885693-20-9Relevant articles and documents
Multigram Synthesis of Heterabicyclo[n.1.0]alkan-1-yl Trifluoroborates
Kleban, Ihor,Krokhmaliuk, Yevhen,Reut, Sofiia,Shuvakin, Serhii,Pendyukh, Vyacheslav V.,Khyzhan, Oleksandr I.,Yarmoliuk, Dmytro S.,Tymtsunik, Andriy V.,Rassukana, Yuliya V.,Grygorenko, Oleksandr O.
, p. 6551 - 6560 (2020/09/17)
An approach to the synthesis of oxa- and azabicyclo[n.1.0]alkan-1-yl trifluoroborates on a multigram scale was developed. Two synthetic strategies were evaluated: the first based on the lithiation–borylation of the corresponding 2-bromoallyl derivatives, and the other relying on regioselective hydroboration of the appropriate hetera-substituted enynes. The second method appeared to be more efficient in terms of scalability and substrate scope. Further steps included ring closing-metathesis, mild palladium-catalyzed cyclopropanation with diazomethane, and reaction with KHF2 and furnished the title compounds in up to 50 g scale in a single run (10–41 % overall yield, 4–5 steps).
Preparation method of N-substituted-tetrahydropyridine-3/4-boric acid/ester
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Paragraph 0041-0043, (2020/04/22)
The invention discloses a preparation method of N-substituted tetrahydropyridine-3/4-boric acid/ester, and belongs to the technical field of organic boric acid chemistry. The method comprises the following steps: carrying out a reaction on pyridine-3/4-boric acid/ester and a halide to form a quaternary salt, and reducing the quaternary salt with sodium/potassium borohydride in an aprotic solvent to generate N-substituted-tetrahydropyridine-3/4-boric acid/ester. According to the method, easily-synthesized pyridine-3/4-boric acid/ester is used as a raw material, the product can be obtained through two continuous steps, and the reaction selectivity is high, so that the defect that palladium-catalyzed coupling or ultralow temperature is needed when substituted piperidone is adopted as a raw material is overcome, the method is verified on the hectogram scale, and a concise and efficient synthesis path is provided for preparation of the compound.
Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration
Tresadern, Gary,Velter, Ingrid,Trabanco, Andrés A.,Van Den Keybus, Frans,MacDonald, Gregor J.,Somers, Marijke V. F.,Vanhoof, Greet,Leonard, Philip M.,Lamers, Marieke B. A. C.,Van Roosbroeck, Yves E. M.,Buijnsters, Peter J. J. A.
, p. 12887 - 12910 (2020/11/13)
We describe the hit-To-lead exploration of a [1,2,4]triazolo[1,5-A]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-Throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC50′s from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 ± 0.39 nM, a 100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.
