Abstract: Synthetic chemists paid great attention on the synthesis of non-natural amino acids due to the improvement in the binding potency, chemical and biological stability and pharmacokinetic characteristics upon introduction of functional groups into peptide based compounds. The methylphenylalanines, the analogs of phenylalanine, play an important role in drug research, such as the drug of anti-hypertension, analogs of enkephalin, the endothelin peptide receptor antagonists and the analogs of hormone. In this paper, o-, m- and p-Boc-L-methylphenylalanines were synthesized using Boc-diethyl malonate and methyl benzylbromide as the starting materials. The racemic amino acids were separated into optical isomers Boc-L-amino acids and Boc-D-amino acid ester by subtilisin. The yields are 42.5%, 47.7% and 64.5%, respectively. In addition, m-L-methylphenylalanine was also prepared using diethyl acetamidomalonate and 2-methyl benzylbromide as the starting materials and the racemic amino acids were separated into optical isomers L-amino acids and Ac-D-amino acids by acylase. The yield is 34.8%. The chemical structures of Boc-L-methylphenylalanines were confirmed by IR, ¹H NMR, MS and optical rotation. In comparison of the two methods, the former is simpler, with a higher yield and lower cost. Therefore, it is suitable for industrial application and laboratory preparation.

Key words: Non-natural amino acids, Boc-L-methylphenylalanine, Resolution