Preparation of 8-substituted xanthine CVT-124 precursor by late stage pyrimidine ring closure.

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.