344329-76-6Relevant articles and documents
Synthesis method for 4-Aaminotetrahydropyran synthesis
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Paragraph 0020; 0028; 0034; 0035; 0036; 0044; 0052, (2018/06/23)
The invention discloses a synthesis method for 4-aminotetrahydropyran. The method comprises the steps that tetrahydro-2H-pyran-4-carboxylic acid is dissolved in water, the temperature is increased to60-70 DEC G by heating, ammonia water is added dropwisely under the condition of stirring, stirring reaction is conducted for 1-2 hours after dropwise adding is completed, the temperature is decreasedto the room temperature after the reaction is completed to obtain tetrahydro-2H-pyran-4-carboxamide mixed solution; cooling is conducted on the prepared tetrahydro-2H-pyran-4-carboxamide mixed solution to reduce the temperature to 5-10 DEC G, NaOH solution is added, NaBrO solution is added dropwisely in the mixed solution after the mixed solution is stirred uniformly, after the dropwise adding iscompleted, the reaction is performed constantly for 1-2 hours under the temperature of 5-10 DEC G, the temperature is decreased to the room temperature after the temperature is increased to 50-60 DECG to perform the reaction constantly for 1 hour, extraction is conducted by using dichloromethane, an organic phase is combined, and after the dichloromethane is removed by distillation through reducing pressure, recrystallization is conducted to obtain the 4-aminotetrahydropyran. The method has the advantages of being simple to operate, mild in condition, less in byproducts, high in product purity, and higher in product yield.
Optimization of diarylthiazole B-Raf inhibitors: Identification of a compound endowed with high oral antitumor activity, mitigated hERG inhibition, and low paradoxical effect
Pulici,Traquandi,Marchionni,Modugno,Lupi,Amboldi,Casale,Colombo,Corti,Fasolini,Gasparri,Pastori,Scolaro,Donati,Felder,Galvani,Isacchi,Pesenti,Ciomei
, p. 276 - 295 (2015/02/05)
Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R1 and R2 groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg-1); it is therefore a suitable candidate for preclinical development.
Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries
Craven, Philip,Aimon, Anthony,Dow, Mark,Fleury-Bregeot, Nicolas,Guilleux, Rachel,Morgentin, Remy,Roche, Didier,Kalliokoski, Tuomo,Foster, Richard,Marsden, Stephen P.,Nelson, Adam
supporting information, p. 2629 - 2635 (2015/01/30)
The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.
