Process
Development of an N‑Benzylated Chloropurine
at the Kilogram Scale
Xianglin Shi
Hexi Chang
Markus Grohmann
William
F. Kiesman
Daw-Iong Albert Kwok
10.1021/op5003903.s001
https://acs.figshare.com/articles/journal_contribution/Process_Development_of_an_N_Benzylated_Chloropurine_at_the_Kilogram_Scale/2184589
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.
2015-03-20 00:00:00
target salt
benzylpurine
manufacturing process
methanesulfonic acid salt
API
chloropurine compound 1
Kilogram ScaleA
DMA filtrate
2CO
DMSO
pyridine hydrochloride 2
hydrolytic instability
crude salt
N 7 benzylation
process Development