Synthesis Research Of Saxagliptin, Intermediate Of Dutogliptin And Zotepine

We finished the following three parts of work in this thesis:1. Saxagliptin is the third dipeptidyl peptidase Ⅳ (DPP-Ⅳ) inhibitor which was approved bythe US FDA in July2009for treatment of Type2diabetes.(S)-Adamantane amino acidfragment was synthesized from1-Adamantanecarboxylic acid by Streacker reaction andfrom1-Adamantaneacetic acid via Hell-Volhard-Zelinski α-bromination, separately. The1-Adamantanecarboxylic acid route was paused because of the α-aminonitrile can not behydrolyzed into α-amino-acid. In the other route we obtained the racemic Adamantaneamino acid on the basis of the original patent, the yield was increased from63.7%to75.8%. The key intermediate (S)-N-Boc-Adamantane amino acid was obtained throughchemical resolution successfully.(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamidefragment was synthesized through methyl esterification, amino protection of Boc,reductive elimination reaction, amidation, Simmons-Smith reaction and removel of Boc.Finally, after coupling the two fragments and the following two reactions, we obtained theSaxagliptin with13linear steps and4.57%total yield.2.(R)-3-aminopyrrolidine and its derivatives was the key intermediate of Dutogliptin, adipeptidyl peptidase Ⅳ (DPP-Ⅳ) inhibitor of Type2diabetes which was development byPhenomix Corporation. We finished two different derivatives of (R)-3-aminopyrrolidine.N-Boc-1-benzyl-3-aminopyrrolidine was synthesized from D-aspartic acid, throughmethyl esterification, amino protection of Boc, reduction, hydroxyl activation andcyclization of benzylamine. The mole yield of all five steps was37.6%.1-benzyl-3-aminopyrrolidine was synthesized from benzylamine and ethyl acrylate, thetarget compound can be obtained through the following six steps, Michael addition,alkylation, Claisen condensation, decarboxylation, oximation and reduction. The totalmole yield is62.8%.3.8-chlorodibenzo[b,f]thiepin-10(11H)-one was a key synthetic intermediate of atypical neuro drug, Zotepine. Starting from1-(2-chlorophenyl)ethanone and4-chlorobenzenethiol, the target product was synthesis by CuI-Proline coupling reaction,Willgerodt-Kindler rearrangement, hydrolysis and intermolecular cyclization reaction.The mole yield of the all four steps is40%.