- The discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine cannabinoid type 2 receptor agonist
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The development of selective CB2 receptor agonists is a promising therapeutic approach for the treatment of inflammatory diseases, without CB1 receptor mediated psychoactive side effects. Preliminary structure-activity relationship studies on pyrazoylidene benzamide agonists revealed the -ylidene benzamide moiety was crucial for functional activity at the CB2 receptor. A small library of compounds with varying linkage moieties between the pyrazole and substituted phenyl group has culminated in the discovery of a potent and selective pyrazolo-[2,3-e]-[1,2,4]-triazine agonist 19 (CB2R EC50 = 19 nM, CB1R EC50 > 10 μM). Docking studies have revealed key structural features of the linkage group that are important for potent functional activity.
- Moir, Michael,Lane, Samuel,Montgomery, Andrew P.,Hibbs, David,Connor, Mark,Kassiou, Michael
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- Enantioselective decarboxylative Mannich reaction of β-keto acids withC-alkynylN-BocN,O-acetals: access to chiral β-keto propargylamines
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The chiral keto-substituted propargylamines are an essential class of multifunctional compounds in the field of organic and pharmaceutical synthesis and have attracted considerable attention, but the related synthetic approaches remain limited. Therefore, a concise and efficient method for the enantioselective synthesis of β-keto propargylaminesviachiral phosphoric acid-catalyzed asymmetric Mannich reaction between β-keto acids andC-alkynylN-BocN,O-acetals as easily availableC-alkynyl imine precursors has been demonstrated here, affording a broad scope of β-ketoN-Boc-propargylamines in high yields (up to 97%) with generally high enantioselectivities (up to 97?:?3 er).
- Chen, Li-Jun,Li, Wei,Shen, Bao-Chun,Sun, Zhong-Wen,Xie, Hui-Ding,Zhang, Cong-Cong
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supporting information
p. 8607 - 8612
(2021/10/20)
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- Cu-Mediated Expeditious Annulation of Alkyl 3-Aminoacrylates with Aryldiazonium Salts: Access to Alkyl N2-Aryl 1,2,3-Triazole-carboxylates for Druglike Molecular Synthesis
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Alkyl N-aryl 1,2,3-triazole-carboxylates are important molecules or intermediates in medicinal chemistry, but the synthesis of N2-aryl counterparts remains elusive. Herein, we describe a Cu-mediated annulation reaction of alkyl 3-aminoacrylates with aryldiazonium salts, both of which are readily available substrates. Furthermore, alkyl 2-aminoacrylates are also viable substrates. Diverse alkyl N2-aryl 1,2,3-triazole-carboxylates and their analogues can be rapidly prepared under mild conditions. Especially, this protocol allows one to access several druglike variants of carbonic anhydrase inhibitors and celecoxib.
- Liu, Hao-Nan,Cao, Hao-Qiang,Cheung, Chi Wai,Ma, Jun-An
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supporting information
p. 1396 - 1401
(2020/02/22)
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- Chiral Vanadyl(V) Complexes Enable Efficient Asymmetric Reduction of β-Ketoamides: Application toward (S)-Duloxetine
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High-valent chiral oxidovanadium(V) complexes derived from 3,5-substituted-N-salicylidene-l-tert-leucine were used as catalysts in asymmetric reduction of N-benzyl-β-ketoamides. Among six different solvents, three different alcohol additives, and two different boranes examined, the use of pinacolborane in tetrahydrofuran (THF) with a t-BuOH additive led to the best results at -20 °C. The corresponding β-hydroxyamides can be furnished with yields up to 92percent and an enantiomeric excess (ee) up to 99percent. We have successfully extended this catalytic protocol for the synthesis of an (S)-duloxetine precursor.
- Chen, Chien-Tien,Maity, Nabin Ch.,Agarwal, Rachit,Lai, Chien-Fu,Liao, Yiya,Yu, Wei-Ru
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supporting information
p. 6408 - 6419
(2020/07/14)
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- Preparation method of 4, 4-dimethyl-3-oxo-methyl pentanoate
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The invention discloses a preparation method of 4, 4-dimethyl-3-oxo-methyl pentanoate. The method includes: taking pinacolone, sodium hydrogen and dimethyl carbonate as the raw materials, and using toluene as the solvent, carrying out stirring reaction at 55-60DEG C, then performing cooling, and at a pH of 4-5, preparing a 4, 4-dimethyl-3-oxo-methyl pentanoate crude product; and subjecting the 4, 4-dimethyl-3-oxo-methyl pentanoate crude product to distillation under the conditions of a vacuum degree of less than 10mm Hg and a temperature of 90-95DEG C. By means of the method provided by the invention, the 4, 4-dimethyl-3-oxo-methyl pentanoate has high distillation yield, the product purity is high, the main content is up to more than 98%, and the total yield is up to 96%.
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Paragraph 0016-0021
(2017/07/01)
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- Direct oxidative coupling of enamines and electron-deficient amines: TBAI/TBHP-mediated synthesis of substituted diaminoalkenes under metal-free conditions
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A metal-free cross-coupling of enamines and electron-de fi cient amines through oxidative C(sp2)-N bond formation has been realized by using TBAI as catalyst and TBHP as oxidant. This novel strategy allows for an efficient organocatalytic synthesis of the synthetically useful diaminoalkene derivatives and is highlighted by appealing features such as readily available of the starting materials, wide substrate scope and transition-metal-free characteristics. (Chemical Equation Presented).
- Yuan, Yucheng,Hou, Wenjuan,Zhang-Negrerie, Daisy,Zhao, Kang,Du, Yunfei
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supporting information
p. 5410 - 5413
(2015/01/09)
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- Diaryl- and triaryl-pyrrole derivatives: Inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions
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Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)- ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM). MDM2-p53 and MDMX-p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5- diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H, 3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX-p53 activity but not for MDM2-p53 inhibition. The Royal Society of Chemistry.
- Blackburn, Tim J.,Ahmed, Shafiq,Coxon, Christopher R.,Liu, Junfeng,Lu, Xiaohong,Golding, Bernard T.,Griffin, Roger J.,Hutton, Claire,Newell, David R.,Ojo, Stephen,Watson, Anna F.,Zaytzev, Andrey,Zhao, Yan,Lunec, John,Hardcastle, Ian R.
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p. 1297 - 1304
(2013/09/12)
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- CHEMICAL COMPOUNDS
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The invention is directed to to substituted indazole derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 - R6 and X are defined herein. The compounds of the invention are inhibitors of PDK1 and can be useful in the treatment of disorders characterized by constitutively activated ACG kinases such as cancer and more specifically leukemia and cancers of the breast, colon, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PDK1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 130
(2010/11/04)
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- Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors
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Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure-activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed.
- Teng, Xin,Keys, Heather,Jeevanandam, Arumugasamy,Porco Jr., John A.,Degterev, Alexei,Yuan, Junying,Cuny, Gregory D.
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p. 6836 - 6840
(2008/03/14)
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- Carbonylation of alpha-chloroketones to beta-keto esters using palladium carbene catalysts
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The present invention is a novel process for producing β-ketoesters 1 by contacting an α-chloroketone 2 with carbon monoxide and a hydroxyl-containing compound of formula R3OH in the presence of a base and a palladium carbene catalyst complex 3. The subject catalysts demonstrate superior rates and selectivity when compared to known (Ph3P)2PdCl2.
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Page/Page column 8
(2008/06/13)
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- Process for generating pivaloylacetate esters via carbonylation of chloropinacolone
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Pivaloylacetate esters (1) are a useful intermediates for producing chemicals for use in photographic and xerographic reproduction processes. Such esters can be generated by contacting chloropinacolone (2) with CO, an alcohol of formula R1OH, and a base in the presence of a catalyst comprising a source of palladium and certain coordinating trisubstituted phosphines of formula (R3)3P.
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Page/Page column 5
(2008/06/13)
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- Carbonylation of alpha-chloroketones to beta-keto esters using palladium carbene catalysts
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The present invention is a novel process for producing β-ketoesters 1 by contacting an α-chloroketone 2 with carbon monoxide and a hydroxyl-containing compound of formula R3OH in the presence of a base and a palladium carbene catalyst complex 3. The subject catalysts demonstrate superior rates and selectivity when compared to known (Ph3P)2PdCl2.
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Page/Page column 5
(2008/06/13)
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- Enantioselective synthesis of α-amino acids from N-tosyloxy β-lactams derived from β-keto esters
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A novel synthetic sequence has been developed to convert simple β-keto esters into enantiomerically enriched α-amino acids. The key features of this sequence include the addition of azide to the C3 position of β-keto ester derived N-tosyloxy-β-lactams through a concomitant nucleophilic addition/N-O bond reduction reaction, a mild CsF-induced N1 benzylation of α-azido monocyclic β-lactams, the preparation of α-keto-β-lactams through a novel four-step sequence from the corresponding 3-azido-1-benzyl-β-lactams, and TEMPO-mediated ring expansion of these compounds to the corresponding N-carboxy anhydrides (NCAs). In addition, the synthesis, isolation, and characterization of unusual 3-imino and 3-chloramino-β-lactams is reported.
- Durham, Timothy B.,Miller, Marvin J.
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- PROCESS FOR THE PREPARATION OF 1,3-DICARBONYL COMPOUNDS
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The condensation reaction of a ketone with either an ester or a carbonate to form, respectively, a 1,3-diketone or a beta -ketoester often affords poor results under the standard condensation reaction conditions. High yields and high purities of the desired product can be obtained by performing the reaction using an alkoxide base in DMSO as the sole solvent.
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- Process for producing pivaloyl-acetic acid ester
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A process for producing a pivaloylacetic acid ester comprises reacting pivaloyl chloride with an acetoacetic acid ester of an alkyl group having 1 to 4 carbon atoms in the presence of at least one nitrogen-containing basic compound (a) selected from among pyridine compounds, N,N-dialkylanilines and imidazole compounds and from 0.01 to 0.5 mole equivalent, based on the pivaloyl chloride, of a magnesium compound (b) to thereby prepare a pivaloylacetoacetic acid ester and then alcholyzing or alkali-hydrolyzing the pivaloylacetoacetic acid ester to thereby give a pivaloylacetic acid ester having a high purity at a low cost.
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- Method of producing pivaloylacetic acid ester
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A pivaloylacetic acid ester is prepared at a high yield by decarbonylating a pivaloylpyruvic acid ester in gas or liquid phase in the presence of an inorganic oxide catalyst which comprises aluminum in an amount of 10% by weight or more in terms of aluminum oxide, and preferably is substantially free from heavy metals, for example, Fe, Cu, Ni, Mn, Cr, Mo and Co, and exhibits a high catalytic activity and chemical stability.
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- Chemical differentiation of enantiotopic groups: Diastereoselective opening of a prochiral dilactone
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Prochiral dilactone 1 has been synthesized and subjected to diastereoselective nucleophilic opening. The structural features of chiral, enantiomerically pure nucleophiles have been optimized regarding their capability to perform prochiral recognition at dilactone 1. 3-Ketoglutaric mono acid products 2 of dilactone opening, which are versatile building blocks for natural product synthesis, have been obtained in diastereomeric ratios up to 84:16 and were enriched by subsequent crystallization to 97.5:2.5.
- Deseke, Eckart,Hoyer, Wolfgang,Winterfeldt, Ekkehard
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p. 14577 - 14598
(2007/10/03)
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- Inhibitors of the advanced glycosylation of proteins and methods of use therefor
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The present invention relates to compositions and methods for inhibiting nonenzymatic cross-linking (protein aging). Accordingly, a composition is disclosed which comprises an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins by reacting with a carbonyl moiety of an early glycosylation product of such target proteins resulting from their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.
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- Process for the production of 3-oxocarboxylic acid esters
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3-Oxocarboxylic acid esters are produced by acylation of the magnesium enolates of acetoacetic acid esters with carboxylic acid chlorides and cleavage of the acetyl group from the acylacetoacetic acid esters formed as the intermediate product. The yields and purity of the products are considerably improved by adding a tertiary amine during the acylation.
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- Flash vacuum pyrolysis of tert-butyl β-ketoesters: Sterically protected α-oxoketenes
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Infrared spectroscopic analysis of the products showed that flash vacuum pyrolyses (FVP) of dimethyl tert-butylmalonate (1b) and methyl tert-butyl(pivaloyl)acetate (1d) at ca. 550°C afforded the corresponding tert-butyl(carbomethoxy)ketene (4b) and tert-butyl(pivaloyl)ketene (4d), respectively, with loss of methanol, together with unreacted 1b and 1d (Ar matrix, 12 K or neat at 77 K; 10-5 mbar). Monitoring by IR spectroscopy showed that 4b reacted with methanol at ca. -50°C to give 1b. Ketene 4d does not react with methanol at room temperature, but afforded ester 1d on refluxing for 8 h. FVP of 1b and 1d at temperatures above 650°C gave the α-oxoketenes 4b and 4d, respectively, unsubstituted dimethyl malonate (1a) and methyl 4,4-dimethyl-3-oxo-pentanoate (1c), respectively, due to retro-ene reactions with elimination of isobutene, as well as pyrolysis products derived from 1a and 1c, respectively. FVP of α-unsubstituted β-ketoesters 1a and 1c at ca. 500°C (10-5 mbar) with argon matrix isolation of the products at 12 K afforded the ketenes 4a and 4c as mixtures of s-Z and s-E conformers together with mixtures of unreacted keto (1a, c) and enol forms (2a, c). On warming to temperatures between -90 and -50°C, back-reaction of ketenes 4a, c with methanol resulted in the re-generation of enols 2a, c without increasing the amounts of the keto forms 1a, c.
- Leung-Toung,Wentrup
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p. 7641 - 7654
(2007/10/02)
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- Process for the preparation of pivaloylacetic acid esters
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An improved process for the preparation of pivaloylacetic acid esters by decarbonylation of pivaloylpyruvic acid esters at elevated temperatures is described. The process is carried out in the presence of 0.01 to 5 percent by weight of a metal of sub-groups one to eight of the periodic system, which metal is in metallic and/or oxidic form. Initially, 30 percent of the pivaloylpyruvic acid ester to be converted is heated in the presence of the metal, and after conversion of the same there is added additional pivaloylpyruvic acid ester according to the rate at which the pivaloylpyruvic acid ester is converted.
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- Aliphatic β-keto esters
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A process for the production of aliphatic β-keto esters by reacting a dialkyl ketone with a dialkylcarbonate in the presence of an at least equivalent quantity of a basic condensation agent based on the dialkyl ketone at a reaction temperature of 20° to 80° C and the reaction product is subsequently converted by acidification into the β-keto ester. By carrying out the condensation reaction in the presence of hexamethylphosphoric acid triamide as solvent advantageously higher yields of 20 to 50 % can be obtained by the inventive process of compared to conventional processes.
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