Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site
amyloid
precursor protein cleaving enzyme (BACE) inhibitors is described.
New methodologies were discovered to overcome safety and scalability
problems with existing procedures. The sterically hindered quaternary,
neopentyl stereocenter was formed in high diastereoselectivity by
the addition of a carbamoyl anion to an N-sulfinyl
ketimine. An aryl nitrile was installed by a palladium- and cyanide-free
electrophilic cyanation affected by transnitrilation of an arylmagnesium
derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine
side chain was devised based on diethyl malonate and dibenzylamine
starting materials. A mild enamine fluorination was developed for
the synthesis of a fluoroisobutylamine side chain.