Carbon-14 labelling of DIOVAN (TM) in its valine-moiety

As a highly specific and non peptide AT(1)-antagonist Valsartan 2 is market ed under TM for effective treatment of hypertension. This paper the tradena me DIOVAN describes the synthesis of C-14 labelled Valsartan 2, which incor porates two C-14 isotopes in the valine-moiety. Reaction of (-)-bromo-[1,2- C-14]acetyl bornane-10.2-sultam 8a ((-)-[C-14(2)]BABS) with benzophenone im ine gave (-)-diphenylmethylene[1,2-C-14(2)]glycinyl bornane-10.2-sultam 9 ( (-)-[C-14(2)]DPMGBS), which was alkylated with 2-iodopropane to build-up th e valine structure 10. Initially the resulting sultam-protected valine 11 w as treated with the benzyl bromide 12 to produce the precursor 13. However, under conditions routinely used for sultarn-cleavage deprotection resulted in the racemization of the amino acid. Successful cleavage was accomplishe d via N-Boc-protection of 11 followed by hydrolytic cleavage of the auxilia ry and esterification to give the L-[C-14(2)]valine benzyl ester 18. Finall y [C-14(2)]Valsartan 2 was synthesised in a 10 step synthesis in an overall radiochemical yield of 10 % relative to the (-)-[1,2-C-14]BABS 8a employed .