title: Preparation of 8-substituted xanthine CVT-124 precursor by late stage pyrimidine ring closure.
abstract: To develop a novel route for the scaleable synthesis of the chiral xanthine CVT-124 (1, aka. BG9719), a method for the late stage pyrimidine ring closure of the nitrogen-protected endo 2-norbornenyl imidazole 3 was developed. The three-component coupling of benzylamine, 2-cyanoglycine ethyl ester (4), and methyl 5-norbornene-2-carboximidate hydrochloride (5) was demonstrated to achieve 3 in 23-46% isolated yields. The imidazole 3 was then elaborated to construct the N-benzyl xanthine 2 as a 1:1 mixture of exo and endo isomers, which were separable at this stage by chromatography. The nitrogen-protected endo xanthine 2 is a key intermediate in the synthesis of CVT-124.
authors.affiliation: Medicinal Chemistry Department, Albany Molecular Research, Inc., Albany, New York 12212-5098, USA. rjasonh@albmolecular.com
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.forename: Paul F
authors.initials: PF
authors.lastname: Vogt
authors.forename: Harold
authors.initials: H
authors.lastname: Meckler
authors.forename: Michael P
authors.initials: MP
authors.lastname: Trova
authors.forename: Steven R
authors.initials: SR
authors.lastname: Schow
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
mesh_terms: D003500:Cyclization; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000737:chemistry; D014970:Xanthines / Q000138:chemical synthesis*
chemical_list: C097280:1,3-dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D014970:Xanthines