102284-41-3Relevant academic research and scientific papers
Efficient and Scalable Synthesis of Glucokinase Activator with a Chiral Thiophenyl-Pyrrolidine Scaffold
Fujieda, Hiroki,Maeda, Koji,Kato, Noriyasu
, p. 69 - 77 (2019)
Herein we describe the practical synthesis of a potent glucokinase activator (1) that has a chiral thiophenyl-pyrrolidine scaffold. The key to the successful synthesis was the application of a telescoped chiral-pool synthesis from a commercially available l-proline methyl ester derivative to introduce the chirality of the thiophenyl-pyrrolidine moiety. This second-generation synthesis of 1 provided several advantages over the previous method including an operational simplicity and avoidance of purification by column chromatography. The industrial relevance of this synthetic method in large-scale preparation was demonstrated by the production of 54.6 kg of 1 with an excellent chemical and optical purity.
Continuous flow synthesis of α-halo ketones: Essential building blocks of antiretroviral agents
Pinho, Vagner D.,Gutmann, Bernhard,Miranda, Leandro S. M.,De Souza, Rodrigo O. M. A.,Kappe, C. Oliver
supporting information, p. 1555 - 1562 (2014/03/21)
The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ～4.5 h (87% yield).
Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP)
Jansen, Koen,Heirbaut, Leen,Verkerk, Robert,Cheng, Jonathan D.,Joossens, Jurgen,Cos, Paul,Maes, Louis,Lambeir, Anne-Marie,De Meester, Ingrid,Augustyns, Koen,Van Der Veken, Pieter
supporting information, p. 3053 - 3074 (2014/05/06)
Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure-activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP) the log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
A one-pot formal [4 + 2] cycloaddition approach to substituted piperidines, indolizidines, and quinolizidines. Total synthesis of indolizidine (-)-209I
Yu, Shanghai,Zhu, Wei,Ma, Dawei
, p. 7364 - 7370 (2007/10/03)
Heating a mixture of substituted N-benzyl γ-chloropropylamines, conjugated alkynoates or alkynones, sodium carbonate, and a catalytic amount of sodium iodide in i-PrOH at 70-83 °C delivers substituted piperidines in good yields. This transformation goes t
A practical method for the preparation of α'-chloroketones of N-carbanaate protected-α-aminoacids
Chen, Ping,Cheng, Peter T. W.,Spergel, Steven H.,Zahler, Robert,Wang, Xuebao,Thottathil, John,Barrish, Joel C.,Polniaszek, Richard P.
, p. 3175 - 3178 (2007/10/03)
A practical method for the preparation of α-N-BOC-epoxides from protected amino acid esters based on the Kowalski homologation reaction is described. This procedure can be readily performed on a large scale without the use of hazardous reagents and has allowed preparation of epoxides 3 in multi-kilogram quantities.
PEPTIDE ELASTASE INHIBITORS AND METHODS
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, (2008/06/13)
Compounds useful as inhibitors of the enzyme elastase are of the following general formula: STR1 wherein Z is selected from the group consisting of R"O--Suc--where R" is lower alkyl of 1 to 3 carbon atoms and CF 3 CO--; X is oxygen or sulfur; R' is selected from the group consisting of straight or secondary branch-chained alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 3 carbon atoms, alkynyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and benzyl, and R is selected from the group consisting of susbstituted or unsubstituted phenyl wherein the substituents are selected from the group consisting of nitro, and pentafluoro; benzyl, CH 2 CF 2 CF 2 CF 3, 1-lower alkyl tetrazolyl, 1-phenyltetrazolyl, 2-thioxo-3-thiazolidinyl-, pyridyl and benzothiazolyl, provided that when R is paranitrophenyl, R' is other than tertiary-butyl, benzyl or cyclohexyl, and when X is sulfur, R is other than benzyl. "
