5751-20-2Relevant academic research and scientific papers
Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo-functionalised 4-aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions
Arce, Elsa M.,Lamont, Scott G.,Davies, Paul W.
, p. 2503 - 2509 (2020/04/30)
Functionalised N-heterocyclic pyridinium N-aminides have been designed and synthesised to evaluate a nitrenoid-based annulation strategy into imidazole-fused oxo-substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold-catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino-sulfenyl substituted nitrogen heterocycles under mild reaction conditions. (Figure presented.).
Scaffold hopping in discovery of HIV-1 non-nucleoside reverse transcriptase inhibitors: From CH(CN)-DABOs to CH(CN)-dapys
Chen, Fen-Er,Li, Ting-Ting,Pannecouque, Christophe,Zhuang, Chun-Lin,de Clercq, Erik
, (2020/04/10)
Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC50 = 6 nM) and B6 (EC50 = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC50 values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC50 = 0.08 μM). The preliminary structure-activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.
Design of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker as HIV-1 NNRTIs via a molecular hybridization strategy
Chen, Fen-Er,Han, Sheng,Lei, Yuan,Pannecouque, Christophe,Yang, Yang,Zhuang, Chunlin,de Clercq, Erik
, (2020/03/17)
The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 μM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 μM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 μM; Y181C, 0.87 μM; K103N, 0.9 μM; L100I, 1.21 μM, respectively), and an IC50 value of 0.059 μM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.
Synthesis method of 4-chloro-2-methylthiopyrimidine
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Paragraph 0022; 0023; 0024; 0025-0028; 0037-009, (2019/06/30)
The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of 4-chloro-2-methylthiopyrimidine. The method includes taking 2-thiouracil as a raw material, dimethyl sulfate as a methylation reagent, thionyl chloride and phosphorus oxychloride as a chlorination reagent, and synthesizing the 4-chloro-2-methylthiopyrimidine through methylation and chlorination.The dimethyl sulfate is taken as the methylation reagent to replace methyl bromide or methyl iodide, and thus the safety of the reaction is increased, and the cost is decreased; sodium hydroxide istaken as alkali to replace sodium methoxide or butyl lithium, and thus the safety of the reaction is increased, and the cost is reduced; toluene is taken as a reaction solvent, and thus the dosage ofthe chlorinated reagent is greatly reduced, the reaction safety is greatly improved, the cost is reduced, and the post-treatment operation is simplified; and the sulfoxide chloride and the phosphorusoxychloride are taken as the mixed chlorinating reagent, and thus the reaction yield is greatly improved.
BF3·SMe2 for Thiomethylation, Nitro Reduction and Tandem Reduction/SMe Insertion of Nitrogen Heterocycles
S?derstr?m, Marcus,Zamaratski, Edouard,Odell, Luke R.
, p. 5402 - 5408 (2019/06/27)
Herein, a general, solvent-free and straightforward thiomethylation of electron deficient heterocycles using BF3·SMe2 as a dual thiomethyl source and Lewis acidic activator is presented. A range of heterocycles including pyrimidine, pyrazine, pyridazine, thiazole and purine derivatives were successfully substituted using this method. An unexpected reductive property of BF3·SMe2 towards nitropyridines was also discovered including an intriguing tandem reduction/SMe insertion process in certain substrates. Notable features of the present work include its convenience and use of a non-malodorous reagent while the discovery of novel chemical transformations using BF3·SMe2 provides fundamental new insights into the reactivity of this commonly employed reagent.
A new and efficient protocol for the synthesis of the key intermediate of palbociclib
Li, Shuting,Yang, Wanfeng,Ji, Min,Cai, Jin,Chen, Junqing
, p. 14 - 19 (2019/06/21)
A new and efficient synthesis of 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one, a key intermediate of Palbociclib, starting from thiouracil was described. This protocol involved methylation, nucleophilic substitution, bromination, nucleophilic substitution, Heck reaction, ring closure, oxidation, and bromination to afford a key intermediate of Palbociclib with approximately 35% overall yield. The advantages of this developed synthetic strategy included improved overall yield, inexpensive starting materials, and readily controllable and cleaner reaction conditions.
NOVEL IN-VIVO PROBE FOR REAL TIME LONGITUDINAL MONITORING OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN LIVING CELLS AND ANIMALS
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Paragraph 0074, (2018/06/06)
The present disclosure relates to an in vivo fluorescent or radioactive probe represented by a compound of formula I which is capable of longitudinal imaging of inducible nitric oxide synthase (iNOS) expression in living cells and living animals on a real time basis. The probe of the present disclosure can exhibit specific and high affinity binding to the iNOS enzyme with reduced enzyme inhibitory property and also enables longitudinal monitoring of iNOS expression along with its activity or NO production in a same experimental subject throughout the progression of a physiological or disease process without employing separate subjects as controls and experimental. The present disclosure further provides a rapid and inexpensive real time method for visualizing iNOS expression and its activity in living cells and living animals precisely, conveniently and reversibly along with simultaneous in vivo imaging of its catalytic product, nitric oxide (NO) in live physiological settings.
Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR
Lu, Huan-Huan,Xue, Ping,Zhu, Yuan-Yuan,Ju, Xiu-Lian,Zheng, Xiao-Jiao,Zhang, Xun,Xiao, Ting,Pannecouque, Christophe,Li, Ting-Ting,Gu, Shuang-Xi
, p. 2491 - 2497 (2017/04/03)
30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8?nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities. The structure-activity relationship (SAR) study was also summarized.
A Palumbo vial preparation method of the key intermediate (by machine translation)
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Paragraph 0008; 0010, (2018/03/24)
The invention discloses a Palumbo Xilin key intermediate 6 - bromo - 2 - methyl sulfonyl - 8 - cyclopentyl - 5 - methyl pyridine and (2, 3 - d) pyrimidine - 7 (8 H) - ketone. The method uses the thiourea pyrimidine as the starting material, by methylation, chloro, bromo synthesis of 5 - bromo - 4 - chloro - 2 - methylthio-pyrimidine, then with the cyclopentamine alkylation, with 2 - butenoic acid by the heck reaction, then the intramolecular acylation reaction for the synthesis of 2 - methylthio - 8 - cyclopentyl - 5 - methyl pyridine and (2, 3 - d) pyrimidine - 7 (8 H) - one, finally with the NBS reaction for the preparation of 6 - bromo - 2 - methyl sulfonyl - 8 - cyclopentyl - 5 - methyl pyridine and (2, 3 - d) pyrimidine - 7 (8 H) - one. The preparation process of the present invention short step, not using the dangerous process, simple and convenient operation, low cost of raw materials, to meet the using requirements of the people. (by machine translation)
Industrial synthesis method of rilpivirine and intermediate compound
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Paragraph 0028; 0038-0040, (2017/10/07)
The invention discloses an industrial synthesis method of rilpivirine. A compound as shown in a formula I and compound hydrochloride as shown in a formula VI react to obtain rilpivirine. The invention further discloses an intermediate compound as shown in the formula I and a synthesis method of the intermediate compound. Compared with the prior art, the synthesis method is simple to operate, mild in condition, high in yield and purity and suitable for industrial production.
