- N-Nitroheterocycles: Bench-Stable Organic Reagents for Catalytic Ipso-Nitration of Aryl- And Heteroarylboronic Acids
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Photocatalytic and metal-free protocols to access various aromatic and heteroaromatic nitro compounds through ipso-nitration of readily available boronic acid derivatives were developed using non-metal-based, bench-stable, and recyclable nitrating reagents. These methods are operationally simple, mild, regioselective, and possess excellent functional group compatibility, delivering desired products in up to 99% yield.
- Budinská, Alena,Katayev, Dmitry,Passera, Alessandro,Zhang, Kun
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supporting information
(2020/03/30)
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- Synthesis process of 2-methoxy-3-bromo-5-fluoropyridine
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The invention discloses a synthesis process of 2-methoxy-3-bromo-5-fluoropyridine, which comprises the following steps: dissolving 2-methoxy-5-aminopyridine in an acid, adding nitrous acid or nitriteto prepare a diazotized intermediate state, reacting with a fluorinating reagent to obtain 2-methoxy-5-fluoropyridine, and carrying out a bromination reaction process on 2-methoxy-5-fluoropyridine anda bromination reagent to obtain 2-methoxy-3-bromo-5-fluoropyridine. The synthesis process provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, high yield, easiness in industrial production and the like.
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Paragraph 0043; 0046-0051
(2021/03/06)
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- Methnaridine is an orally bioavailable, fast-killing and long-acting antimalarial agent that cures Plasmodium infections in mice
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Background and Purpose: Malaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy. Experimental Approach: An integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed. Key Results: Methnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC50 = 0.0066 μM; Dd2: IC50 = 0.0056 μM). In P. berghei-infected mice, oral administration effectively suppressed parasitemia (ED50 = 0.52 mg·kg?1·day?1) and cured the established infection (CD50 = 10.13 mg·kg?1·day?1). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four-dose oral regimen at a dosage of 25 mg·kg?1 achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT99 = 36.0 h) and showed no cross-resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long-lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg?1). In addition, following methnaridine treatment, infection-induced Th1 immune response was almost fully alleviated in mice. Conclusion and Implications: Methnaridine is an orally bioavailable, fast-acting and long-lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.
- Wang, Weisi,Yao, Junmin,Chen, Zhuo,Sun, Yiming,Shi, Yuqing,Wei, Yufen,Zhou, Hejun,Yu, Yingfang,Li, Shizhu,Duan, Liping
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supporting information
p. 5569 - 5579
(2020/11/03)
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- Preparation method for malaridine intermediate 2-methoxy-5-aminopyridine
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The invention provides a green environment-friendly preparation method for a malaridine intermediate 2-methoxy-5-aminopyridine. The preparation method comprises the specific method: with 2-aminopyridine as a raw material, nitrating 2-aminopyridine with a mixed acid in the presence of a solvent to obtain 2-amino-5-nitropyridine; and carrying out hydrolysis, chlorination, methoxylation and reduction to obtain the intermediate 2-methoxy-5-aminopyridine. The preparation method has the advantages of simple process, short production cycle, mild reaction conditions, fewer three wastes, high product purity and yield, cheap and easily obtained raw materials, and higher economic property and environmental protection, and is suitable for industrialized production.
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Paragraph 0026; 0057; 0058
(2016/10/10)
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- TRI-HETEROCYCLIC DERIVATIVES, PREPARATION PROCESS AND USES THEREOF
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The present invention relates to a tri-heterocyclic derivatives, preparation process and uses thereof, specifically relates to a tri-heterocyclic derivatives of the formula (I) or a pharmaceutically acceptable salt thereof, preparation process, and further relates to a pharmaceutically acceptable composition comprising compounds of formula (I), or a pharmaceutically acceptable salt thereof, and their pharmaceutical use as inhibitors of kinase.
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Paragraph 0123; 0237
(2014/11/13)
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- TRI-HETEROCYCLIC DERIVATIVES, PREPARATION PROCESS AND USES THEREOF
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The present invention relates to a tri-heterocyclic derivatives, preparation process and uses thereof, specifically relates to a tri-heterocyclic derivatives of the formula (I) or a pharmaceutically acceptable salt thereof, preparation process, and further relates to a pharmaceutically acceptable composition comprising compounds of formula (I), or a pharmaceutically acceptable salt thereof, and their pharmaceutical use as inhibitors of kinase
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Page/Page column 30
(2013/07/05)
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- Triton B-mediated efficient and convenient alkoxylation of activated aryl and heteroaryl halides
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A simple and convenient one-pot synthesis of aryl alkyl ethers by the alkoxylation of aryl halides with alcohol in the presence of Triton B as a base is described. The procedure is applicable for a variety of aryl and heteroaryl halides, and yields are very good. The use of a nonmetallic base and solvent-free conditions are important features of the reaction. Copyright Taylor & Francis Group, LLC.
- Meshram,Goud, P. Ramesh,Reddy, B. Chennakesava,Kumar, D. Aravind
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experimental part
p. 2122 - 2129
(2010/08/13)
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- Substitution reactions of 5-nitropyridine-2-sulfonic acid. A new pathway to 2,5-disubstituted pyridines
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We have investigated reactions of 5-nitropyridine-2-sulfonic acid and its potassium salt in which substitution of the sulfonate group by oxygen, nitrogen and halogen nucleophiles has been attempted. By this approach, 2-methoxy-(95% yield), 2-ethoxy- (97%), 2-isopropoxy- (65%), 2-amino- (92%), 2- butylamino- (76%), 2-diethylamino- (62%), 2-ethylamino- (32%), 2-benzylamino- (77%), 2-(R-1-phenylethylamino)- (71%) and 2-chloro-5-nitropyridine (87%) have been obtained. No reactions were observed with phenols or anilines. With t-BuOH, 2-hydroxy-5-nitropyridine was formed together with 2-methylpropene.
- Bakke, Jan M.,Sletvold, Ingrid
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p. 2710 - 2715
(2007/10/03)
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- On the thermally induced rearrangement of 2-alkoxypyridines to N-alkylpyridones
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Analogues of 2-methoxypyridine undergo rearrangement to N-methylpyridones under flash vacuum pyrolysis (FVP) conditions. Ethoxy derivatives undergo competitive ethyl migration and elimination of ethylene. Analogues of 4-methoxypyridine do not undergo rearrangement under FVP conditions, but demethylation on silica may occur. The ease of rearrangement follows the basicity of the alkoxyhetarene to some extent. The vapour-phase rearrangements have been contrasted to condensed-phase pyrolyses. and a four-centre transition state for the former is supported by computation. The rearrangement allows structural assignment to the two products from the reaction of 2,4-dichloroquinoline with pyrrolidine.
- Lister, Troy,Prager, Rolf H.,Tsaconas, Michael,Wilkinson, Kerry L.
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p. 913 - 916
(2007/10/03)
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- Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5- substituted quinazolinones
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The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-resolution ternary crystal complex of Escherichia coli TS, 5'-fluorodeoxyuridylate (5-FdUMP) and a classical glutamate-containing folic acid analog. A preliminary ternary crystal structure of a novel compound was successfully solved. Upon analysis of this initial complex, further structural elaborations were made, and a series of active 5- (arylthio)quinazolinones was developed. The synthetic strategy was based on the displacement of a halogen at the 5-position of a quinazolinone by various arylthioanions. The compounds were tested for inhibition of purified E. coli and/or human TS, and were assayed for cytotoxicity against three tumor cell lines in vitro. Significant thymidine protection effects were observed with several of the inhibitors, indicating that TS was the intracellular locus of activity.
- Webber,Bleckman,Attard,Deal,Kathardekar,Welsh,Webber,Janson,Matthews,Smith,Freer,Jordan,Bacquet,Howland,Booth,Ward,Hermann,White,Morse,et al.
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p. 733 - 746
(2007/10/02)
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- Acrylamide derivatives as antiallergic agents. 2. Synthesis and structure-activity relationships of N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamides
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A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compounds 1a [(E)-N-[4 [4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, 4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.
- Nishikawa,Shindo,Ishii,Nakamura,Kon,Uno
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p. 583 - 593
(2007/10/02)
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- Reactions in Strongly Basic Media. Part 9. Correlation of the Rates of Methoxide-catalysed Methanolysis of 1-Substituted 2,4-Dinitrobenzenes and 2-Substituted 5-Nitropyridines in Methanolic Dimethyl Sulphoxide with an Acidity Function. Details of the Mechanistic Pathway
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The rate coefficients for the methoxide-catalised methanolysis of a series of 1-substituted 2,4-dinitrobenzenes and 2-substituted 5-nitropyridines have been measured in methanolic DMSO at 20.0 or 21.0 deg C.For the 2-substituted 5-nitropyridines and for the 1-substituted 2,4-dinitrobenzenes below ca. 55 mol percent DMSO, the rates have been correlated with an acidity function of the medium.The slopes of these linear relations are discussed.The 1-substituted 2,4-dinitrobenzenes above ca. 55 mol percent DMSO give rise to Meisenheimer complexes as intermediates and/or as the product of the reaction.The product of the reaction then becomes the 1,1-Meiseheimer complex of methoxide and 2,4-dinitroanisole.For the 1-fluoro substrate the formation of the latter becomes rate determining.For other 1-substituted substrates the decomposition of a 1,3-Meisenheimer complex becomes rate determining.
- Bowden, Keith,Nadvi, Nighat S.
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p. 189 - 192
(2007/10/02)
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- Liquid Crystalline Compounds Bearing Pyridine Ring: 3-(4-Alkoxyphenylazoxy)-6-alkoxypyridines
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3-(4-Alkoxyphenylazo)-6-alkoxypyridines (6) with n-alkoxyl (C1-C6) groups were synthesized by the coupling reaction of phenol with 6-alkoxy-3-pyridine diazonium chloride prepared from 2-chloro-5-nitropyridine via 2-alkoxy-5-nitro and 2-alkoxy-5-aminopyridines and subsequent etherification with n-alkyl iodides.Mild oxidation of 6 with hydrogen peroxide in acetic acid provided 3-6-alkoxy-pyridines (7) containing nearly equimolar amounts of ONN (8) and NNO (8') isomers.Centrifugal liquid chromatography satisfactorily separated these two isomers.Mesomorphic behaviors of 8 and 8' are characteristic in that the pyridine ring exerts polar effects and 8 are more balanced in polarity than 8'.Compounds 7 possess rather lower mesomorphic ranges than 8 and 8'.Some of compounds 6 indicate mesomorphic ranges but generally azo compounds are inferior to azoxy ones.
- Kamogawa, Hiroyoshi,Kasai, Tsuneharu
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- REACTIVITIES OF HETEROCYCLIC COMPOUNDS IN NITRATION. 7. EXPERIMENTAL AND THEORETICAL STUDY OF THE REACTIVITIES OF PYRIDINES
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The relationship between the rates of nitration of pyridines and the calculated indexes of aromatic electrophilic substitution was investigated.The possibility of the use of two-center components of the location energies for the theoretical description of the reactivities of pyridines in nitration is demonstrated.The rates of nitration of a number of previously uninvestigated pyridines are predicted.
- Sharnin, G. P.,Saifullin, I. Sh.,Falyakhov, I. F.,Khairutdinov, F. G.,Bol'shakova, T. G.,Zverev, V. V.
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p. 514 - 517
(2007/10/02)
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