Acetic Acid → Quilostigmine

Participants

Reaction Steps

To a solution of physostigmine (2.75g) in dry THF (28 mL) at 25° C. under a nitrogen atmosphere was added KOtBu (1.28 g) over 0.25 hour. The mixture was kept at 25° C. for 0.5 hour and then treated with glacial HOAc (0.6 mL, 1 equiv., pH=10) to give a mixture containing physostigmine (II) and eseroline (HI) in a 1/99 HPLC ratio. Addition of 1,1'-carbonyldiimidazole (1.92 g, 1.2 equiv) in 1.0, 0.05, 0.05 and 0.1 equiv. portions at 0.25 hour intervals at 20° C. gave after 10 min following each addition the following HPLC ratio of imidazolecarbonyl intermediate (V) and eseroline: 95/5, 96/4, 97/3 and 98/2. Addition of glacial HOAc (3.4 mL, 6 equiv., pH=5) followed by 1,2,3,4-tetrahydroisoquinoline (1.6 g, 1.2 equiv., added over 0.5 hour at 15° C.) gave after 15 hour at 25° C. a mixture containing (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo-[2,3-b]indol-5-y13,4-dihydro-2(1H)-isoquinolinecarboxylate and eseroline in a 97/3 HPLC ratio.

Provenance & Evidence