- Copper-mediated reaction of 2-halopyridines with ethyl bromodifluoroacetate
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A facile process for the preparation of substituted ethyl 2′-pyridyldifluoroacetates 3 is described starting from readily available ethyl bromodifluoroacetate 2 and substituted 2-bromo or 2-chloropyridines 1. This process features a copper-mediated cross-coupling reaction in DMSO and is the first to utilise pyridylbromides or chlorides with ethyl bromodifluoroacetate 2 in this reaction.
- Ashwood, Michael S.,Cottrell, Ian F.,Cowden, Cameron J.,Wallace, Debra J.,Davies, Antony J.,Kennedy, Derek J.,Dolling, Ulf H.
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Read Online
- PROCESSES FOR FLUORINATION
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The present technology relates to fluorination reactions. Specifically, processes useful for making the fungicide compound, DFT are disclosed. More broadly, also disclosed herein are processes useful for deoxyfluorination at the α-aromatic position of a given compound.
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Paragraph 0179; 0184; 0230
(2021/04/10)
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- Synthesis and some transformations of all three isomers of α,α-difluoropyridinylacetonitrile
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An effective preparative approach to fluorinated pyridinylacetonitriles, based on electrophilic fluorination of pyridinylacetonitriles, was developed. Their synthetic potential for obtaining new fluorine-containing building blocks and heterocyclic systems was disclosed.
- Shavrina, Oksana M.,Bezdudny, Andrii V.,Rassukana, Yuliya V.
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- Method for catalyzing ethoxycarbonyldifluoromethylation of aromatic compound by iron
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The invention discloses a method for catalyzing ethoxycarbonyldifluoromethylation of an aromatic compound by iron, which comprises the following steps of: in a solvent, with ethyl halodifluoroacetate as a fluorine reagent, peroxide as an oxidant, iron as
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Paragraph 0106-0108; 0156
(2021/06/21)
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- PROCESSES FOR FLUORINATION
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The present technology relates to fluorination reactions. Specifically, processes useful for making the fungicide compound, DFT are disclosed. More broadly, also disclosed herein are processes useful for deoxyfluorination at the α-aromatic position of a given compound.
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Paragraph 0188
(2020/03/05)
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- Synthetic method of aromatic ring group or aromatic heterocyclic tetrazole
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The synthetic method comprises the following steps: (1) reacting 1.0 eq of ArI or HArI with 1.2 eq of ethyl 2, 2-difluoroacetate in the presence of DMSO as a solvent and 4.0 eq of Cu under the protection of nitrogen at 30 DEG C and 50 DEG C, and purifying to obtain a first intermediate compound; (2) dissolving 1.0 eq of the first intermediate compound in a mixed solvent of THF and water, adding 2.0 eq of LiOH, reacting at room temperature for 2 hours, spin-drying the solvent, adding HCl until the pH value is equal to 3, and filtering to obtain a second intermediate compound; and (3) reacting 1.0 eq of the second intermediate compound with 2.0 eq of diphenyl azide phosphate in the presence of 2.5 eq of triethylamine by taking tert-butyl alcohol as a solvent to generate aromatic ring group or aromatic heterocyclic tetrazole. The invention provides a novel synthetic method of aromatic ring group or aromatic heterocyclic tetrazole, wherein a target compound can be more conveniently obtained, and reagents participating in the reaction are low in toxicity, mild in reaction condition, simple and safe in aftertreatment, good in product quality and suitable for large-scale production.
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Paragraph 0036-0042; 0051
(2020/12/30)
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- Room Temperature Deoxyfluorination of Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and Tetramethylammonium Fluoride
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A method for the room temperature deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride and Me4NF is described. A large scope of aryl and heteroaryl substrates is demonstrated, and this method compares favorably to other common deoxyfluorination methods for many substrates.
- Melvin, Patrick R.,Ferguson, Devin M.,Schimler, Sydonie D.,Bland, Douglas C.,Sanford, Melanie S.
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supporting information
p. 1350 - 1353
(2019/03/08)
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- Lewis acid-mediated defluorinative [3+2] cycloaddition/aromatization cascade of 2,2-difluoroethanol systems with nitriles
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The properties of C?F bonds, including high thermal and chemical stability, make derivatization of organic fluorine-containing compounds by the activation of the C?F bond and subsequent functionalization quite challenging. We herein report a Lewis acid-mediated defluorinative cycloaddition/aromatization cascade of 2,2-difluoroethanols with nitriles as a novel synthetic method for the preparation of 2,4,5-trisubstituted oxazoles. This reaction, which involves cleavage of two C?F bonds and the consecutive formation of C?O and C?N bonds in a one-pot fashion, features a broad substrate scope and moderate to high reaction yields. Mechanistic studies revealed that the reaction is initiated by the Lewis acid-mediated ring closure of the 2,2-difluoroethanol to produce the fluoroepoxide intermediate. (Figure presented.).
- Hsieh, Min-Tsang,Lee, Kuo-Hsiung,Kuo, Sheng-Chu,Lin, Hui-Chang
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supporting information
p. 1605 - 1610
(2018/03/05)
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- Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate
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The potential safety hazards associated with the copper-mediated cross-coupling of 2-bromopyridines with ethyl bromodifluoroacetate were evaluated. Thermal stability evaluation of the postreaction mixture of 50.6 mmol of 2-bromopyridine with 1.3 equiv of ethyl bromodifluoroacetate in the presence of 2.1 equiv of copper in 40 mL of dimethyl sulfoxide (DMSO) indicated a significant decomposition event with an onset temperature of 115.5 °C by accelerating rate calorimetry, which was significantly lower than that of neat DMSO. In contrast, the reaction mixture in N,N-dimethylformamide did not show any exothermic decomposition up to 400 °C by differential scanning calorimetry. Reaction calorimetry evaluation of this reaction in DMSO revealed a heat output (ΔH) of -13.5 kJ and an adiabatic temperature rise (ΔTad) of 129.5 °C, resulting in a maximum temperature of a synthesis reaction (MTSR) of 189.5 °C. The predicted heat of reaction using density functional theory with the BLYP functional was in good agreement with the experimental data. The scope studies with a variety of substituted 2-bromopyridines revealed similar magnitudes of ΔH and ΔTad compared to 2-bromopyridine when reacted at the same concentration. In all of the studied cases, the MTSR was significantly higher than the onset temperature of reaction mixture decomposition, indicating that in the absence of active cooling the system could quickly trigger the decomposition of the reaction mixture, resulting in a runaway reaction.
- Yang, Qiang,Cabrera, Pablo J.,Li, Xiaoyong,Sheng, Min,Wang, Nick X.
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p. 1441 - 1447
(2018/10/15)
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- PYRROLOPYRIMIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
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Disclosed are chemical entities of formula I: [INSERT CHEMICAL FORMULA HERE] wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.
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Paragraph 0261
(2016/04/09)
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- Manufacturing method of making heteroarylacetic compd. defluoromethyl
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PROBLEM TO BE SOLVED: To provide a method for easily producing a difluoromethyl heteroaryl compound with high yield at low cost. SOLUTION: In the method for producing the difluoro methyl heteroaryl compound, a halogenated heteroaryl compound and a α-silyldifluoro acetate ester compound are reacted with each other in the presence of a metal halogenated compound. COPYRIGHT: (C)2012,JPOandINPIT
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Paragraph 0102-0104
(2018/10/03)
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- DIFLUOROETHYLPYRIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
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Disclosed are chemical entities of formula (I) wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.
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Paragraph 0189
(2016/02/16)
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- Design and optimization of highly-selective fungal CYP51 inhibitors
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While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, li
- Hoekstra, William J.,Garvey, Edward P.,Moore, William R.,Rafferty, Stephen W.,Yates, Christopher M.,Schotzinger, Robert J.
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p. 3455 - 3458
(2014/07/22)
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- METALLOENZYME INHIBITOR COMPOUNDS
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The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Page/Page column 116-119
(2013/02/28)
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- 2,6-Diaminopyridine Compounds Suitable For Treating Diseases Associated With Amyloid Or Amyloid-Like Proteins Or For Treating Or Preventing Ocular Diseases Or Conditions Associated With A Pathological Abnormality/Change In The Tissue Of The Visual System
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The present invention relates to 2,6-diaminopyridine compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system.
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Page/Page column 49
(2011/05/03)
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- 2,6-Diaminopyridine compounds for treating diseases associated with amyloid proteins or for treating ocular diseases
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The present invention relates to 2,6-diaminopyridine compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein and of diseases or conditions associated with amyloid-like proteins. The compoun
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Page/Page column 49
(2011/05/04)
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- 2,6-DIAMINOPYRIDINE COMPOUNDS SUITABLE FOR TREATING DISEASES ASSOCIATED WITH AMYLOID OR AMYLOID-LIKE PROTEINS OR FOR TREATING OR PREVENTING OCULAR DISEASES OR CONDITIONS ASSOCIATED WITH A PATHOLOGICAL ABNORMALITY/CHANGE IN THE TISSUE OF THE VISUAL SYSTEM
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The present invention relates to 2.6-diaminopyridine compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein and of diseases or conditions associated with amyloid-like proteins. The compoun
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Page/Page column 100-101
(2011/05/05)
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- PROCESS FOR THE PREPARATION OF PYRAZINONE THROMBIN INHIBITOR AND ITS INTERMEDIATES
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Improved process for the preparation of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide of formula (I) and its intermediates is provided.
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Page/Page column 6
(2011/05/08)
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- PROCESS FOR THE PREPARATION OF PYRAZINONE THROMBIN INHIBITOR AND ITS INTERMEDIATES
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An improved process for the preparation of 3-fruoro-2-pyridylmethyl-3-(2,2- difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one- 1 -acetamide and its intermediates.
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Page/Page column 12; 13
(2011/06/11)
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- MONOACYLGLYCEROL LIPASE INHIBITORS FOR MODULATION OF CANNABINOID ACTIVITY
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Disclosed are compounds and compositions that inhibit the action of monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), methods of inhibiting MGL and FAAH, methods of modulating cannabinoid receptors, and methods of treating various disorders related to the modulation of cannabinoid receptors.
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Page/Page column 142
(2009/05/28)
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- Non-acidic pyrazole EP1 receptor antagonists with in vivo analgesic efficacy
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Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP1 receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified
- Hall, Adrian,Billinton, Andy,Brown, Susan H.,Clayton, Nicholas M.,Chowdhury, Anita,Giblin, Gerard M.P.,Goldsmith, Paul,Hayhow, Thomas G.,Hurst, David N.,Kilford, Ian R.,Naylor, Alan,Passingham, Barry,Winyard, Lisa
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scheme or table
p. 3392 - 3399
(2009/04/06)
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- FATTY ACID AMIDE HYDROLASE INHIBITORS
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Disclosed are compounds of formula R-X-Y that may be used to inhibit the action of fatty acid amide hydrolase (FAAH). Inhibition of fatty acid amide hydrolase (FAAH) will slow the normal degradation and inactivation of endogenous cannabinoid ligands by FAAH hydrolysis and allow higher levels of those endogenous cannabinergic ligands to remain present. These higher levels of endocannabinoid ligands provide increased stimulation of the cannabinoid CBl and CB2 receptors and produce physiological effects related to the activation of the cannabinoid receptors. They will also enhance the effects of other exogenous cannabinergic ligands and allow them to produce their effects at lower concentrations as compared to systems in which fatty acid amide hydrolase (FAAH) action is hot inhibited. Thus, a compound that inhibits the inactivation of endogenous cannabinoid ligands by fatty acid amide hydrolase (FAAH) may increase the levels of endocannabinoids and, thus, enhance the activation of cannabinoid receptors. Thus, the compound may not directly modulate the cannabinoid receptors but has the effect of indirectly stimulating the cannabinoid receptors by increasing the levels of endocannabinoid ligands. It may also enhance the effects and duration of action of other exogenous cannabinergic ligands that are administered in order to elicit a cannabinergic response.
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Page/Page column 99
(2008/06/13)
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- Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif
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2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (Ki = 1.2 nM) that exhibits robust effica
- Kreutter, Kevin D.,Lu, Tianbao,Lee, Lily,Giardino, Edward C.,Patel, Sharmila,Huang, Hui,Xu, Guozhang,Fitzgerald, Mark,Haertlein, Barbara J.,Mohan, Venkatraman,Crysler, Carl,Eisennagel, Stephen,Dasgupta, Malini,McMillan, Martin,Spurlino, John C.,Huebert, Norman D.,Maryanoff, Bruce E.,Tomczuk, Bruce E.,Damiano, Bruce P.,Player, Mark R.
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p. 2865 - 2870
(2008/12/21)
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- Thiazolinone unsubstituted quinolines
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Thiazolinone quinoline derivatives having no substitution on the quinoline ring active as CDK1 inhibitors which are useful as anti-proliferation agents such as for treating solid tumors.
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Page/Page column 23
(2010/02/15)
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- HALOALKYL CONTAINING COMPOUNDS AS CYSTEINE PROTEASE INHIBITORS
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The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
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Page/Page column 62
(2008/06/13)
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- Development of a scaleable synthesis of a 3-aminopyrazinone acetamide thrombin inhibitor
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A scaleable route to 2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)-animo]-6- chloro-2-oxohydropyrazinyl}-N-(3-fluoro(2-pyridyl))-methyl]acetamide 1 is described in which various scaleup issues were addressed to provide a safe, efficient, and robust route for th
- Ashwood, Michael S.,Alabaster, Ramon J.,Cottrell, Ian F.,Cowden, Cameron J.,Davies, Antony J.,Dolling, Ulf H.,Emerson, Khateeta M.,Gibb, Andrew D.,Hands, David,Wallace, Debra J.,Wilson, Robert D.
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p. 192 - 200
(2013/09/04)
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- Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines
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Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phen
- Burgey, Christopher S.,Robinson, Kyle A.,Lyle, Terry A.,Sanderson, Philip E. J.,Lewis, S. Dale,Lucas, Bobby J.,Krueger, Julie A.,Singh, Rominder,Miller-Stein, Cynthia,White, Rebecca B.,Wong, Bradley,Lyle, Elizabeth A.,Williams, Peter D.,Coburn, Craig A.,Dorsey, Bruce D.,Barrow, James C.,Stranieri, Maria T.,Holahan, Marie A.,Sitko, Gary R.,Cook, Jacquelynn J.,McMasters, Daniel R.,McDonough, Colleen M.,Sanders, William M.,Wallace, Audrey A.,Clayton, Franklin C.,Bohn, Dennis,Leonard, Yvonne M.,Detwiler Jr., Theodore J.,Lynch Jr., Joseph J.,Yan, Youwei,Chen, Zhongguo,Kuo, Lawrence,Gardell, Stephen J.,Shafer, Jules A.,Vacca, Joseph P.
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p. 461 - 473
(2007/10/03)
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- Process for making a thrombin inhibitor
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The invention is a process for preparing 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide which comprises coupling with 2-aminomethyl-3-fluoropyridine dihydrochloric acid salt in the presence of a coupling reagent and a base to form 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide.
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and treating blood coagulation and cardiovascular disorders and have the following structure: wherein R3 is hydrogen or halogen, and u is N or CH.
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- Pyrazinone thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein A is
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- Pyrazinone thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: A is ?wherein Y1and Y2are independently hydrogen, C1-4alkyl, C1-4alkoxy, FuHvC(CH2)0-1O—, wherein u and v are either 1 or 2, provided that when u is 1, v is 2, and when u is 2, v is 1, C3-7cycloalkyl, thio C1-4alkyl, C1-4sulfinylalkyl, C1-4sulfonylalkyl, halogen cyano, or trifluoromethyl, and wherein b is 0 or 1.
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula 1: (wherein R1, R2, R3, R4, R5, R6and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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- New antifungal 1,2,4-triazoles with difluoro(heteroaryl)methyl moiety
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New 1,2,4-triazoles (1) having a difluoro(heteroaryl)methyl moiety were designed and synthesized via 1-aryl-2,2-difluoro-2- (heteroaryl)ethanones (2), which were prepared by two routes starting from the reaction of ethyl 2,2- difluoro(heteroaryl)acetate with phenyllithiums (Route A) and from the reaction of chlorodifluoro(heteroaryl)methane with benzaldehydes (Route B). The compounds 1 except for 1g show antifungal activities against yeasts and filamentous fungi in vitro, especially (+)-If have equal or superior activities compared to those of itraconazole.
- Eto, Hiromichi,Kaneko, Yasushi,Sakamoto, Takao
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p. 982 - 990
(2007/10/03)
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