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

Abstract

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.

Synthesis of beta‐site amyloid precursor protein‐cleaving enzyme 1 inhibitors BI 1147560 and BI 1181181 labeled with carbon‐14 and deuterium

“…With the availability of the chiral bromide intermediate 3 , 19 Scheme 1, the syntheses of carbon‐14 labeled BI 1147560 and BI 1181181 were completed in five and six steps, respectively. First, cyanation of this bromide using zinc [ 14 C]cyanide gave the nitrile [ 14 C]‐4 in good yield 20 .…”

“…Conversion of this amine to the isothiocyanate [ 14 C]‐6 was accomplished using bis(2‐pyridyloxy)methanethione in acetonitrile. This reagent was reported as a safe thiophosgene replacement 19 . The isothiocyanate [ 14 C]‐6 was treated in situ with the oxetan‐3‐ylmethanamine 7 19 to give the cyclic thiourea derivative [ 14 C]‐8 in 75% yield.…”

“…This reagent was reported as a safe thiophosgene replacement 19 . The isothiocyanate [ 14 C]‐6 was treated in situ with the oxetan‐3‐ylmethanamine 7 19 to give the cyclic thiourea derivative [ 14 C]‐8 in 75% yield. Finally, oxidation with tert ‐butyl hydroperoxide (TBHP) in the presence of aqueous ammonium hydroxide furnished [ 14 C]‐BI 1147560 .…”

“…The isothiocyanate [ 14 C]‐6 was similarly reacted with 2‐fluoro‐2‐methylpropane amine 9 to furnish [ 14 C]‐10 in 65% yield. The use of the bases sodium methoxide and triethylamine was required as the ring closure proceeds via a stepwise procedure 19 . Conversion to the aminoimidazolidine [ 14 C]‐11 was accomplished as described above in 60% yield.…”

“…As mentioned in the carbon‐14 synthesis, the availability of advanced chiral intermediate 5 19 allowed us to focus on the preparation of deuterium labeled amines 7 and 9 to access deuterium labeled BI 1147560 and BI 1181181 in fewer synthetic steps. Thus, (oxetan‐3‐yl‐2,2,4,4‐ d 4 )methan‐ d 2 ‐amine [ 2 H 6 ]‐7 was obtained in four steps starting from diethylmalonate, which was condensed with dibenzylamine and deuterium labeled formaldehyde in deuterium oxide.…”