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Synthesis of [ 13 C 4 ]Baraclude ® (entecavir)
Author(s) -
Tran Scott B.,
Ekhato Ihoezo V.,
Rinehart J. Kent
Publication year - 2009
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1664
Subject(s) - chemistry , entecavir , diethyl malonate , cyanamide , yield (engineering) , pyrimidine , reagent , formylation , medicinal chemistry , stereochemistry , organic chemistry , virus , materials science , virology , hepatitis b virus , lamivudine , metallurgy , biology , catalysis
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.