Solid phase extraction purification of carboxylic acid products from 96-well format solution phase synthesis with DOWEX 1x8-400 formate anion exchange resin

The anion exchange resin DOWEX 1 x 8-400 formate has been developed for the isolation or resin capture of carboxylic acids from solution phase reactio ns in a 96-well format using a batchwise solid phase extraction technique. Eleven different anion exchange resins (formate forms) were evaluated for t heir efficiency at scavenging aryl and aliphatic carboxylic acids from solu tion. The model carboxylic acids had pK(a)s ranging from 3.40 to 4.89. Exch ange efficiency onto the resin was pK(a) dependent with the carboxylic acid s but not with their diisopropylethylammonium salts. Exchange off of the re sin also showed pK(a) dependence with the stronger acids requiring more con centrated solvent acid for exchange. DOWEX 1 x 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 aci ds off of the resin were TFA/solvent or HCO2H/solvent mixtures. The resin w as 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 m ixtures from an arrayed reductive amination and an arrayed Stille reaction provided product carboxylic acids in yields averaging 57% and purities aver aging 89%.