Synthesis of [ 13 C 4 ]Baraclude ® (entecavir)

Entecavir, labeled as 1H‐[ 13 C 4 ]purin‐6(9H)‐one, was prepared from commercially available [ 13 C]guanidine HCl, 1 and diethyl [1,2,3‐ 13 C 3 ]malonate, 2 . The reagents were condensed together to give 2‐amino‐4,6‐dichloro[2,4,5,6‐ 13 C 4 ]pyrimidine 3 , which in turn was coupled to an optically active amino cyclopentanol derivative, 9 . A further sequence of eight reaction steps completed the constructions of the purine ring system and the exocyclic olefin attachment on the cyclic pentyl portion, 18 . The removal of the methoxide and benzyl protecting groups gave [ 13 C 4 ]entecavir, 20 in an overall yield of 6.8%. The chemical purity of the title compound was determined by HPLC to be 99.23%. The percent isotopic [ 13 C 4 ] abundance was found by mass spectral analysis to be 96.7%. No detectable level of the unlabeled entecavir was found by LC‐MS analysis. Copyright © 2009 John Wiley & Sons, Ltd.