![(5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester](/Databaselist/images/loading.webp)
709031-38-9Relevant academic research and scientific papers
Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: Preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin
Gill, Iqbal,Patel, Ramesh
, p. 705 - 709 (2006)
An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H- pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). (Chemical presented) Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.
Preparation method of key intermediate of saxagliptin
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Paragraph 0036; 0037, (2017/06/02)
The invention relates to a preparation method of (1S, 3S, 5S)-3-(amidogen carbonyl)-2- azabicyalo [3.1.0] hexane-2-tert-butyl formate. The preparation method comprises the following steps that (1), Boc-L-pyroglutamic acid methyl ester is restored through lithium triethylborohydride and then dewatered through trifluoroacetic anhydride to obtain (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole ethyl formate; (2), DIPEA is added in the hydrolysis reaction of (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole ethyl formate under a alkaline condition, then salifying is conducted, and (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formic acid N, N-diisopropyl ethylamine salt is obtained; (3), (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formic acid N and N-diisopropyl ethylamine salt obtained in the step (2) are subjected to amidating, and (S)-1-N- tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formamide is obtained; and (4), (S)-1-N-tert-butyloxycarbonyl-2,3-dihydro-2-pyrrole formamide is catalyzed through a chirality nickel catalyst and subjected to a ciprofloxacin reaction, and a target material with single configuration, namely (1S, 3S, 5S)-3-(amidogen carbonyl)-2-azabicyalo [3.1.0] hexane-2-tert-butyl formate (SM1), is obtained.
(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid-1(1,1-dimethylethyl)ester preparation method
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Paragraph 0017; 0018; 0019; 0020; 0021; 0022, (2016/12/01)
The present invention discloses a (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid-1(1,1-dimethylethyl)ester preparation method, wherein is 4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid[1-(1,1-dimethylethyl), 5-ethyl]ester is adopted as a raw material, sodium isopropoxide is adopted as an alkali reagent, and the raw material, the alkali reagent and formamide are subjected to a reaction in a solvent so as to obtain the target product. According to the present invention, the reaction conditions in the prior art are further optimized so as to improve the yield and easily achieve industrial production.
PROCESS FOR PREPARING DIPEPTIDYL PEPTIDASE IV INHIBITORS AND INTERMEDIATES THEREFOR
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, (2016/07/27)
A process for preparing an amine of the structure which comprises a. treating an aqueous solution of a keto acid of the structure with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified phenylalanine dehydrogenase and/or formate dehydrogenase enzyme (PDH/FDH); and b. adjusting pH of the reaction mixture with sodium hydroxide to form the desired amine which is substantially free of undesirable excess ammonium ions.
An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin, via an improved Simmons-Smith reaction
Ding, Ding,Pan, Xianhua,Yu, Wansheng,Li, Xiaojun,Chen, Suke,Liu, Feng
, p. 719 - 726 (2015/05/05)
L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin, was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid was formed through Zn/CuBr and CH2I2, under the optimized condition, the title compound was gained with 68% yield and excellent diastereomeric selectivity (40:1 d.r.). The absence of the flammable and expensive ZnEt2 makes this procedure very attractive in large scale production.
Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin
Dong, Jizhe,Gong, Yanchun,Liu, Jun,Chen, Xiangfeng,Wen, Xiaoan,Sun, Hongbin
, p. 1383 - 1393 (2014/03/21)
All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.
The effect of additives on the zinc carbenoid-mediated cyclopropanation of a dihydropyrrole
Ramirez, Antonio,Truc, Vu Chi,Lawler, Michael,Ye, Yun K.,Wang, Jianji,Wang, Chenchi,Chen, Steven,Laporte, Thomas,Liu, Nian,Kolotuchin, Sergei,Jones, Scott,Bordawekar, Shailendra,Tummala, Srinivas,Waltermire, Robert E.,Kronenthal, David
, p. 6233 - 6243 (2014/07/21)
The synthesis of a key intermediate in the preparation of oral antidiabetic drug Saxagliptin is discussed with an emphasis on the challenges posed by the cyclopropanation of a dihydropyrrole. Kinetic studies on the cyclopropanation show an induction period that is consistent with a change in the structure of the carbenoid reagent during the course of the reaction. This mechanistic transition is associated with an underlying Schlenk equilibrium that favors the formation of monoalkylzinc carbenoid IZnCH2I relative to dialkylzinc carbenoid Zn(CH2I)2, which is responsible for the initiation of the cyclopropanation. The factors influencing reaction rates and diastereoselectivities are discussed with the aid of DFT computational studies. The rate accelerations observed in the presence of Br?nsted acid-type additives correlate with the minimization of the undesired induction period and offer insights for the development of a robust process.
Ammonolysis process for the preparation of intermediates for DPP IV inhibitors
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Page/Page column 6, (2010/10/19)
A process is provided for preparing the intermediate A in accordance with the following reaction sequence The intermediate A is used in preparing DPP IV inhibitors which are useful in treating diabetes.
METHODS AND COMPOUNDS PRODUCING DIPEPTIDYL PEPTIDASE IV INHIBITORS AND INTERMEDIATES THEREOF
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Page 73, (2008/06/13)
Methods and compounds for production of cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV are provided
