Highly efficient resolutions of 1,4-benzodioxane-2-carboxylic acid with para substituted 1-phenylethylamines

The salts of (S)- and (R)-1.4-benzodioxane-2-carboxylic acid with eight (S)-1-arylethylamines were prepared. The determination of their melting points and of their solubilities in alcohol solvents revealed large differences between the diastereomeric benzodioxanecarboxylates of (S)-1-(p-nitrophenyl)ethylamine and of (S)-1-(p-methylphenyl)ethylamine. Therefore, these latter amines were selected to resolve (+/-)-1,4-benzodioxane-2-carboxylic acid by diastereoselective crystallization finding that both of them display a very high resolution ability for such a substrate, which contrasts with the null efficiency of unsubstituted 1-phenylethylamine. These results are consistent with DSC evidences, which indicated that the two successfully resolved diastereomeric systems are binary mixtures exhibiting a eutectic with a high content of the more soluble diastereomeric salt. The new procedures can advantageously replace the two resolutions we had previously reported, that of the same acid with dehydroabietylamine and that of glycerol acetonide, a precursor of 1,4-benzodioxane-2-carboxylic acid, with I-phenylethylamine. (C) 2005 Elsevier Ltd. All rights reserved.