Solid Phase Extraction Purification of Carboxylic Acid Products from 96-Well Format Solution Phase Synthesis with DOWEX 1×8-400 Formate Anion Exchange Resin

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Abstract
The anion exchange resin DOWEX 1×8-400 formate has been developed for the isolation or resin capture of carboxylic acids from solution phase reactions in a 96-well format using a batchwise solid phase extraction technique. Eleven different anion exchange resins (formate forms) were evaluated for their efficiency at scavenging aryl and aliphatic carboxylic acids from solution. The model carboxylic acids had pKas ranging from 3.40 to 4.89. Exchange efficiency onto the resin was pKa dependent with the carboxylic acids but not with their diisopropylethylammonium salts. Exchange off of the resin also showed pKa dependence with the stronger acids requiring more concentrated solvent acid for exchange. DOWEX 1×8-400 formate was determined to have superior capacity and the fastest exchange rate. Solvents suitable for exchanging the acids onto the resin were CH2Cl2, methanol, and various solvent/water mixtures. Solvents suitable for exchanging the carboxylic acids off of the resin were TFA/solvent or HCO2H/solvent mixtures. The resin was found to swell best in CH2Cl2 and in polar protic solvents such as water, alcohols, and acids. Application of this technique to the crude product mixtures from an arrayed reductive amination and an arrayed Stille reaction provided product carboxylic acids in yields averaging 57% and purities averaging 89%.