Practical Synthesis of 5,6,7,8-Tetrahydro-4-methoxy-6-methyl-1,3-dioxoloisoquinolin-5-ol (Cotarnine)

Article abstract of DOI:10.1021/jo00299a016

5,6,7,8-Tetrahydro-4-methoxy-6-methyl-1,3-dioxolo<4,5-g>isoquinolin-5-ol (cotarnine, 1), an oxidative degradation product of (3S)-6,7-dimethoxy-3-<(5R)-5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo<4,5-g>isoquinolin-5-yl>phthalide (noscapine), has efficiently been synthesized from 2-methoxy-3,4-(methylenedioxy)benzaldehyde (7) in 66percent overall yield. -N-methylamino>acetaldehyde dimethyl acetal, obtained by reductive amination of 7 with aminoacetaldehyde dimethyl acetal followed by N-methylation, was cylized in acid to 5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo<4,5-g>isoquinolin-8-ol (12).The major byproduct of the cyclization was C-8 methoxy derivative of 12, and the amount of this byproduct was decreased by removal of MeOH formed in the reaction mixture.Acetylation of the hydroxyl group in 12 and hydrogenolysis gave 5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo<4,5-g>isoquinoline (hydrocotarnine), which was oxidized with I2 followed by basification to afford 1.