Process Research and Large-Scale Synthesis of 4‘‘,6‘‘-Bis((2-fluorophenyl)carbamoyl)hecogenyl β-O-Cellobioside:  A Potent Cholesterol Absorption Inhibitor

This paper describes process research leading to the successful scale-up of a potent cholesterol absorption inhibitor 4‘‘,6‘‘-bis((2-fluorophenyl)carbamoyl)hecogenyl β-O-cellobioside 3. The synthesis of 3 from hecogenyl β-O-cellobioside 4 required five synthetic steps: (1) the selective protection of the 4‘‘,6‘‘-diol group, (2) acylation of the remaining five hydroxyl groups, (3) unmasking of the diol moiety, (4) carbamoylation with 2-fluorophenyl isocyanate, and finally, (5) deacylation. The synthesis by our discovery group utilized chloroacetate protecting groups for five of the sugar alcohols at step two, which led to problems on scale-up due to the instability of this group in solution and the poor crystallinity of the intermediates. Methoxyacetates were identified as the optimal acyl-protecting group. The identification of mild reaction conditions led to an efficient synthesis of bis(carbamate) 3 in very high purity and 42% yield from 4 over five synthetic steps and one recrystallization/polymorph conversion. The process was simple to operate and was carried out to provide 80 kg of 4‘‘,6‘‘-bis(2-fluorophenylcarbamoyl)hecogenyl β-O-cellobioside 3.