op5003903_si_001.pdf (146.21 kB)
Process Development of an N‑Benzylated Chloropurine at the Kilogram Scale
journal contribution
posted on 2015-03-20, 00:00 authored by Xianglin Shi, Hexi Chang, Markus Grohmann, William
F. Kiesman, Daw-Iong Albert KwokA two-step pharmaceutical manufacturing
process was developed for
the large-scale preparation of 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine methanesulfonic acid salt (4) from commercially available starting materials. In the first step,
the benzylpurine free base (3) was prepared by benzylation
of 6-chloro-9H-purin-2-amine (1) with
2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (2). The benzylpurine free base was then directly converted
into the methanesulfonic acid salt. It was necessary to charge the
pyridine hydrochloride 2 in portions into the mixture
of K2CO3 (−325 mesh) and the chloropurine
compound 1 in dimethylacetamide (DMA). The major regioisomeric
impurity (6), formed by N7 benzylation, and inorganic salts were removed by filtration. Treatment
of the DMA filtrate with MsOH afforded the target salt with negligible
degradation. In the second step, recrystallization of the crude salt
from DMSO–EtOAc with seeding gave crystalline API in high yield
and purity despite the hydrolytic instability of the product in solution.