropanenitrile has been difficult to achieve, a library of baker s yeast reductases was screened. As a result, this approach allowed the synthesis of both antipodes of antidepressants fluoxetine, atomoxetine, and nisoxetine [128]. 

This approach was also taken for reduction of 3-oxo-3-phenylpropanenitrile for the synthesis of precursors for both antipodes of fluoxetine, atomoxetine, and nisoxetine, which are popular serotonin/norepinephrine reuptake inhibitors. " Four enzymes were found to reduce this substrate, and by changing the enzyme, both enantiomers of 3-hydroxy-3-phenylpropanitrile could be prepared with a high ee as shown in Scheme 33.1b. 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

Hammond RJ, Poston BW, Ghiviriga I, Feske BD. Biocatalytic synthesis towards both antipodes of 3-hydroxy-3-phenylpropanitrile a precursor to fluoxetine, atomoxetine and nisoxetine. Tetrahedron Lett. 2007 48 1217-1219. 

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