Interesting Selectivity of Nucleophilic Nitrogens

Synthesis Route to Avibactam Used to Supply Phase II Clinical Material

◆Initially, attempts to form the urea 4 directly from 11 were unsuccessful.

◆Triphosgene acted to dehydrate the primary amide to form the corresponding nitrile.

◆Use of alternative phosgenating agents (such as CDI and various chloroformates) were unsuccessful but did reveal interesting selectivity between the two nucleophilic nitrogens in the molecule.

◆While CDI is seen to react(approximately) equally on both nitrogens, chloroformates are highly selective for reaction on the piperidine(>99:1 selectivity).

◆Attempts to cyclize the resultant carbamate to form the urea were not successful, but it was realizedthat this selectivity could be effectively utilized as aprotecting group strategy.

◆Both BOC and FMOC protectioncan be readily achieved on the piperidine nitrogen, with subsequent quantitative acylation of the hydroxylamine nitrogen with CDI.

◆The much milder deprotection conditions required to remove the FMOC group meant that this groupwas likely to offer better operability than the BOC group, and thus, the FMOC approach was selected for further development.

Commercial Manufacturing Route to Avibactam