title: An alternative and robust synthesis of [(13) C4 ]Baraclude® (entecavir).
abstract: Stable isotope-labeled [(13) C4 ]entecavir (1) was prepared in 11 steps. Commercially available [(13) C]guanidine hydrochloride and diethyl[1,2,3-(13) C3 ]malonate were condensed to yield 2-amino[2,4,5,6-(13) C4 ]pyrimidine-4,6-diol (8). This was converted to the desired purine (7) in five steps. Introduction of the chiral epoxide was followed by subsequent deprotection to give [(13) C4 ]entecavir (1), in an overall yield of 5.7% from labeled precursors. The chemical purity of the title compound was determined to be >99% by HPLC. The isotopic distribution was determined by mass spectrometry to be 282[M + 4], 98.4%; 281[M + 3], 1.6%; and 278[M + 0], <0.1%.
authors.affiliation: Radiochemical Synthesis Group, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Easter
authors.forename: Richard C
authors.initials: RC
authors.lastname: Burrell
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bonacorsi
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D002247:Carbon Isotopes / Q000138:chemical synthesis; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D007553:Isotope Labeling / Q000379:methods*
chemical_list: D000998:Antiviral Agents; D002247:Carbon Isotopes; C413685:entecavir; D006147:Guanine
keywords: Baraclude®; antiviral; carbon-13; entecavir; nucleoside; stable isotope labeling