Two optimized synthetic pathways toward a chiral precursor of Mivacurium chloride and other skeletal muscle relaxants

A chiral precursor of Mivacurium chloride, (R)-5′-methoxylaudanosine, was prepared using two different methods. The chiral resolution of racemic 5′-methoxylaudanosine, typically used in industry, was carried out in parallel with a procedure consisting of asymmetric transfer hydrogenation (ATH) and reductive methylation. A novel one-pot synthetic step was developed for the synthesis of racemic 5′-methoxylaudanosine. In both routes, the enantioselectivity was high but further purification was necessary to reach the level of a pharmaceutical standard. The individual synthetic steps reported herein can also be used for the synthesis of analogous bistetrahydroisoquinoline-based skeletal muscle relaxants.

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(1R)-(−)-6,7-Dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinolineC22H29NO5[α]D20=-46.0 (c 1.26, CHCl3)Absolute configuration: (1R)Source of chirality: asymmetric synthesis