Synthesis of (~(13)C_4)Baraclude~R (entecavir)

摘要

Entecavir, labeled as 1H-[~(13)C_4]purin-6(9H)-one, was prepared from commercially available [~(13)C]guanidine HCI, 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 [ 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.