PROCESS RESEARCH AND LARGE-SCALE SYNTHESIS OF 4'',6''-BIS((2-FLUOROPHENYL)CARBAMOYL)HECOGENYL BETA-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<double p '',6 ''-bis ((2-fluorophenyl)carbamoyl)hecogenyl beta-O-cellobioside 3. The synthe sis of 3 from hecogenyl beta-O-cellobioside 4 required five synthetic steps: (1) the selective protection of the 4 '',6 ''-diol group, (2) a cylation of the remaining five hydroxyl groups, (3) unmasking of the d iol moiety, (4) carbamoylation with 2-fluorophenyl isocyanate, and fin ally, (5) deacylation. The synthesis by our discovery group utilized c hloroacetate 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. Met hoxyacetates were identified as the optimal acyl-protecting group. The identification of mild reaction conditions led to an efficient synthe sis of bis(carbamate) 3 in very high purity and 42% yield from 4 over five synthetic steps and one recrystallization/polymorph conversion. T he process was simple to operate and was carried out to provide 80 kg of 4 '',6 ''-bis(2-fluorophenylcarbamoyl)hecogenyl beta-O-cellobioside 3.