Synthesis Of4-Methylpipecolic Acid

Cyclic a-amino acids containing a piperidine ring are often employed in producing important muti-biological activities compounds. Pipecolic acids,which always show high biological activity, are non-natural amino acids,they were first found in fungi, plant and biological fluids of human. The largest subgroup of pipecolicacid derivatives is4-substituted compounds. The4-Substituted pipecolic acid derivatives are unnatural amino acids with modification, which often present very important biological activities. Among the4-substituted derivatives,(2R,4R)-4-methylpipecolic acid is a key intermediate for the preparation of the high selectivity thrombin inhibitor Argatroban. This paper is focusing on the research of synthesis and chiral separation of (2R,4R)-4-methylpipecolic acid. S-methyl-benzylamine and ethyl glyoxylate were employed to give chiral imine,and then chiral imine was combined with isoprene to give (6R/S)-[1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine via Diels-Alder reacition, which is the precursor of (2R,4R)-4-methylpipecolic acid. We also found that Lipase PS Amano SD and pig liver esterase can specially degrade the (6R)-[1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine to give (6R)-[1-(S)-benzyl]-4-methyl-3-en-6-pipecolic acid(de:99%), which means we can obtain (6S)-[1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine via this method. After that, a lot experiments have been done in the hydrogenation of [1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine to obtain optimized reaction conditions. Actually, we found that [1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine can be deoxygenized by Pd/C completely, while PtO2.3H2O can only deoxygenize them partly. In detail,(2S,4R)-4-methyl-2-piperidinecarboxylate and (2S,4R/S)-[1-(S)-benzyl]-4-methyl-2-piperidinecarboxylate were obtain by using above-mentioned catalysts respectively. In addtion, this paper were trying to achieve the chiral separation of (2S,4R/S)[1-(S)-benzyl]-4-methyl-2-piperidinecarboxylate,but none positive results were obtained.