Process Development of an N‑Benzylated Chloropurine at the Kilogram Scale
2015-03-20T00:00:00Z (GMT) by
A two-step pharmaceutical manufacturing process was developed for the large-scale preparation of 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9<i>H</i>-purin-2-amine methanesulfonic acid salt (<b>4</b>) from commercially available starting materials. In the first step, the benzylpurine free base (<b>3</b>) was prepared by benzylation of 6-chloro-9<i>H</i>-purin-2-amine (<b>1</b>) with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (<b>2</b>). The benzylpurine free base was then directly converted into the methanesulfonic acid salt. It was necessary to charge the pyridine hydrochloride <b>2</b> in portions into the mixture of K<sub>2</sub>CO<sub>3</sub> (−325 mesh) and the chloropurine compound <b>1</b> in dimethylacetamide (DMA). The major regioisomeric impurity (<b>6</b>), formed by <i>N</i><sup>7</sup> 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.
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