Development of a Practical Synthesis of a Purine Nucleoside Phosphorylase Inhibitor: BCX-4208

Abstract

A practical synthesis of the purine nucleoside phosphorylase (PNP) inhibitor BCX-4208 (1) was accomplished in three telescoped steps. Mannich condensation of the 4-benzyloxy-9-deazahypoxanthine with (3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidine and formaldehyde followed by removal of the protecting group and crystallization furnished the desired product as a hydrochloride salt in 85% overall yield and 99.8% purity. A scalable synthesis of 9-deazahypoxanthine is also reported.

Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

“…While it was likely that the positioning of the nitrogen in compounds 4 , 19 – 22 was optimal for mimicking the positive charge of a ribooxacarbenium ion transition state, we decided to explore the effect of moving the nitrogen along the chain. To this end, treatment of 25 28 with dimethylamine and formaldehyde in a Mannich reaction afforded 26 (Scheme 3), which after reaction with methyl iodide and then basic nitromethane gave 27 . Reduction of the nitro group generated amine 28 which underwent reductive alkylation with phosphonate aldehydes 29 to give 30 .…”

Efficient and Selective Construction of Pyrrolo[3,2-d]pyrimidine Derivatives

“…MS were measured on a Finnigan Trace MS spectrometer. NMR spectra were recorded in CDCl 3 on a Varian Mercury 400 or 600 spectrometer and chemical shifts () were given in ppm using (CH 3 ) 4 Si as an internal reference ( = 0). IR were recorded on a PE-983 infrared spectrometer as KBr pellets with absorption in cm…”

Infinite ladder-like chains organized into a three-dimensional zigzag supramolecular architecture in 9-deazahypoxanthine

“…The title compound, (I), was prepared by a modification of the threestep procedure of Kamath et al (2009) and was characterized as a chemical individuum. The modifications to the published synthesis lie primarily in a shortening of the reaction time and differences in the purification methods for obtaining the intermediates in the reaction process.…”

“…The use of a smaller amount of ethanol [pyrrole-ethanol molar ratio = 1:24, compared with a molar ratio of 1:31 used byKamath et al (2009)] enabled direct isolation of methyl 4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxylate from the reaction solution. This intermediate was purified by recrystallization from acetic acid.…”