Synthesis And Applications Of Chiral Phenylpiperazine Derivatives

Chiral 3-phenylpiperazine and 2-phenylpiperazine derivatives are the important intermediates of PDE10A enzyme inhibitors, which is used in treatment of neurodegenerative and psychiatric disorders especially schizophrenia, and 17β-hydroxysteroid dehydrogenase inhibitors (therapeutical agent in treatment of androgen-dependent diseases). In this thesis we study their synthesis, process optimization and applications.(S)-3-phenyl-1-benzylpiperazine was synthesized from easily available animo acids with two different methods.One is (S)-2-phenylglycine as a starting materials, the target product was synthesized by esterification, reaction with chloroacetyl chloride, cyclization and reduction; The other is the target product was prepared by (S)-2-phenylglycine via Boc-protection, condensation with N-benzylglycine easter, cyclization and reduction. To our surprise, racemization happened during the cyclization in method one. (S)-N-Boc-2-phenylpiperazine was obtained by using (S)-3-phenyl-1-benzylpiperazine as raw material via N-Boc-protection and debenzylation. In this paper we explored the materials ratio, reaction time, reaction temperature, solvent, and processing method factors and economic factors to survey its optimal process conditions and optimal parameters. The intermediates structures were characterized by IR, MS,1H NMR,13C NMR. Finally we studied the preliminary applications of chiral phenylpiperazine derivatives in the catalytic asymmetric Michael addition reactions.