Synthesis towards nemonapride and its derivatives / Siti Norazra Khairina Muhamad

Nemonapride 1, was introduced into pharmaceutical industry by a Japanese company, Yamanouchi Co. Ltd. in 1991. It has a unique N-benzyl-pyrrolidine moiety bonded to an amide functional group, linking the substituted benzene ring. Nemonapride or commercially known as emilace, is an atypical antipsychotic drug used for the treatment of schizophrenia. Since the number of patients nowadays has been increasing, global demand for antidepressant and antipsychotic medicines such as nemonapride increases too. In this study, an efficient synthetic strategy towards synthesizing nemonapride and their derivatives was constructed by using 2,4-pyrrolidinedione (tetramic acid) as the key intermediate. In the first part, derivatives of tetramic acid 5, 91 and 95 were synthesized from several amino acid methyl esters using a stepwise reaction which includes condensation, Dieckmann cyclization and decarboxylation. In the second part, only the synthesized tetramic acid 5 proceeded further that was reduced to form hydroxypyrrolidine 11 and hydroxylactam pyrrolidine 14, while at the same time underwent amination reaction that produced oxime 98 and enamine 99. Towards the synthesis of aminopyrrolidine 2, the hydroxyl group on 11 underwent a substitution reaction to produce O-mesylated 96 and azide-pyrrolidine 97. The final part focused on synthesizing nemonapride and its derivatives using the synthesized intermediate via peptide coupling and esterification reactions. Substituted benzoic acid 3 was synthesized from substituted benzoate as the starting material which was then condensed with the intermediates 11, 14 and 99. A few methods were employed which then only the acylated 101 was obtained. Nevertheless, none of the nemonapride-skeleton-alike was successfully synthesized.