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.
Herr
R Jason
RJ
Medicinal Chemistry Department, Albany Molecular Research, Inc., Albany, New York 12212-5098, USA. rjasonh@albmolecular.com
Vogt
Paul F
PF
Meckler
Harold
H
Trova
Michael P
MP
Schow
Steven R
SR
Petter
Russell C
RC
D003500:Cyclization; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000737:chemistry; D014970:Xanthines / Q000138:chemical synthesis*
C097280:1,3-dipropyl-8-(2-(5,6-epoxy)norbornyl)xanthine; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D014970:Xanthines