Issue in Honor of Prof. Binne Zwanenburg ARKIVOC 2004 (ii) 64-71 resolving agents and practical procedures.8-10 The role of nucleation inhibition in understanding the phenomenon of Dutch Resolution 8 is a prime example of this approach. A continuous stream of new resolving agents is thus becoming available: cyclic phosphoric acids,6 substituted glycolic acids,11 new derivatives of phthalic acid,7 several 1-aryl-1-butyl amines 12 and amino-alcohols derived from simple amino acids.13 Recent compilations of resolving agents are available.3,13 Through the years, resolution of amino acids and hydroxy acids have reached a sophisticated stage of technological development. Efficient procedures are available for resolution, 3,13 racemization of the undesired stereo-isomer14 as well as processes for asymmetric transformation.4,14, 15 The commercial importance of these acids has spurred development of several practical and well documented procedures. The presence of an additional polar substituent, i.e. hydroxy or amino groups, facilitates chiral discrimination in the formation of the crystal lattices of the diastereomeric salts. Both factors have played a role in the less developed methods available for the resolution of alkyl and/or aryl substituted carboxylic acids. The commercial success of several 2-aryl substituted propionic acids, i.e. Naproxen, Ibuprofen, Ketoprofen etc. has stimulated research in resolving these types of compounds. Because predictions of successful conditions and resolving agents are difficult and rather unreliable, trial and error and practical experience has served as the basis for a number of successful combinations of racemic arylpropionic acid and resolving agent9. Thus, Naproxen was well resolved by N-octyl-glucamine, N-methyl-D-(-)-glucamine, (-)-2-phenethylamine and other basic agents.15,16 Ibuprofen was best resolved by 2-aryl-2-alkylamines such as 2-phenethyl amine, several 1,2-diarylethylamines and S-phenylglycinol as the most efficient resolving agent.17 The phase diagram for the latter combination showed a very asymmetric shape, predicting a resolution efficiency of 0.80 (defined as 2 × e.e. × yield). In practice, efficiencies of around 0.5 were found. This may well be typical for this type of resolutions. In the series of amino acids and hydroxy acids numerous examples of resolutions with proven efficiencies of 0.80 or better are known: mandelic acid/2-phenethylamine: 0.86,17 camphor-10-sulphonic acid/phenylglycine: 0.98.18-20 Results and Discussion Resolution of 2-phenyl- 2-alkyl carboxylic acids As part of a wider study on resolutions several 2-amino alcohols, derived from simple, cheaply available amino acids, were tested as resolving agent for 2-aryl-alkyl carboxylic acids. Preparation of these amino alcohols is straightforward using known general methods. A general procedure and a typical example are included in the Experimental Section. Twelve amino alcohols were prepared derived from L-alanine, L-phenylalanine and L-phenylglycine. Although most of these compounds are known in the literature,22-24 they have not been used in systematic studies towards resolutions. As an extension of our studies 15, 17 on 2-arylpropionic acids we ISSN 1424-6376 Page 65 ©ARKAT USA, Inc
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