Dutch resolution of racemic 4-hydroxy- and 4-fluorophenylglycine with mixtures of phenylglycine and (+)-10-camphorsulfonic acid

Abstract 4-Hydroxyphenylglycine and 4-fluorophenylglycine can be resolved with (+)-10-camphorsulfonic acid only if dl - or d -(−)-phenylglycine is added. When using dl -phenylglycine this is co-resolved in this process. In this resolution process mixed crystals are formed of the (+)-10-camphorsulfonic acid salts of the d -(−)-enantiomers of phenylglycine and the para substituted phenylglycines. In the crystal lattice of the mixed salts approximately 25–30% of the d -(−)-phenylglycine molecules can be randomly replaced by d -(−)- para substituted phenylglycines, resulting in the desired resolution. The overall non-stoichiometric composition of the mixed crystals reflects to some extent the composition in solution. This behaviour is typical for solid solutions. The solid solution behaviour in this so called ‘Dutch resolution’ is proven by differential scanning calorimetry (DSC), X-ray crystal structure determination and powder diffraction.