ALPHA-ALKYLATION OF AMINO-ACID DERIVATIVES - SYNTHESIS AND CHIRAL RESOLUTION OF [C-11] BETA-AMINOISOBUTYRIC ACID

A synthesis of C-11-labeled beta-aminoisobutyric acid ([C-11]beta-AIB) and its enantiomeric resolution by high performance liquid chromatogr aphy (HPLC) are reported. beta-Alanine ethyl ester 2 was converted to benzaldimine-beta-alanine ethyl ester 3 in 87% yield. Treatment of the imine derivative 3 with lithium diisopropylamide (1.1 eq) in tetrahyd rofuran at -78 degrees C, followed by addition of cold iodomethane (1. 1 eq) produced the alpha-methylated benzaldimine-beta-alanine ethyl es ter 4 in 73% chemical yield. Deprotection of the amino group by acidic hydrolysis followed by basic hydrolysis of the ester group produced t he desired product 1 in 37% chemical yield. Labeling was accomplished using [C-11]methyl iodide. The radiolabeled product was purified by HP LC using a semipreparative reversed phase C-18 column and 2 mM phospha te buffer (pH 5.9) as the mobile phase. The synthesis time was 35-40 m in including HPLC purification, with 20-60% radiochemical yield (decay corrected). Radiochemical purity was >99%, with average specific acti vity being 450 mCi/mu mol. Enantiomers of beta-AIB were well separated by analytical HPLC using a chiral column and aqueous perchloric acid as the mobile phase. (S)-beta-AIB was eluted at 17.4 min and the (R)-e nantiomer was eluted at 20.0 min when the jacketed column was maintain ed at low temperature by circulation of ice-cold water, and the pH of the mobile phase was 1.05.