- One-step Synthesis of Stabilized Phosphonates
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Phosphonates possessing α-electron withdrawing functionalities can be readily prepared by treatment of nitriles, nitroalkanes, and esters with 2 molar equivalents of base followed by phosphonylation with diethyl chlorophosphate.
- Kandil, Ali A.,Porter, Terence M.,Slessor, Keith N.
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Read Online
- Carbanionic displacement reactions at phosphorus. Part III.1 Cyanomethylphosphonate vs. cyanomethylenediphosphonate. Synthesis and solid-state structures
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The results of the carbanionic reaction between acetonitrile and chlorophosphates depend strongly on the nature of the metallating agent (LiTMP, LDA, LiHMDS). According to the nature of the base, the reaction can be directed towards the formation of either cyanomethylphosphonates 3 or cyanomethylenediphosphonates 5. Electrophilic halogenation of lithiated cyanomethylphosphonate 2a leads to the mono-chloro 17, -bromo 18 and -iodo 19 derivatives. Only the monochloro product 17 is stable enough to be isolated in pure form. The structures of cyanobenzylphosphonate 10b, cyanomethylenediphosphonate 5b and its corresponding lithiated carbanion 4b are determined by X-ray crystallography. The polymeric structure, coupled with a wide charge delocalization, without C-Li contacts, is in agreement with the lack of reactivity towards electrophiles. The Royal Society of Chemistry 2000.
- Lorga, Bogdan,Ricard, Louis,Savignac, Philippe
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Read Online
- Photocatalytic Alkylation of Pyrroles and Indoles with α-Diazo Esters
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This article describes the photoalkylation of electron-rich aromatic compounds with diazo esters. C-2-alkylated indoles and pyrroles are obtained with good yields even though the photocatalyst loading is as low as 0.075 mol %. For EWG-substituted substrates, the addition of a catalytic amount of N,N-dimethyl-4-methoxyaniline is required. Both EWG-EWG- and EWG-EDG-substituted diazo esters are suitable as alkylating agents. The reaction selectivity and mechanistic experiments suggest that carbenes/carbenoid intermediates are not involved in the reaction pathway.
- Ciszewski, Lukasz W.,Durka, Jakub,Gryko, Dorota
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supporting information
p. 7028 - 7032
(2019/09/12)
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- Truncated borrelidin analogues: Synthesis by sequential cross metathesis/olefination for the southern fragment and biological evaluation
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The construction of novel borrelidin analogues is reported in which the northern fragment is truncated to a simple hydroxyundecanecarboxylate and the original cyclopentanecarboxylic acid in the southern fragment is replaced with different six-membered rings. The required precursors were prepared by cross metathesis of the appropriate carbocycle-based homoallylic alcohol with crotonaldehyde followed by HWE olefination of the resulting enal with bromocyanophosphonate. The key aldehyde for intramolecular cross coupling was accessible by oxidation of the hydroxy group of the linked undecanecarboxylate unit. Grignard mediated macrocyclization finally yielded the borrelidin related products. The investigation is complemented by SAR studies and quantum-chemical calculations.
- Gündemir-Durmaz, Tülay,Schmid, Fabian,El Baz, Yana,H?usser, Annette,Schneider, Carmen,Bilitewski, Ursula,Rauhut, Guntram,Garnier, Delphine,Baro, Angelika,Laschat, Sabine
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supporting information
p. 8261 - 8269
(2016/09/09)
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- Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation
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Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f?exhibited moderate antioxidant properties as found by in?vitro assessment. This compound represents a novel donepezil–hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD.
- Wu, Ming-Yu,Esteban, Gerard,Brogi, Simone,Shionoya, Masahi,Wang, Li,Campiani, Giuseppe,Unzeta, Mercedes,Inokuchi, Tsutomu,Butini, Stefania,Marco-Contelles, Jose
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p. 864 - 879
(2016/08/18)
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- Design, synthesis and SAR study of novel sulfonylureas containing an alkenyl moiety
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A series of sulfonylurea compounds was designed and synthesized via introducing an alkenyl moiety into the aryl-5 position and most title compounds exhibited enhanced antifungal activities and limited herbicidal activities compared with chlorsulfuron. Then, a CoMSIA calculation for antifungal activities was carried out to establish a 3D-QSAR model in which a cross-validated q2 of 0.585 and a correlation coefficient r2 of 0.989 were obtained. The derived model revealed that hydrophobic and electrostatic fields were the two most important factors for antifungal activity. Structure optimization was performed according to the CoMSIA model and compound 9z was found to be as potent as chlorothalonil in vitro against C. cornigerum, the pathogen of the wheat sharp eyespot disease. In order to study the fungicidal mechanism, 9z was successfully docked into yeast AHAS using a flexible molecular docking method and the resulting binding pattern was similar to that of chlorimuron-ethyl, indicating that the antifungal activity of compounds 9 was probably due to the inhibition of fungal AHAS.
- Wei, Wei,Cheng, Dandan,Liu, Jingbo,Li, Yuxin,Ma, Yi,Li, Yonghong,Yu, Shujing,Zhang, Xiao,Li, Zhengming
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p. 8356 - 8366
(2016/09/09)
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- Multi-target-oriented protective agent neurocyte
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PROBLEM TO BE SOLVED: To provide a promising multi target direction type pharmaceutical candidate molecule which is promising for treatments of Alzheimer-type dementia (AD), which is a molecule having good cell membrane permeability including blood brain barrier.SOLUTION: A compound designed by a conjunction method with which a benzylpiperidine part of an acetylcholine esterase (AChE) inhibitor, donepezil is connected through an oligomethylene linker and combined with a propargyl part having a monoamine oxidase(MAO) inhibition activity and 8-hydroxy-5-methylaminoquinoline functional group, i.e. a center nitrogen atom substituted by a pro-chelator motif of a biochemical metal, interacts with AChE and butyrylcholinesterase(BuChE), further MAOA and B.
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Paragraph 0118; 0119; 0120
(2017/03/28)
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- Simple synthesis of new 3-substituted 4-(3-chloro-4-fluorophenyl)-1h- pyrrole derivatives and their anticancer activity in vitro
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The preparation of the new 3-substituted 4-(3-chloro-4-fluorophenyl)- 1H-pyrrole derivatives was based on the Van Leusen pyrrole synthesis. In this article, eighteen compounds were readily synthesized in satisfactory to good yields and their cell proliferation inhibiting activities against 2 normal cell lines and 16 cancer cell lines were evaluated. It was particularly important that the new pyrroles displayed barely cytotoxicity against the tested normal cell, which meant these pyrrole analogues might show excellent selectivity towards cancer cell and normal cell. Cell cycle analysis by flow cytometry (FCM) showed that the G0/G1 phase decreased a lot and S phase arrested, in between a minor and transient G2/M block was observed. Cell death induced by 3-cyano-4-(3-chloro-4- fluorophenyl)-1H-pyrrole (2r) was also verified by multiple methods.
- Lan, Lan,Zhan, Xiaoping,Qin, Weixi,Liu, Zenglu,Maoa, Zhenmin
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p. 375 - 397
(2014/03/21)
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- Neuroprotective multi-target directed drugs
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A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil, connected through an oligomethylene linker, to a central nitrogen atom substituted with the propargyl moiety responsible for the MAO inhibition, and a 8-hydroxy-5-methylaminoquinoline functional group, the biometal pro-chelator motif. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potencial impact for AD therapy.
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Paragraph 0101
(2014/05/20)
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- Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease
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The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl) methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.
- Wang, Li,Esteban, Gerard,Ojima, Masaki,Bautista-Aguilera, Oscar M.,Inokuchi, Tsutomu,Moraleda, Ignacio,Iriepa, Isabel,Samadi, Abdelouahid,Youdim, Moussa B.H.,Romero, Alejandro,Soriano, Elena,Herrero, Raquel,Fernández Fernández, Ana Patricia,Ricardo-Martínez-Murillo,Marco-Contelles, José,Unzeta, Mercedes
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p. 543 - 561
(2014/06/09)
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- Metal Oxide Nanoparticles Coated With Specific N-Acylaminomethylene Phosphonates
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The present invention relates to new metal oxide nanoparticles coated with specific phosphonates, to the use of these nanoparticles as antimicrobials, especially in the home and personal care areas, to the production of such nanoparticles as well as to the new phosphonates and the corresponding process of production.
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Page/Page column 15
(2009/05/28)
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- Phosphorylacetic acid thioamides as key substances for phosphorylated heterocycles
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Diethoxyphosphorylthioacetamide in a reaction with 2,3-dichloroquinoxaline acted as a thionating reagent, giving diethoxyphosphorylacetonitrile and 2-chloro-3-[(3-chloro-2-quinoxalinyl)-thio]quinoxaline. Base-catalyzed reactions of phosphorythioacetamides with N-methylquinoxalinium iodide proceeded stereoselectively to yield cis-3-phosphoryl-1,3,3a,4,9,9a-hexahydro-2H-pynola[2, 3-b]quinoxaline-2-thiones. Copyright Taylor & Francis Group, LLC.
- Kozlov,Odinets,Aleksanyan,Petrovskii,Mastryukova
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scheme or table
p. 683 - 684
(2009/04/06)
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- PROCESS FOR THE PREPARATION OF PYRIDINE DERIVATIVES
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Process for the preparation of substituted pyridine derivatives of formula (I) comprising reaction of a α-β-unsaturated carbonyl compound of formula (II) R3-C(O)-C(R1)=C(R2)-G with a Wittig reagent or Horner-Wadsworth-Emmons reagent in the presence of a base and optionally subsequent cyclization.
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Page/Page column 13
(2010/02/12)
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- Heterocyclization of 2-chloro-1-cyano-1-diethoxyphosphoryl-2- trifluoromethylethylene and 2-chloro-2-chlorodifluoromethyl-1-cyano-1- diethoxyphosphorylethylene
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The reactions of 2-chloro-1-cyano-1-diethoxyphosphoryl-2- trifluoromethylethylene (2a) and 2-chloro-2-chlorodifluoromethyl-1-cyano-1- diethoxyphosphorylethylene (2b) with arylamines, arylhydrazines, amidines, 2-aminopyridines, and 5-aminopyrazoles were studied. Alkenes 2a, b can serve as precursors of aminopyrazoles, pyrimidines, pyrido[1,2-a]pyrimidines, and pyrazolo[1,5-a]pyrimidines modified with the fluoroalkyl and diethoxyphosphoryl groups. Intermediates of some heterocyclization reactions were detected by NMR spectroscopy. The structures of the compounds were confirmed by X ray diffraction analysis.
- Shidlovskii,Peregudov,Averkiev,Antipin,Chkanikov
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p. 2060 - 2070
(2007/10/03)
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- Microwave irradiation in organophosphorus chemistry 1: The Michaelis-Arbuzov reaction
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A diverse series of phosphonate esters have been prepared using a domestic microwave oven. The microwave enhanced Michaelis-Arbuzov reaction shows remarkable rate acceleration under microwave irradiation and allows the facile synthesis, and in certain cases easy workup, of alkyl, α-substituted and aryl phosphonates.
- Kiddle, James J.,Gurley, Alison F.
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p. 195 - 205
(2007/10/03)
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In recent years phosphonylated ketones were considered as valuable intermediates in organic synthesis. In the present work we studied the reaction of cyanoalkylphosphonates 1 with organozinc compounds which led after hydrolysis to the corresponding phosph
- Harizi, Abdallah,Hajjem, Bechir,Zantour, Hedi,Baccar, Belgacem
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- Synthesis of isotopically labelled L-phenylalanine and L-tyrosine
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A synthetic route to stable-isotope-substituted L-phenylalanine is presented, which allows the introduction of 13C, 15N, and deuterium labels at any position or combination of positions. For labelling of the aromatic ring, a synthetic route to ethyl benzoate (or benzonitrile) has been developed, based on the electrocyclic ring-closure of a 1,6-disubstituted hexatriene system, with in situ aromatization by elimination of one (amino) substituent. Several important (highly isotopically enriched) synthons have been prepared, namely benzonitrile, benzaldehyde, ethyl benzoate, and ethyl diphenyloxyacetate. Labelled L-phenylalanines have been synthesized from both aromatic precursors by initial conversion into sodium phenylpyruvate and subsequent transformation of this intermediate into the L-α-amino acid by an enzymatic reductive amination reaction. In this manner, highly enriched phenylalanines are obtained on the 10-gram scale and with high enantiomeric purities (≥ 99% ee). The method has been validated by the synthesis of [1'13C]-L-Phe and [2-D]-L-Phe. In addition, two methods are described for the introduction of isotopes into L-tyrosine starting from the isotopically enriched precursors benzonitrile and ethyl benzoate.
- Raap, Jan,Nieuwenhuis, Saskia,Creemers, Alain,Hexspoor, Sander,Kragl, Udo,Lugtenburg, Johan
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p. 2609 - 2621
(2007/10/03)
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- PHASE TRANSFER ACYLATION OF PHOSPHORUS-CONTAINING CH ACIDS. I. EQUILIBRIUM CH ACIDITY OF PHOSPHINOYLACETONITRILES
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Equilibrium CH acidity of phosphinoylacetonitriles was determined by the indicator method in dimethyl sulfoxide (standard 9-phenylfluorene, pK 18.5, K+ as counterion).The compounds are CH acids of medium acidity; their pK values obey the Hammett equation with the constants ΣP and ΣCH2.
- Matveeva, A. G.,Odinets, I. L.,Artyushin, O. I.,Kalyanova, R. M.,Terekhova, M. I.,et al.
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p. 1735 - 1737
(2007/10/03)
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- Synthesis of L-histidine specifically labelled with stable isotopes
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(2'-13C)-, (1'-15N)- and (3'-15N)-L-Histidine were prepared according to a synthetic scheme that allows the 13C or 15N labelling of all carbon and nitrogen positions or any combination of positions.A 1,5-disubstituted imidazole ring was constructed via condensation of tosylmethyl isocyanide with 3-phenylpropenal and subsequent cycloaddition of benzylamine.The imidazole intermediate was converted into 1-benzyl-5-(chloromethyl)-imidazolium chloride which was coupled to a glycine moiety via an enantioselective coupling with the bislactim ether of cyclo-D-valylglycine.Deprotection of the coupling product afforded L-histidine in high optical purity.Syntheses for the isotopically labelled synthons were developed starting from simple, comercially available, highly enriched compounds.The labelled L-histidines were characterized by mass spectrometry and 1H-, 13C- and 15N-NMR spectroscopy.
- Cappon, J. J.,Witters, K. D.,Baart, J.,Verdegem, P. J. E.,Hoek, A. C.,et al.
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p. 318 - 328
(2007/10/02)
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- Synthesis and vibrational analysis of a locked 14-s-cis conformer of retinal
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A 12-N-ethano retinal Schiff base is synthesized to study the vibrational properties of a C14-C15 s-cis conformer of retinal. The synthesis of the 12-N-ethano retinal Schiff base and seven of its isotopomers is described. Raman and FTIR spectra of this compound and its isotopic derivatives are analyzed and the normal mode assignments compared to MNDO normal coordinate calculations. The frequency of the C14-C15 stretch at 1096 cm-1 is ~100 cm-1 below typical values for s-trans conformers of retinal polyenes, supporting previous arguments that s-cis conformers will have characteristically low frequencies for the C-C stretch of the s-cis bond (Smith et al., Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 967-971). Deuteriation at the 15-position produces two modes at 950 and 1044 cm-1 that contain C15D rock character. The elevated frequency (1044 cm-1) of the high-frequency component is a marker band for the C=N syn geometry and confirms an earlier analysis of the sensitivity of the C15D rock frequency to Schiff base configuration (Ames et al., Biochemistry 1989, 28, 3681-3687). This work on retinals with chemically defined configuration and conformation provides a basis for further analysis of the geometry of these bonds in retinal-containing pigments.
- Cromwell, Mary E.M.,Gebhard, Ronald,Li, Xiao-Yuan,Batenburg, Elvira S.,Hopman, Johan C.P.,Lugtenburg, Johan,Mathies, Richard A.
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p. 10860 - 10869
(2007/10/02)
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- Potential Inhibitors of Phosphoenolpyruvate Carboxylase. II. Phosphonic Acid Substrate Analogues Derived from Reactions of Trialkyl Phosphites with Halomethacrylates
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Analogues of phosphoenolpyruvate (PEP), the substrate of PEP carboxylase, were synthesized as potential inhibitors of the enzyme.Esterified analogue precursors were obtained by nucleophilic substitution of various halomethacrylate derivatives with trialkyl phosphites.Substitution of the halomethacrylates can occur either α to the leaving halogen or in the γ position with subsequent allylic shift of the double bond.The course of the reaction was influenced both by reaction conditions and the nature of the substituents on the reactants.The phosphonomethacrylates obtained were hydrolysed to PEP analogues that were found to be moderate to good inhibitors of PEP carboxylase.Phosphonomethacrylic acid derivatives bearing two halogen substituents in the γ position were found to be the most potent inhibitors of this enzyme.
- McFadden, Helen G.,Harris, Roger L. N.,Jenkins, Colin L. D.
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p. 301 - 314
(2007/10/02)
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- Synthesis of the highly cardioselective β-sympathicolytic pacrinolol
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The synthesis is described of the enantiomerically pure (-)-3-(3,4-dimethoxyphenylethylamino-2-hydroxypropoxy] phenyl]-cis-crotonic acid nitrile (13b) (free base) and its hydrochloride (13c) (pacrinolol, Hoe 224 A) starting from p-hydroxyacetophenone (1) and racemic epichlorohydrin (2). The p-(2,3-oxidopropoxy)acetophenone (2) resulting from this reaction is C-homologisized to (8); reactions of this with homoveratrylamine (9) leads to (10a), the racemic structural analog of (13b). Resolution of the racemate is achieved by fractional crystallisation of the diastereoisomeric mandelates (13a) and (14a) to afford the enantiomerically pure title compound (13c) and its dextrarotatory optical antipode (14c). Structural confirmation of (13b) and (13c) was achieved through physicochemical and spectroscopic data especially from the 1H-NMR- and MS-spectra. Pacrinolol (13c) is a highly cardioselective β-sympathicolytic with significant and long acting blood pressure lowering properties (intravenous and oral in the dog).
- Stache,Fritsch,Fehlhaber
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p. 1217 - 1221
(2007/10/02)
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- The Photochemistry of 1-Cyano-2-methyl-3-phenylpropene and Ring substituted Derivatives
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The E- and Z-isomers of 1-cyano-2-methyl-3-phenylpropene and ring-substituted derivatives of the E-isomer, are shown to fluoresce and undergo Z-E-isomerization and di-?-methane rearrangement on irradiation.The rate constants for these processes, obtained from fluorescence lifetimes and quantum yields, can be analysed in terms of an initial interaction between the two ? systems, facilitated by partial charge-transfer, followed by two diverging pathways, one, towards a diradicaloid species leading to cyclopropane formation, the other towards a 'zwitterionic' species and relaxation to the ground state and resulting in singlet state Z-E-isommerization.
- Ferreira, Aurelio B. B.,Salisbury, Kingsley
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- Inhibitors of Pyrimidine Biosynthesis. Part 2. The Synthesis of Amidine Phosphonates as Potential Inhibitors of Carbamoyl Phosphate Synthase
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The synthesis of a series of amidine phosphonates (8) and (9) via a thioimidate intermediate is described.
- Wharton, Clifford J.,Wrigglesworth, Roger
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p. 433 - 436
(2007/10/02)
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- Synthese d'analogues tetrazoles de l'acide phosphonoacetique
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Several routes to 5-(phosphonomethyl)-1(H)-tetrazole, a new antiviral agent, have been investigated.
- Yaouanc,Sturtz,Kraus,Chastel,Colin
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p. 2689 - 2692
(2007/10/02)
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