1361389-75-4Relevant articles and documents
Synthesis method of sitagliptin
-
, (2020/05/29)
The invention discloses a synthetic method of sitagliptin. The synthesis method comprises the following steps of: carrying out a reaction on 1,3,5-trifluorophenylacetic acid as a raw material and pivaloyl chloride to convert into acyl chloride; under the
Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas
Hayama, Noboru,Kuramoto, Ryuta,F?ldes, Tamás,Nishibayashi, Kazuya,Kobayashi, Yusuke,Pápai, Imre,Takemoto, Yoshiji
, p. 12216 - 12225 (2018/09/25)
Carboxylic acids and their corresponding carboxylate anions are generally utilized as Br?nsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Br?nsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.
First generation process for the preparation of the DPP-IV inhibitor sitagliptin
Hansen, Karl B.,Balsells, Jaume,Dreher, Spencer,Hsiao, Yi,Kubryk, Michele,Palucki, Michael,Rivera, Nelo,Steinhuebel, Dietrich,Armstrong III, Joseph D.,Askin, David,Grabowski, Edward J. J.
, p. 634 - 639 (2012/12/25)
A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.
