An Expeditious Scalable Synthesis of (<i>S</i>)-2-Amino-5-methoxytetralin via Resolution

Abstract

The first resolution of (±)-2-amino-5-methoxytetralin 1 is achieved via diastereomeric salt formation with ( S )-mandelic acid to give ( S )- 1 ·HCl of 99.7% ee in 29% overall yield from (±)- 1 ·HCl, ( S )- 1 ·HCl being a chiral intermediate to assemble N-0923 2, a potent dopamine D 2 agonist effective against Parkinson's disease. Preparation of (±)- 1 ·HCl involves the Birch reduction of 1,6-dimethoxynaphthalene 3b and reductive amination of 5-methoxy-2-tetralone 4 with aqueous NH 3 over Raney Ni under a hydrogen atmosphere (2.9−3.9 bar) between 70 and 80 °C. With the off-enantiomer ( R )- 1 arising from the resolution, its xylene solution is heated at 130 °C over Raney Co under a hydrogen atmosphere (2.0−2.7 bar) to regenerate (±)- 1 ·HCl in 95% yield, which should enhance the overall throughput of the resolution process.