Acetic Acid → Quilostigmine

Participants

Reaction Steps

To a solution of physostigmine (2.75 g) in dry THF (28 mL) at 25° C. under a nitrogen atmosphere was treated with KOtBu (1.28 g), added over 0.25 hour, aged 0.5 hour at 25° C., then treated with glacial HOAc (0.6 mL, 1 equiv., pH=10) to give a mixture containing physostigmine (II) and eseroline (III) in a 1/99 HPLC ratio. Addition of 1,1'-carbonyldiimidazole (1.7 g, 1.05 equiv) added in 1.0 and 0.05 equiv. portions at 1.25 hour intervals at -20° C. gave after 1.0 hour following each addition the following HPLC ratio of imidazolecarbonyl intermediate (V) and eseroline: 97/3 and 99/1. Addition of glacial HOAc (3.4 mL, 6 equiv., pH=5) followed by 1,2,3,4-tetrahydroisoquinoline (1.5 g, 1.1 equiv., added over 0.5 hour at 15° C.) gave after 4 hours at 25° C. a mixture containing (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl 3,4-dihyclro-2(1H)-isoquinolinecarboxylate and eseroline in a 98/2 HPLC ratio.

Provenance & Evidence