Process Development of an N‑Benzylated Chloropurine at the Kilogram Scale

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 K₂CO₃ (−325 mesh) and the chloropurine compound <b>1</b> in dimethylacetamide (DMA). The major regioisomeric impurity (<b>6</b>), formed by <i>N</i>⁷ 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

Fluorescent pH Sensors for Broad-Range pH Measurement Based on a Single Fluorophore

We constructed a series of novel optical sensors for determination of broad-range pH based on a single fluorophore and multi-ionophores with different p<i>K</i>_a values. These optical sensors use photoinduced electron transfer (PET) as the signal transduction and follow the design concept of “fluorophore-spacer-receptor (ionophore)” which employs 4-amino-1,8-naphthalimide as the single fluorophore, ethyl moiety as the spacer, and a series of phenols and anilines as the receptors. Key to the successful development of this sensor system is that coupling the receptors with six different p<i>K</i>_a values with a single fluorophore produces the correct optical properties. This rational design affords a series of optical pH sensors with unique fluorescence property and accurately tunable pH measurement ranging from 1 to 14 pH units. Because of covalent immobilization of the indicators, these sensors demonstrate excellent stability, adequate reversibility, and satisfactory dynamic range up to full pH ranges (pH 1–14)