- Preparation method of sitagliptin phosphate
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The invention discloses a preparation method of sitagliptin phosphate. The preparation method comprises the following steps: taking 4-(2, 4, 5-trifluorophenyl)-3-methyl oxobutyrate I as a raw material; the reaction is mainly divided into five steps: carrying out asymmetric reduction on the raw material I through an N-heterocyclic carbene palladium catalyst to obtain chiral alcohol ester s-4-(2, 4,5-trifluorophenyl)-3-methyl hydroxybutyrate II; carrying out intramolecular condensation cyclization on the II to obtain chiral lactam quaternary ring (R)-N-benzyloxy-4-[1-methyl-(2, 4, 5-trifluorophenyl)]-2-azetidinone III; carrying out ring opening on the III under an alkaline condition to obtain IV; performing condensation reaction to form amide to obtain V; carrying out catalytic reduction onthe V through recycled N-heterocyclic carbene palladium to remove benzyloxy and form phosphate to obtain sitagliptin phosphate VI, wherein the N-heterocyclic carbene palladium catalyst is Pd (IPr-NHC) (acac) Cl or Pd (IPr-NHC) (acac) Oac or Pd (IPr-NHC) (dba) Cl or Pd (IPr-NHC) (dba) OAc; the catalyst is cheap and easily available, can be recycled, and is beneficial to batch production.
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- Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas
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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.
- Hayama, Noboru,Kuramoto, Ryuta,F?ldes, Tamás,Nishibayashi, Kazuya,Kobayashi, Yusuke,Pápai, Imre,Takemoto, Yoshiji
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p. 12216 - 12225
(2018/09/25)
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- PREPARATION OF OPTICALLY PURE ?-AMINO ACID TYPE ACTIVE PHARMACEUTICAL INGREDIENTS AND INTERMEDIATES THEREOF
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The present invention relates to the preparation of optically resolved chiral compounds of β-amino acid type active pharmaceutical ingredients (API), more specifically to β-aminobutyryl substituted compounds and especially β-aminobutyryl compounds having γ-bound aryl groups. The present invention more particularly relates to the preparation of enantiomerically enriched chiral compounds useful as intermediates for the preparation of anti-diabetic agents, preferably sitagliptin.
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- Preparation of Optically Pure ?-Amino Acid Type Active Pharmaceutical Ingredients and Intermediates thereof
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The present invention relates to the preparation of optically resolved chiral compounds of β-amino acid type active pharmaceutical ingredients (API), more specifically to β-aminobutyryl substituted compounds and especially β-aminobutyryl compounds having γ-bound aryl groups. The present invention more particularly relates to the preparation of enantiomerically enriched chiral compounds useful as intermediates for the preparation of anti-diabetic agents, preferably sitagliptin.
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Paragraph 0075; 0076
(2013/07/25)
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- Synthesis, biological assay in vitro and molecular docking studies of new imidazopyrazinone derivatives as potential dipeptidyl peptidase IV inhibitors
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A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)- hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan- 2-amine fumaric acid (17h, IC50 = 78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h.
- Zhu, Yanyun,Xia, Shuang,Zhu, Mingjie,Yi, Weiyin,Cheng, Jiagao,Song, Gonghua,Li, Zhong,Lu, Peng
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experimental part
p. 4953 - 4962
(2010/11/18)
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- First generation process for the preparation of the DPP-IV inhibitor sitagliptin
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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.
- 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.
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p. 634 - 639
(2012/12/25)
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