6966-45-6Relevant articles and documents
Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a Meta-Selective Inverse Sonogashira Coupling
Bhowmick, Suman,Guin, Srimanta,Kumar Singh, Vikas,Maiti, Debabrata,Paton, Robert S.,Porey, Sandip,Zhang, Xinglong
supporting information, p. 3762 - 3774 (2020/03/10)
The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the β-bromide elimination step.
Optimization of P2Y12 Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties
Kong, Deyu,Xue, Tao,Guo, Bin,Cheng, Jianjun,Liu, Shunyin,Wei, Jianhai,Lu, Zhengyu,Liu, Haoran,Gong, Guoqing,Lan, Tian,Hu, Wenhao,Yang, Yushe
supporting information, p. 3088 - 3106 (2019/04/01)
P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.
Photocatalytic Radical Alkylation of Electrophilic Olefins by Benzylic and Alkylic Zinc-Sulfinates
Gualandi, Andrea,Mazzarella, Daniele,Ortega-Martínez, Aitor,Mengozzi, Luca,Calcinelli, Fabio,Matteucci, Elia,Monti, Filippo,Armaroli, Nicola,Sambri, Letizia,Cozzi, Pier Giorgio
, p. 5357 - 5362 (2017/08/17)
Alkyl radicals are obtained by photocatalytic oxidation of readily prepared or commercially available zinc sulfinates. The convenient benzylation and alkylation of a variety of electron-poor olefins triggered by the iridium(III) complex 6 Ir[dF(CF3)ppy]2(dtbbpy)PF6 as photocatalyst is described. Moreover, it is shown that zinc sulfinates can be used for facile nonradical sulfonylation reactions with highly electrophilic Michael acceptors.
