- 'Cascade' radical reactions in synthesis: Condensed thiophenes from ketenethioacetals
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A novel radical centred tandem cyclisation - tandem fragmentation sequence is described for the direct convertion of ketenethioacetals e.g. 1, 6, 9, 12 and 16 into condensed thiophenes e.g. 2, 7, 10, 13 and 17.
- Harrowven, David C.
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Read Online
- Synthetic strategies based on aromatic metalation - Cross coupling links. A concise formal synthesis of the azaphenanthrene alkaloid eupolauramine
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An efficient synthesis of azaphenanthraquinone 9, previously converted into eupolauramine (10), has been achieved using combinational metalation (ortho and remote) - cross coupling tactics.
- Wang,Snieckus
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Read Online
- Synthesis, Structure and Basicity of 1,16-Diazahelicene
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The extension of 'proton sponges' 1 and 2 by further anellation to 1,16-diazahelicene (3) was of interest to define scope and limitation of 'proton sponge' properties. 3 was prepared by photocyclisation of 2,7-bis(3-pyridylvinyl)naphthalene 4 and by Pd-catalyzed aryl-aryl coupling of the corresponding tetrabromo derivative 7.As consequence of the helical structure, 3 does not show 'proton sponge' basicity.X-ray structure analyses of 3 and 3*2HBr are in accordance with these findings.
- Staab, Heinz A.,Diehm, Michael,Krieger, Claus
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Read Online
- Improved synthesis of 2-bromonicotin-aldehyde and acid
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Synthetically useful 2-bromonicotinaldehyde and 2-bromonicotinic acid can be conveniently prepared in high yield from the directed ortho metalation of 2-bromopyridine.
- Melnyk,Gasche,Thal
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Read Online
- Synthesis method of 3, 4-dihydro-2H-pyrano [2, 3-b] pyridine
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The invention relates to a synthesis method of 3, 4-dihydro-2H-pyrano [2, 3-b] pyridine. The problems of difficult availability of raw materials, expensive reagents, complicated operation, high risk, high energy consumption and the like in the existing route are mainly solved. The method is realized through the following technical scheme: (1) reacting 2-bromopyridine with a formylation reagent under the action of alkali to generate 2-bromo-3-formylpyridine; (2) reacting an aldehyde group of the 2-bromine-3-formylpyridine with triethyl phosphonoacetate to generate 2-bromine-3-pyridine ethyl acrylate; (3) simultaneously reducing double bonds and ester groups of 2-bromo-3-pyridine ethyl acrylate by lithium borohydride in one step while enabling bromine not to be influenced, so as to obtain 2-bromo-3-pyridine propanol; and (4) carrying out ring closing on the 2-bromo-3-pyridyl propanol under the action of alkali to obtain a target compound.
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Paragraph 0007; 0010; 0013
(2021/05/26)
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- S29434, a quinone reductase 2 inhibitor: Main biochemical and cellular characterization
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Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC505 5–16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.
- Boutin, Jean A.,Bouillaud, Frederic,Janda, Elzbieta,Gacsalyi, István,Guillaumet, Gérald,Hirsch, Etienne C.,Kane, Daniel A.,Nepveu, Fran?oise,Reybier, Karine,Dupuis, Philippe,Bertrand, Marc,Chhour, Monivan,Le Diguarher, Thierry,Antoine, Mathias,Brebner, Karen,Da Costa, Hervé,Ducrot, Pierre,Giganti, Adeline,Goswami, Vishalgiri,Guedouari, Hala,Michel, Patrick P.,Patel, Aakash,Paysant, Jér?me,Stojko, Johann,Viaud-Massuard, Marie-Claude,Ferry, Gilles
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supporting information
p. 269 - 285
(2019/05/14)
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- Strategies to develop selective CB2 receptor agonists from indole carboxamide synthetic cannabinoids
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Activation of the CB2 receptor is an attractive therapeutic strategy for the treatment of a wide range of inflammatory diseases. However, receptor subtype selectivity is necessary in order to circumvent the psychoactive effects associated with activation of the CB1 receptor. We aimed to use potent, non-selective synthetic cannabinoids designer drugs to develop selective CB2 receptor agonists. Simple structural modifications such as moving the amide substituent of 3-amidoalkylindole synthetic cannabinoids to the 2-position and bioisosteric replacement of the indole core to the 7-azaindole scaffold are shown to be effective and general strategies to impart receptor subtype selectivity. 2-Amidoalkylindole 16 (EC50 CB1 > 10 μM, EC50 CB2 = 189 nM) and 3-amidoalkyl-7-azaindole 21 (EC50 CB1 > 10 μM, EC50 = 49 nM) were found to be potent and selective agonists with favourable physicochemical properties. Docking studies were used to elucidate the molecular basis for the observed receptor subtype selectivity for these compounds.
- Moir, Michael,Lane, Samuel,Lai, Felcia,Connor, Mark,Hibbs, David E.,Kassiou, Michael
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p. 291 - 309
(2019/07/17)
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- Zincation and Magnesiation of Functionalized Silylated Cyanohydrins Using TMP-Bases
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Polyfunctional silylated cyanohydrins are readily magnesiated or zincated with TMPMgCl·LiCl or TMP 2 Zn·2MgCl 2 ·2LiCl leading to the corresponding metallated derivatives. These Mg- or Zn-derivatives react with various electrophiles such as benzylic bromides, allylic bromides, acid chlorides, aldehydes, NCCO 2 Et, or MeSO 2 SMe. Subsequently, TBAF-deprotection provides the corresponding keto or 1,2-diketo derivatives.
- Castelló-Micó, Alicia,Knochel, Paul
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p. 155 - 169
(2017/10/07)
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- Approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines
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An approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines via the cyclization of 1-(2-(3-azidopropyl)pyridin-3-yl)alkanones under Staudinger–aza-Wittig reaction conditions is described. The overall reaction sequence includes eight steps and allows for the preparation of gram quantities of the title products. In some cases, the formation of 5,7,8,9-tetrahydrooxepino[4,3-b]pyridine derivatives was observed.
- Subota, Andrii I.,Artamonov, Oleksiy S.,Gorlova, Alina,Volochnyuk, Dmitriy M.,Grygorenko, Oleksandr O.
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supporting information
p. 1989 - 1991
(2017/04/27)
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- 1,3,8-TRIAZASPIRO[4,5]DECAN-4-ONE DERIVATIVES USEFUL FOR THE TREATMENT OF ORL-1 RECEPTOR MEDIATED DISORDERS
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The present invention is directed to novel 1,3,8-triazaspiro[4.5]decan-4-one derivatives of the general formulawherein all variables are as defined herein, useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.
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Paragraph 0201-0203
(2017/02/28)
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- Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines
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In order to investigate systematically the effect of the position of the pyridine N-atom on the σ1 receptor affinity four regioisomeric furopyridines 2a-d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a-d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a-d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a-d showed 7- to 12-fold lower σ1 affinity than the benzofuran analog 1. The reduced σ1 affinity of the furopyridines 2a-d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same σ1 affinity (Ki = 4.9-10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded.
- Miyata, Kengo,Schepmann, Dirk,Wünsch, Bernhard
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p. 709 - 716
(2014/07/22)
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- Diastereoselective synthesis of rotationally restricted chiral phenylpyridines via intramolecular cascade cyclization of n-acyliminium ions containing α-amino acid residues
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A series of chiral phenylpyridines possessing a fused chiral bridge were synthesized diastereoselectively via cascade cyclizations, where N-acyliminium ions including an enantiopure α-amino acid residue were involved. The absolute configuration of the synthesized phenylpyridines was identified unambiguously by using nuclear Overhauser effect difference and circular dichroism (CD) measurements on the basis of literature methods. Taylor & Francis Group, LLC.
- Li, Jin-Ling,Zhao, Hong-Wu,Qin, Xiao,Cui, Jin,Su, Shi,Li, Hai-Long,Yue, Yuan-Yuan,Song, Xiu-Qing
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p. 3175 - 3180
(2014/01/06)
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- LRRK2 INHIBITORS
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Provided herein are compounds that inhibit or partially inhibit the activity of leucine rich repeat kinases. Also provided herein are methods of treatment of CNS disorders comprising administration of inhibitors of leucine rich repeat kinases.
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Page/Page column 112-113
(2013/02/28)
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- Formation of optically pure cyclic amines by intramolecular conjugate displacement
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Intramolecular conjugate displacement (ICD) has been applied to the Morita-Baylis-Hillman adducts formed from (5S)-5-(l-menthyloxy)-2(5H)-furanone and aldehydes that carry a protected β- or γ-amino group. DIBAL-H reduction of the resulting ICD products releases optically pure six- or seven-membered cyclic amines having a stereogenic center α to nitrogen.
- Cheng, Ping,Clive, Derrick L. J.
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scheme or table
p. 3348 - 3364
(2012/05/20)
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- Inter- and intramolecular hydroacylation of alkenes employing a bifunctional catalyst system
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Based on a conceptually innovative bifunctional P,N ligand, an efficient protocol for the rhodium-catalyzed inter- and intramolecular hydroacylation of alkenes has been developed.
- Vautravers, Nicolas R.,Regent, Damien D.,Breit, Bernhard
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supporting information; experimental part
p. 6635 - 6637
(2011/06/27)
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- Intramolecular N-arylation in heterocyclization: synthesis of new pyrido-fused pyrrolo[1,2-a][1,4]diazepinones
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Alkylation of l-prolinamide with 3-(chloromethyl)-2-halopyridines, followed by cyclization through an intramolecular Pd-catalysed amidation, provided an entry to the pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-one scaffold. Furthermore, a synthetic route towards diverse new pyrido[f]pyrrolo[1,2-a][1,4]diazepin-7-ones has been developed by acylation of contiguously substituted (aminomethyl)halopyridines with Boc-l-proline followed by intramolecular amination.
- Legerén, Loreto,Domínguez, Domingo
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body text
p. 4053 - 4057
(2010/08/07)
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- Synthesis of 1-phenyl- and 1-pyridyl-3-pyridoazepines by reductive cyclization of diarylacetonitriles
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Several pyrido[2,3-d]azepines and pyrido[3,4-d]azepines, novel aza analogs of the pharmacologically relevant 1-aryl-3-benzazepines, were synthesized by assembling the azepine ring by reductive cyclization of (2-methoxyvinyl)pyridinyl(aryl)acetonitrile derivatives, which were easily derived from contiguously substituted bromo(2-methoxyvinyl)pyridines and the corresponding arylacetonitriles.
- de la Fuente, M. Carmen,Domínguez, Domingo
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scheme or table
p. 3653 - 3658
(2009/09/08)
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- Alternative approaches to (Z)-1,2-bis(2-bromopyridin-3-yl)ethenes, key intermediates in the synthesis of the 1,10-phenanthroline core
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A study on the synthesis of (Z)-1,2-bis(2-bromopyridin-3-yl)ethenes, key intermediates in the preparation of 1,10-phenanthrolines, based on selective Sonogashira and Suzuki-Miyaura cross-coupling reactions has been carried out.
- Chelucci, Giorgio,Baldino, Salvatore,Pinna, Gerard A.,Sechi, Barbara
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p. 2839 - 2843
(2008/09/20)
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- Conjugate addition of 2- and 4-pyridylcuprates: An expeditious asymmetric synthesis of natural (-)-evoninic acid
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(Chemical Equation Presented) The scope and limitations of the conjugate addition of 2- and the first 4-pyridyl Gilman homocuprates to various α,β-unsaturated Michael acceptors are delineated. The conjugate addition of the cuprate of 2-bromo-3-methylpyridine to (E)-methyl crotonate then diastereoselective enolate alkylation and lipase-mediated enantioselective ester hydrolysis have enabled an efficient four-step first asymmetric synthesis of the Celastraceae sesquiterpenoid esterifying ligand (-)-(1′S,2′S) -evoninic acid.
- Spivey, Alan C.,Shukla, Lena,Hayler, Judy F.
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p. 891 - 894
(2007/10/03)
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- Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor
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Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a Ki value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
- Tran, Joe A.,Jiang, Wanlong,Tucci, Fabio C.,Fleck, Beth A.,Wen, Jenny,Sai, Yang,Madan, Ajay,Ta, Kung Chen,Markison, Stacy,Foster, Alan C.,Hoare, Sam R.,Marks, Daniel,Harman, John,Chen, Caroline W.,Arellano, Melissa,Marinkovic, Dragan,Bozigian, Haig,Saunders, John,Chen, Chen
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p. 6356 - 6366
(2008/03/30)
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- β-Substituted cyclohexanecarboxamide cathepsin K inhibitors: Modification of the 1,2-disubstituted aromatic core
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Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (-)-1 has demonstrated that the solvent exposed P2-P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some potency loss was observed in the 6-membered heteroaromatic series (IC50 = 1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked (±)-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-fold for (-)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly improved for thiazole 9 (IC50 = 0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.
- Robichaud, Joel,Bayly, Christopher I.,Black, W. Cameron,Desmarais, Sylvie,Leger, Serge,Masse, Frederic,McKay, Daniel J.,Oballa, Renata M.,Paquet, Julie,Percival, M. David,Truchon, Jean-Francois,Wesolowski, Gregg,Crane, Sheldon N.
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p. 3146 - 3151
(2008/02/05)
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- Aminobenzoannulated hetero- and carbocycles from 2-azahepta-2,4-dien-6- ynyllithium compounds: Scope and limitation of a novel benzoannulation reaction
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Deprotonation of the N-benzylhetarylmethanimines 9, 12, 15, and 18 at -78°C with subsequent warming to room temperature over 16 hours and treatment with electrophiles furnished polysubstituted aminobenzoannulated heterocycles 19-25 in good to excellent yields. In a similar fashion, the deprotonation of the N-allyl-2-(alk-1-ynyl)phenylmethanimines 26 and 27 led to 2-vinylnaphthalen-1-amines 28 and 29, respectively, in moderate yields. The reaction of N-[(trimethylsilyl)methyl]imine 31 afforded naphthalen-1-amine 33, unsubstituted at the ortho position after removal of the trimethylsilyl group. The deprotonation of imine 34, bearing a trimethylsilyl group on the C≡C bond, gave none of expected amines, but the substituted imine 35, whose structure was identified using 2D NMR spectroscopy. Georg Thieme Verlag Stuttgart.
- Lyaskovskyy, Volodymyr,Froehlich, Roland,Wuerthwein, Ernst-Ulrich
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p. 2135 - 2144
(2008/03/28)
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- Intramolecular cyclisation of functionalised heteroaryllithiums. Synthesis of novel indolizinone-based compounds
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The intramolecular cyclisation of heteroaryllithiums derived from N-heteroarylmethylpyrrole-2-carboxamides takes place smoothly at low temperature when N-methoxy-N-methyl and morpholine amides are used as internal electrophiles. Halogen-lithium exchange using n-BuLi is the method of choice to achieve metalation on the quinoline and pyridine derivatives, while directed lithiation (LDA) works better for furan. In the case of thiophene both methodologies can be applied. These metalation-cyclisation sequences provide a useful entry to several types of indolizidine based compounds (pyrrolo[1,2-b]acridinones, pyrrolo[1,2-g]quinolones, thieno and furo[3,2-f]indolizinones).
- Ruiz, Javier,Lete, Esther,Sotomayor, Nuria
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p. 6182 - 6189
(2007/10/03)
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- LIGANDS OF MELANOCORTIN RECEPTORS AND COMPOSITIONS AND METHODS RELATED THERETO
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Compounds which function as melanocortin receptor ligands and having utility in the treatment of melanocortin receptor-based disorders. The compounds have the following structure (I): (I) including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein m, n, q, s, R1, R1a, R1b, R2, R3, R4a, R4b, R5a, R5b, X1, X2, X3, X4 and Ar are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.
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Page/Page column 24-25
(2010/02/11)
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- Free radical-mediated aryl amination: A practical synthesis of (R)- and (S)-7-azaindoline α-amino acid
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Two nonnatural proline derivatives, (S)- and (R)-7-azaindoline α-amino acid have been prepared and isolated as their trifluoro-acetate salt on gram scale. The convergent sequence (6 steps from 2-bromopyridine) employs a combination of enantioselective phase transfer catalyzed glycine alkylation and free radical-mediated aryl animation. Implementation of the solid-liquid phase transfer conditions requires manual pulverization of cesium hydroxide, efficient mechanical stirring, and effective low temperature control. This large scale free radical cyclization protocol replaces benzene solvent with toluene without complication, and the crystalline nature of the intermediates and final product enables straightforward purification at each stage, including enantiomeric enrichment (89% to >99% ee for 4b, Scheme 1).
- Srinivasan, Jayasree M.,Burks, Heather E.,Smith, Colin R.,Viswanathan, Rajesh,Johnston, Jeffrey N.
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p. 330 - 333
(2007/10/03)
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- The expedient access to bromo-pyridine carbaldehyde scaffolds using gem-dibromomethyl intermediates
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A simple, efficient, and general two-step synthesis to bromo-pyridine carbaldehyde scaffolds is described. This direct route involves sequential reactions employing the dibromination of bromo-picolines followed by hydrolysis using an aqueous solution of calcium carbonate. Bromo-pyridine carbaldehyde scaffolds 1-7 were obtained in good overall yield. Bromo-dibromomethyl-pyridine intermediates have been isolated and characterized.
- Mandal, Ashis Baran,Augustine, John Kallikat,Quattropani, Anna,Bombrun, Agnes
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p. 6033 - 6036
(2007/10/03)
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- 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
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The present invention is directed to novel 1,3,8-triazaspiro[4.5]decan-4-one derivatives of the general formula wherein all variables are as defined herein, useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.
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- Alkyl substituted piperadinyl and piperazinyl anti-AIDS compounds
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Anti-AIDS compounds of formula (I) STR1 wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification and R8 is alkyl of substituted alkyl.
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- General synthetic method for naphthyridines and their N-oxides containing isoquinolinic nitrogen
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Substituted naphthyridines containing isoquinolinic nitrogen were synthesized by the reaction of o-ethynylpyridinecarbaldehydes with ammonia. The synthesis of their N-oxides was also achieved by a basic cyclization reaction of the same pyridine derivatives via the corresponding oximes.
- Numata, Atsushi,Kondo, Yoshinori,Sakamoto, Takao
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p. 306 - 311
(2007/10/03)
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- First Synthesis of the Benzopyridopyrrolonaphthyridine Ring System
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The lithiated pyridine 7 on reaction with methyl 4-methylquinoline-3-carboxylate (8) gave the ketone 9, which could be converted to the biaryl 11 via an effective two step anellation procedure.Treatment of 11 with dilute sulfuric acid resulted in an unexpected ring closure to give the title ring system.
- Bracher, Franz
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p. 157 - 159
(2007/10/02)
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- Migration du lithium en serie pyridinique: double catalyse et reformage. Acces aux derives de la bromo-2 lithio-3 pyridine et des bromo-4 halogeno-2 lithio-3 pyridines
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The lithium of an organolithium-pyridinic derivative can be moved from one position to an another by an intermolecular reaction.Two new reactions are possible for pyridinic organic synthesis: the isomerisation of any lithio derivative to a more stable one, and a reaction that transforms a mixture of various bromo-lithio derivatives into a single one.The processes involved and the experimental tools used are described in terms of the 2-bromo-3-lithio- and 4-bromo-2-halogeno-3-lithiopyridines derivatives synthesis.
- Mallet, Marc,Branger, Gilles,Marsais, Francis,Queguiner, Guy
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p. 319 - 332
(2007/10/02)
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