BMS-688521

The process development and the kilogram-scale synthesis of BMS-688521 (1) are described.The synthesis features a highly efficient telescoped sequence which utilizes the spirocyclic dichlorophenyl-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl benzonitrile hydantoin ((+)-2,3-di(p-toluyl) tartaric acid) DTTA salt to produce the final intermediate via a sequential nucleophilic aromatic substitution (SN_AR) reaction.A final deprotection step affords BMS-688521 in high quality with an overall yield of 65% from the key intermediate, spirocyclic hydantoin.

An efficient synthesis of 6-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic acid I is described.This new process involves an in situ protection of 6-chloronicotinic acid as trimethylsilyl ester followed by coupling with spirocyclic hydantoin core to give the target product in 89% overall yield after one-pot deprotection and final API recrystallization