Synthesis of [13C4]Baraclude® (entecavir)

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 52; no. 11; pp. 485 - 489
• Main Authors: Tran, Scott B., Ekhato, Ihoezo V., Rinehart, J. Kent
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15-09-2009; Wiley
• Subjects: 3-13C3]malonate; Antibiotics. Antiinfectious agents. Antiparasitic agents; antiviral; Antiviral agents; Baraclude; Biological and medical sciences; Carbohydrates. Nucleosides and nucleotides; carbon-13; Chemistry; diethyl; diethyl [1, 2, 3‐13C3]malonate; entecavir; Exact sciences and technology; Medical sciences; Nucleosides, nucleotides and oligonucleotides; nucleotide; Organic chemistry; Pharmacology. Drug treatments; Preparations and properties; Purine derivatives; C; diethyl; Entecavir; Carbon Isotopes; malonate; 3; Baraclude; Nucleotide; Antiviral; carbon-13; Chemical synthesis; Carbon 13; Labelled compound; Cyclopentane derivatives
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.1664

Entecavir, labeled as 1H‐[13C4]purin‐6(9H)‐one, was prepared from commercially available [13C]guanidine HCl, 1 and diethyl [1,2,3‐13C3]malonate, 2. The reagents were condensed together to give 2‐amino‐4,6‐dichloro[2,4,5,6‐13C4]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 [13C4]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 [13C4] 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.
Baraclude™ (entecavir) is a potent and selective inhibitor of the hepatitis B virus. Baraclude™ received marketing approval from the US FDA in March 2005 as a treatment for chronic hepatitis B infection. The drug is effective in adults suffering liver damage due to virus replication. The following report describes the synthesis of isotopically labeled [13C4]entecavir. Entecavir, labeled as the ‐1H‐[13C4]purin‐6(9H)‐one, was prepared from commercially available [13C]guanidine hydrochloride and diethyl [1,2,3‐13C3]malonate. The labeled reagents were first transformed into 2‐amino‐4,6‐dichloro[2,4,5,6‐13C4]pyrimidine and coupled to an optically active amino cyclopentanol derivative. A further sequence of eight reaction steps completed the construction of the purine ring system with an exocyclic olefin attachment and the removal of protecting groups gave [13C4]entecavir in an overall yield of 6.8% and with a chemical purity of 99.23% by HPLC. The stable labeled entecavir was used as an internal standard to support bioanalytical LC‐MS analyses of clinical samples. Copyright © 2009 John Wiley & Sons, Ltd.