Strategies for the analysis of highly reactive pinacolboronate esters.
Pinacolboronate esters (or boronic acid, pinacol esters) are widely used in the Suzuki coupling reaction to connect organic building blocks for the total synthesis of complex molecules. The 2-aminopyrimidine-5-pinacolboronate ester was used as a starting material in the synthesis of a development compound, necessitating a chromatographic purity method to assess its quality. This aryl pinacolboronate ester posed unique analytical challenges due to its facile hydrolysis to the corresponding boronic acid, which is nonvolatile and poorly soluble in organic solvents. This made GC and normal-phase HPLC analysis unsuitable. In reversed-phase mode, typical sample preparation and analysis conditions promoted rapid sample degradation to the boronic acid. To overcome these challenges, unconventional approaches were necessary in order to stabilize 2-aminopyrimidine-5-pinacolboronate ester, adequately solubilize its boronic acid, and produce acceptable separation and retention. The final method employed non-aqueous and aprotic diluent, and a reversed-phase separation using highly basic mobile phases (pH 12.4) with an ion pairing reagent. These strategies were successfully applied to several other reactive pinacolboronate esters for purity analysis, demonstrating broad applicability to this unique class of compounds.
Genentech Small Molecule Pharmaceutical Sciences, 1 DNA Way, South San Francisco, CA 94080, USA. zhong.qiqing@gene.com
Qiqing
Q
Zhong
Kenley K
KK
Ngim
Megan
M
Sun
Jane
J
Li
Alan
A
Deese
Nik P
NP
Chetwyn
D000097:Acetonitriles / Q000737:chemistry; D000475:Alkenes / Q000032:analysis*; D001897:Boronic Acids / Q000032:analysis*; D002073:Butanes / Q000032:analysis*; D056246:Chemistry, Analytic; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004952:Esters / Q000032:analysis*; D008752:Methylene Chloride / Q000737:chemistry
D000097:Acetonitriles; D000475:Alkenes; D001897:Boronic Acids; D002073:Butanes; D004952:Esters; C523175:pinacolyl allylboronate; D008752:Methylene Chloride; C032159:acetonitrile