Studies on 1, 2, 3, 4-Tetrahydroisoquinolines. V. A Convenient Synthesis of (±)-5, 7-Dihydroxy-1-(3, 4, 5-trimethoxybenzyl)-1, 2, 3, 4-tetrahydroisoquinoline (Racemic TA-073)

Abstract

A convenient synthetic route to (±)-5, 7-dihydroxy-1-(3, 4, 5-trimethoxybenzyl)-1, 2, 3, 4-tetrahydroisoquinoline (racemic TA-073), an orally active bronchodilator, through the cyclization of the amine 4 or its N-acyl derivative (10b, c) is presented. Catalytic reduction of 4 over 10% Pd-C in EtOH-H₂O in the presence of oxalic acid (6 eq) afforded racemic TA-073 in 65% yield. The acid-catalyzed reaction of 10b, c was also investigated. Cyclization of 10b, c with 1 N HCl (1 eq) in THF gave the corresponding N-acyl enamine 12b, c in quantitative yield. Further treatment of 12b with conc. HCl in THF afforded the pavine derivative 14 in 80% yield. Cyclization of 10b with neat HCOOH, however, resulted in the formation of the isopavine derivative 11b in 80% yield. This result parallels the reported observation by McDonald et al.