881995-73-9Relevant articles and documents
Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin
Sudhakaran, Shana,Shinde, Prasad G.,Aratikatla, Eswar K.,Kaulage, Sandeep H.,Rana, Priksha,Parit, Ratan S.,Kavale, Dattatry S.,Senthilkumar, Beeran,Punji, Benudhar
, (2021/12/09)
Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75–92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)- and (S)-1-phenylethylamines, the partially enantioenriched (R)- and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided >99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.
A west he row sandbank chiral intermediate and asymmetric synthesis method
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, (2017/08/25)
The invention relates to a sitagliptin chiral intermediate and an asymmetric synthesis method thereof. The asymmetric synthesis method comprises the steps: with 2,4,5-trifluorophenyl acetic acid as a starting material, carrying out a reduction reaction to obtain 2-(2,4,5-trifluorophenyl)ethanol, then carrying out a reaction with an oxidant, carrying out condensation of the product without separation and (R)-(+)-tert-butyl sulfinamide to obtain corresponding acetal, carrying out a reaction of the obtained product with dialkyl malonate to obtain a key chiral intermediate, hydrolyzing to obtain a corresponding organic amine, carrying out a reaction of the amine with caustic alkali and then acidifying to obtain a corresponding carboxylic acid, then carrying out condensation with 3-(trifluoromethyl)-5,6,7,8- tetrahydro-[1,2,4] triazolo[4,3-a]pyrazine hydrochloride to obtain sitagliptin tert-butyl oxanamide, and finally deprotecting with hydrochloric acid to obtain sitagliptin. The yields of all the steps are all higher, the used reagents are all conventional cheap reagents, no expensive chiral catalysts are used, the reaction conditions are quite mild, and the asymmetric synthesis method is suitable for industrialization.
Glucovance west Geleg sandbank intermediate process for the preparation of amino acid derivatives
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, (2019/02/02)
The invention discloses a preparation method of a new diabetes drug sitagliptin intermediate aminobenzene butyric acid derivative. The preparation method comprises the following steps of: (1) mixing a compound shown in a formula I with R(+)-alpha-phenethyl and acetic acid to obtain a compound shown in a formula II; (2) mixing the compound shown in the formula II with sodium borohydride and protonic acid or lewis acid to obtain a compound shown in a formula III; (3) mixing the compound shown in the formula III with X to obtain a compound shown in a formula IV; (4) mixing the compound as shown in the formula IV with an inorganic base 1 to obtain a compound shown in a formula V; (5) obtaining a compound shown in a formula VI by the compound shown in the formula V; and (6) mixing the compound shown in the formula VI with an inorganic base 2 to obtain a compound shown in a formula VII.