824-94-2Relevant academic research and scientific papers
Facile synthesis of 3,6-diaminopyridazine
Xing, Liyan,Petitjean, Anne,Schmidt, Rolf,Cuccia, Louis
, p. 2349 - 2353 (2007)
An efficient two-step synthesis of 3,6-diaminopyridazine from 3,6-dichloropyridazine is reported. In this synthetic procedure, 4-methoxybenzylamine was used as a nitrogen source to substitute the chloro groups of 3,6-dichloropyridazine to form N,N'-bis-(4-methoxybenzyl)-pyridazine- 3,6-diamine. The 4-methoxybenzyl groups were then removed by treatment with hydrochloric acid to provide the target 3,6-diaminopyridazine with an overall yield of 78%. Copyright Taylor & Francis Group, LLC.
Triphosgene/triphenylphosphine: A mild reagent for the conversion of alcohols to chlorides
Rivero,Somanathan,Hellberg
, p. 711 - 714 (1993)
A mixture of triphosgene/triphenylphosphine in methylene chloride converts primary and secondary alcohols to chlorides at room temperature.
Two approaches to the chemical development and large-scale preparation of a pyrimidyl tetrazole intermediate
Mullens, Peter,Cleator, Ed,McLaughlin, Mark,Bishop, Brian,Edwards, John,Goodyear, Adrian,Andreani, Teresa,Jin, Yan,Kong, Jongrock,Li, Hongmei,Williams, Michael,Zacuto, Michael
, p. 1075 - 1087 (2016)
Two new routes to a pyrimidyl tetrazole intermediate are described. The first-generation route featured an ironcatalyzed cross-coupling between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. A subsequent intramolecular Heck cyclization afforded the desired bicyclic core, which was subsequently converted to the corresponding carboxylic acid via hydroboration and oxidation. This route was rapidly defined and used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate, which supported early toxicology and clinical studies of a drug candidate. A second-generation, eight-step route to the pyrimidyl tetrazole intermediate was defined and demonstrated on multikilogram scale in a 21% overall yield. The key transformation in this sequence was a copper(I) mediated cyclization of an iodopyrimidine, affording the bicyclic core of the target in quantitative yield. Due to the larger scale involved for the secondgeneration approach, significant process safety evaluation was undertaken for a number of steps in this route, and the highlights of these studies are presented.
Mechanism of solvolysis of substituted benzyl chlorides in aqueous ethanol
Denegri, Bernard,Mati?, Mirela,Va?ko, Monika
supporting information, (2021/11/22)
The mechanism of solvolyses of activated ortho-, meta- and para-substituted benzyl chlorides in aqueous ethanol has been studied by using the Hammett-Brown and Yukawa-Tsuno treatments as well as by correlating logarithms of solvolysis rate constants with relative stabilities of corresponding benzyl carbocations in water calculated at the IEFPCM-M06–2X/6-311+G(3df,3pd) level of theory. Benzyl chlorides containing strong conjugative electron-donors in the para-position solvolyze by the SN1 mechanism, whereas other activated benzyl chlorides solvolyze by the SN2 mechanism via loose transition states.
Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense
Cullen, Danica R.,Gallagher, Ashlee,Duncan, Caitlin L.,Pengon, Jutharat,Rattanajak, Roonglawan,Chaplin, Jason,Gunosewoyo, Hendra,Kamchonwongpaisan, Sumalee,Payne, Alan,Mocerino, Mauro
, (2021/10/07)
Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25–70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.
COMPOUNDS AND METHODS FOR TREATING OXALATE-RELATED DISEASES
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Paragraph 0506, (2021/02/26)
Disclosed herein are compounds and compositions for modulating glycolate oxidase, useful for treating oxalate-related diseases, such as hyperoxaluria, where modulating glycolate oxidase is expected to be therapeutic to a patent in need thereof. Methods of modulating glycolate oxidase activity in a human or animal subject are also provided.
Copper-catalyzed sp3-sp3 cross-coupling of turbo grignards with benzyl halides
Elahi-Mohassel, Synah,Girgis, Michael,Paige, Mikell,Petruncio, Greg
supporting information, (2021/11/17)
The aromatic ring in benzyl halides and sulfonates imparts unique reactivity at the benzylic carbon atom. Photoredox sp3-sp3 cross-coupling proved ineffective for coupling p-methoxybenzyl chloride (PMBCl), leading to a new strategy for the sp3-sp3 cross-coupling of benzyl halides and sulfonates. This strategy involved LiCl-accelerated synthesis of a Grignard reagent followed by a copper-catalyzed cross-coupling. The conditions worked well for PMBCl due to its exceptional reactivity but other benzyl bromides or sulfonates reacted poorly.
Methods of synthesizing ionic liquids from primary alcohol-containing lignin compounds
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Page/Page column 19, (2021/06/09)
Methods and compositions are provided for synthesizing ionic liquids from lignin. Methods and compositions are also provided for treating lignin with ionic liquids.
The Detosylation of Chiral 1,2-Bis(tosylamides)
Butler, Nicholas M.,Clark, Timothy,Gaston, Jayden J.,Keller, Paul A.,Smyth, Jamie E.,Tague, Andrew J.,Van Eikema Hommes, Nico,Willis, Anthony C.,Yu, Haibo
, p. 9163 - 9180 (2021/07/19)
The deprotection of chiral 1,2-bis(tosylamides) to their corresponding 1,2-diamines is mostly unsuccessful under standard conditions. In a new methodology, the use of Mg/MeOH with sufficient steric additions allows the facile synthesis of 1,2-diamines in 78-98% yields. These results are rationalized using density functional theory and the examination of inner and outer-sphere reduction mechanisms.
Turnover and Inactivation Mechanisms for (S)-3-Amino-4,4-difluorocyclopent-1-enecarboxylic Acid, a Selective Mechanism-Based Inactivator of Human Ornithine Aminotransferase
Beaupre, Brett A.,Butrin, Arseniy,Doubleday, Peter F.,Ferreira, Glaucio M.,Kelleher, Neil L.,Liu, Dali,Melani, Rafael D.,Moran, Graham R.,Shen, Sida,Silverman, Richard B.,Tavares, Mauricio T.
supporting information, p. 8689 - 8703 (2021/06/28)
The inhibition of human ornithine δ-aminotransferase (hOAT) is a potential therapeutic approach to treat hepatocellular carcinoma. In this work, (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid (SS-1-148, 6) was identified as a potent mechanism-based inactivator of hOAT while showing excellent selectivity over other related aminotransferases (e.g., GABA-AT). An integrated mechanistic study was performed to investigate the turnover and inactivation mechanisms of 6. A monofluorinated ketone (M10) was identified as the primary metabolite of 6 in hOAT. By soaking hOAT holoenzyme crystals with 6, a precursor to M10 was successfully captured. This gem-diamine intermediate, covalently bound to Lys292, observed for the first time in hOAT/ligand crystals, validates the turnover mechanism proposed for 6. Co-crystallization yielded hOAT in complex with 6 and revealed a novel noncovalent inactivation mechanism in hOAT. Native protein mass spectrometry was utilized for the first time in a study of an aminotransferase inactivator to validate the noncovalent interactions between the ligand and the enzyme; a covalently bonded complex was also identified as a minor form observed in the denaturing intact protein mass spectrum. Spectral and stopped-flow kinetic experiments supported a lysine-assisted E2 fluoride ion elimination, which has never been observed experimentally in other studies of related aminotransferase inactivators. This elimination generated the second external aldimine directly from the initial external aldimine, rather than the typical E1cB elimination mechanism, forming a quinonoid transient state between the two external aldimines. The use of native protein mass spectrometry, X-ray crystallography employing both soaking and co-crystallization methods, and stopped-flow kinetics allowed for the detailed elucidation of unusual turnover and inactivation pathways.
