- Phosphinic acid analogues of thiaproline and the related heterocyclic aminophosphinic acids
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Bis(trimethylsilyl) phosphonite adds in a 1,2 fashion to the C = N bond in 3-thiazolines 3a-d to give after hydrolysis phosphinic acids 5a-d. Starting from 3-oxazines, the corresponding 6a,b phosphinic acids 7a,b were obtained.
- Hatam,Martens
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- Synthesis of phosphinate analogues of the phospholipid anti-tumour agent hexadecylphosphocholine (miltefosine)
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Efficient synthesis of phosphinate analogues (in six steps and 68-69% overall yields) of the anti-tumour agent miltefosine are reported, which involve a radical hydrophosphinylation addition reaction followed by conversion to the P(III) silyloxy intermediate and Michael-type addition as the key steps.
- Markoulides, Marios S.,Regan, Andrew C.
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- Complexes of divalent transition metal ions with bis(aminomethyl)phosphinic acid in aqueous solution and in the solid state
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Bis(aminomethyl)phosphinic acid, (NH2CH2)2PO2H (HL), was synthesized using a new procedure. Its coordination ability towards CO(II)/(III), Ni(II), Cu(II) and Zn(II) was studied both in solution and in the solid state. Because of the presence of two nitrogen atoms the ligand exhibits a higher overall basicity than common (aminoalkyl)phosphinic acids. Consequently, the values of the determined stability constants are comparable with those found for (aminoalkyl)phosphonic acids. NMR titrations of Zn(II) point to the interaction of phosphinate with the metal ion in a strong acid solution. The X-ray structures show several coordination modes in the solid state. All-trans-[MCl2(H2L-O)2 (H2O)2]Cl2, where M(II) are Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Ca(II), and Cd(II), crystallized from acid solutions. The central ion is octahedrally coordinated with two phosphinate oxygen atoms, two molecules of water and two chlorides in all-trans arrangement. Amine groups are protonated and non-coordinated. Participation of the donor groups in crystals isolated from neutral solutions depends on the metal ion. All donor atoms are coordinated in monomeric fac-N,N,O-trans-O,O'-[Co(L-N,N,O)2]+. On the other hand, in the zinc(II) complex, two phosphinate oxygen atoms and two amine nitrogen atoms (trans to each other) of two different ligand molecules are coordinated in an equatorial plane and two amino groups of the two other ligand molecules are bound in axial positions. Thus, each molecule of the amino acid forms a five-membered N,O-chelate to one zinc(II) ion and the other amino group is bound to the neighbouring ion creating an infinite chain. Nickel(II) forms a trans-O,O′-[Ni(H2O)2-(L-N,N)2] complex in which the metal ion is chelated by four amine nitrogen atoms forming two six-membered chelates in an equatorial plane and the octahedron is completed with two water molecules at the apical positions. The phosphinate group is not coordinated. The above results point to a relatively low coordination ability of the phosphinate group; however, due to its low pKA, it is able to bind metal ions at lower pH than other coordinating groups do.
- Kubicek, Vojtech,Vojtisek, Pavel,Rudovsky, Jakub,Hermann, Petr,Lukes, Ivan
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- Application of in situ silylation for improved, convenient preparation of fluorenylmethoxycarbonyl (Fmoc)-protected phosphinate amino acids
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(Chemical Equation Presented) A convenient and efficient method has been developed for the preparation of 9-fluorenylmethoxycarbonyl (Fmoc)-protected 1-aminoalkylphosphinic acids. Reproducible procedures for the synthesis and purification of free α-amino H-phosphinates are provided. Protection of free amino phosphinates as the N-Fmoc derivative was achieved by in situ trimethylsilylation of aminoalkylphosphinic acids, which then reacted with Fmoc-Cl to provide corresponding products in excellent yields and in high purity after simple extractive isolation. Mechanistic aspects of the silylation are discussed, and the application of the procedure to another class of amino phosphorus acids is presented.
- Li, Shunzi,Whitehead, John K.,Hammer, Robert P.
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- Reactions of Unsaturated Ketones with Bis(trimethylsilyl) Hypophosphite
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Bis(trimethylsilyl) hypophosphite reacts with unsaturated ketones (methyl vinyl ketone and mesityl oxide) to give, depending on the reaction conditions, 1: 1 or 1: 2 adducts after hydrolysis. It was found that the intramolecular cyclization of the 1: 2 reaction product with mesityl oxide, trimethylsilyl bis(2-methyl-4- oxopentan-2-yl)phosphinate, yields, after hydrolysis, a phosphorinane with exocyclic carbonyl and hydroxyl groups.
- Tatarinov,Kundina,Dobrynin,Mironov
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- Synthesis of a bifunctional monophosphinate DOTA derivative having a free carboxylate group in the phosphorus side chain
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A new bifunctional cyclen-based ligand, 3-[hydroxy({4,7,10-tris[(tert- butoxycarbonyl)methyl]-1,4,7,10-tetraazacyclododecan-1-yl}methyl)phosphoryl] propanoic acid, was synthesized by alkylation of tri-tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (t-Bu3DO3A) by ethyl 3-{ethoxy[(mesyloxy)methyl]phosphoryl}propanoate [MsOCH2P(O)(OEt) CH2CH2CO2Et]. The ethyl carboxylate group in the side chain was selectively deprotected to obtain the esterified bifunctional ligand. More efficient syntheses of some phosphinopropanoic acid derivatives were devised and the phosphorus alkylation reagent was prepared starting from hypophosphorus acid or its salt. Georg Thieme Verlag Stuttgart.
- Rezanka, Pavel,Kubicek, Vojtech,Hermann, Petr,Lukes, Ivan
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- Synthesis of phosphinic acids on the basis of hypophosphites: VI. General methods for synthesis of pseudo-γ-glutamylpeptides
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A general method for synthesis of 2-substituted pseudo-γ- glutamylpeptides, namely, [2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl) propyl]phosphinic acids I which are phosphinic acid analogs of γ-glutamylpeptides. Bis(trimethylsilyl) hypophosphite (IV) formed from ammonium hypophosphite (II) in situ was added to the respective α-substituted acrylate to form bis(trimethylsilyl) [2-R-2-(alkoxycarbonyl) ethyl]-phosphonites V. Treatment of compounds V in situ with excess dibromoethane followed by alcoholysis gave [2-R-2-(alkoxycarbonyl)ethyl](2- bromoethyl)phosphinic acids VI which without isolation were treated with excess triethyl orthoformate. The simultanious esterification and dehydrobromination led to [2-R-2-(alkoxy-carbonyl)ethyl](vinyl)phosphinates III which were isolated and characterized. The Michael addition of diethyl acetamidomalonate to vinylphosphinates III followed by acid hydrolysis of phosphinates VII without their isolation resulted in formation of target [2-R-2-(hydroxycarbonyl)ethyl] [3-amino-3-(hydroxycarbonyl)]proly]phosphinic acids-pseudo-γ- glutamylpeptides I. Nauka/Interperiodica 2007.
- Ragulin
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- Nucleoside H-boranophosphonates: A new class of boron-containing nucleotide analogues
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A study on the synthesis of nucleoside H-boranophosphonates, a new class of nucleotide analogues having a P→BH3 and a P-H group, via condensation of the corresponding nucleosides with H-boranophosphonate derivatives is described. The Royal Soci
- Higashida, Renpei,Oka, Natsuhisa,Kawanaka, Toshihide,Wada, Takeshi
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- Mechanism of Phosphorus-Carbon Bond Formation in the Amidoalkylation of Phosphonous Carboxylic Acids
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An unusual greater reactivity of phosphonous propionic acids was found in comparison with phosphonous propionic esters in carbamate version of Kabachnik-Fields reaction. Compounds of tricoordinated phosphorus generated in situ during the amidoalkylation o
- Dmitriev, Maxim E.,Golovash, Sofia R.,Borodachev, Alexei V.,Ragulin, Valery V.
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supporting information
p. 593 - 600
(2021/01/14)
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- Covalent Inhibition of Bacterial Urease by Bifunctional Catechol-Based Phosphonates and Phosphinates
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In this study, a new class of bifunctional inhibitors of bacterial ureases, important molecular targets for antimicrobial therapies, was developed. The structures of the inhibitors consist of a combination of a phosphonate or (2-carboxyethyl)phosphinate functionality with a catechol-based fragment, which are designed for complexation of the catalytic nickel ions and covalent bonding with the thiol group of Cys322, respectively. Compounds with three types of frameworks, including β-3,4-dihydroxyphenyl-, α-3,4-dihydroxybenzyl-, and α-3,4-dihydroxybenzylidene-substituted derivatives, exhibited complex and varying structure-dependent kinetics of inhibition. Among irreversible binders, methyl β-(3,4-dihydroxyphenyl)-β-(2-carboxyethyl)phosphorylpropionate was observed to be a remarkably reactive inhibitor of Sporosarcina pasteurii urease (kinact/KI = 10 420 s-1 M-1). The high potential of this group of compounds was also confirmed in Proteus mirabilis whole-cell-based inhibition assays. Some compounds followed slow-binding and reversible kinetics, e.g., methyl β-(3,4-dihydroxyphenyl)-β-phosphonopropionate, with Ki? = 0.13 μM, and an atypical low dissociation rate (residence time τ = 205 min).
- Pagoni, Aikaterini,Grabowiecka, Agnieszka,Tabor, Wojciech,Mucha, Artur,Vassiliou, Stamatia,Berlicki, ?ukasz
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p. 404 - 416
(2021/01/13)
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- A Carbodiimide-Mediated P-C Bond-Forming Reaction: Mild Amidoalkylation of P-Nucleophiles by Boc-Aminals
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The first example of a carbodiimide-mediated P-C bond-forming reaction is described. The reaction involves activation of β-carboxyethylphosphinic acids and subsequent reaction with Boc-aminals using acid-catalysis. Mechanistic experiments using 31P NMR spectroscopy and DFT calculations support the contribution of unusually reactive cyclic phosphinic/carboxylic mixed anhydrides in a reaction pathway involving ion-pair "swapping". The utility of this protocol is highlighted by the direct synthesis of Boc-protected phosphinic dipeptides, as precursors to potent Zn-aminopeptidase inhibitors.
- Kokkala, Paraskevi,Rajeshkumar, Thayalan,Mpakali, Anastasia,Stratikos, Efstratios,Vogiatzis, Konstantinos D.,Georgiadis, Dimitris
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supporting information
p. 1726 - 1730
(2021/03/08)
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- One-pot synthesis of phosphinylphosphonate derivatives and their anti-tumor evaluations
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This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).
- Deschamp, Julia,Dussart-Gautheret, Jade,Lecouvey, Marc,Legigan, Thibaut,Migianu-Griffoni, Evelyne,Monteil, Maelle
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- Formation of 1-hydroxymethylene-1,1-bisphosphinates through the addition of a silylated phosphonite on various trivalent derivatives
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An easily handled one-pot synthetic procedure was previously developed for the synthesis of bisphosphinates starting from acyl chlorides. Herein, other trivalent derivatives as acid anhydrides and activated esters were tested to form various bisphosphinates. This modulation of the reactivity can be controlled according to the nature of the acid derivative for the use of sensitive and functionalized substrates.
- Dussart-Gautheret, Jade,Deschamp, Julia,Monteil, Maelle,Gager, Olivier,Legigan, Thibaut,Migianu-Griffoni, Evelyne,Lecouvey, Marc
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p. 14559 - 14569
(2020/12/29)
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- A General Protocol for the Synthesis of H-α-Hydroxyphosphinates
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A general synthetic procedure was developed for H-α-hydroxyphosphinates via Abramov reaction. The present work is a complementary study to those reported till now. This methodology has the advantage that it can be applied to various aliphatic and (hetero)aromatic substrates. The H-α-hydroxyphosphinates were easily purified and obtained in good to excellent yields in shorter times. A 31 P NMR spectroscopy study has shown that only 2 equivalents of a silylating agent were required.
- Dussart, Jade,Deschamp, Julia,Monteil, Maelle,Gager, Olivier,Migianu-Griffoni, Evelyne,Lecouvey, Marc
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p. 421 - 432
(2019/01/10)
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- A convenient one-pot synthesis of 1-hydroxymethylene-1,1-bisphosphinic acids
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A convenient and generalizable procedure has been optimized to access to 1-hydroxymethylene-1,1-bisphosphinate compounds. Several alkyl, including an alendronate bisphosphinate analog, and (hetero)aryl compounds were rapidly obtained in satisfying to exce
- Guedeney, Nicolas,Dussart, Jade,Deschamp, Julia,Ouechtati, Mouna,Migianu-Griffoni, Evelyne,Lecouvey, Marc
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p. 323 - 325
(2019/01/04)
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- A convenient synthetic route towards H-bisphosphinates
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A practical generalisable procedure to synthesize hydroxymethylene H-bisphosphinates has been optimised. Unlike previous reports, numerous alkyl (including an alendronate bisphosphinate analogue) or (hetero)aryl compounds were rapidly obtained in satisfactory to excellent yields. A side product could have been identified as a phosphino-phosphonate isomer and plausible mechanistic pathways are proposed here. Moreover to check the literature data, a pKa value study was also performed.
- Dussart, Jade,Guedeney, Nicolas,Deschamp, Julia,Monteil, Maelle,Gager, Olivier,Legigan, Thibaut,Migianu-Griffoni, Evelyne,Lecouvey, Marc
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p. 6969 - 6979
(2018/10/17)
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- Novel organophosphorus scaffolds of urease inhibitors obtained by substitution of Morita-Baylis-Hillman adducts with phosphorus nucleophiles
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The reactivity of Morita-Baylis-Hillman allyl acetates was employed to introduce phosphorus-containing functionalities to the side chain of the cinnamic acid conjugated system by nucleophilic displacement. The proximity of two acidic groups, the carboxyla
- Ntatsopoulos, Vassilis,Vassiliou, Stamatia,Macegoniuk, Katarzyna,Berlicki, ?ukasz,Mucha, Artur
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p. 107 - 120
(2017/04/07)
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- Hydroxy-bisphosphinic acids: Synthesis and complexation properties with transition metals and lanthanide ions in aqueous solution
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Treatment of acyl chlorides with a mixture of ammonium hypophosphite and hexamethyl disilazene gave 1-hydroxy-1,1-bisphosphinic acids. Acid dissociation constants (pKa) of 1-hydroxy-1,1-bisphosphinic acids were determined by the pH-potentiometric techniqu
- Kaboudin, Babak,Ezzati, Ali,Faghihi, Mohammad Reza,Barati, Ali,Kazemi, Foad,Abdollahi, Hamid,Yokomatsu, Tsutomu
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p. 747 - 752
(2016/02/20)
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- Penicillin G acylase-mediated kinetic resolution of racemic 1-(N-acylamino)alkylphosphonic and 1-(N-acylamino)alkylphosphinic acids and their esters
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Extensive studies on the penicillin G acylase-mediated kinetic resolution of N-acylated 1-aminoalkylphosphonic and 1-aminoalkylphosphinic acids as well as their esters were carried out to recognise the relationships between the substrate structure, reacti
- Zielińska, Katarzyna,Mazurkiewicz, Roman,Szymańska, Katarzyna,Jarz?bski, Andrzej,Magiera, Sylwia,Erfurt, Karol
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- Diethyl inferior phosphine acid aluminum method for the synthesis of
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The invention relates to the field of organic synthesis, and provides a synthesis method of aluminum diethylphosphinate. The method comprises the following steps of mixing ammonium hypophosphite and an organic solvent, adding a catalyst, and dropwise adding hexamethyldisilazane into the solution under the temperature condition of 80 to 130 DEG C to obtain di-trimethylsiloxy phosphorus; adding the prepared di-trimethylsiloxy phosphorus into a pressure reaction kettle, introducing ethylene and hydrogen bromide gas, maintaining the reaction pressure by utilizing the nitrogen to obtain an intermediate product, carrying out reduced-pressure distillation to collect methylbenzene, adding dissolving water into the solution, and separating the solution to collect the water layer to obtain a diethyl phosphinic acid solution; and adjusting the pH value of the diethyl phosphinic acid solution to 3.0 +/-0.2 by utilizing sulfuric acid, and dropwise adding an aluminum sulfide aqueous solution to generate the aluminum diethylphosphinate. The synthesis method of the aluminum diethylphosphinate is high in product purity, high in conversion rate, low in cost and simple in process.
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Paragraph 0037; 0038
(2017/03/22)
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- NOVEL LINKERS FOR CONJUGATION OF CELL-BINDING MOLECULES
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Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.
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Paragraph 0043
(2015/10/28)
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- Synthesis of phosphorus isosters of β-amyloid peptides fragments
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We have developed a synthetic route to pseudo dipeptides, analogs of certain fragments of β-amyloid peptides (products of the APP protein hydrolysis). These compounds can be used for preparation of phosphinic acidic oligopeptides representing the peptide sequence of the β-amyloid but containing the phosphorus isoster peptide fragment. Synthesis of pseudo ornityl-glutamate, pseudo arginyl-glutamate, pseudo glycyl-leucine, and pseudo isoleucyl-glycine via amino- and amidoalkylation of phosphonic acids containing the structural isoster of the corresponding amino acid is described.
- Dmitriev,Ragulin
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p. 2091 - 2098
(2015/11/02)
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- HYDROPHILIC LINKERS AND THEIR USES FOR CONJUGATION OF DRUGS TO CELL BINDING MOLECULES
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Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.
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Page/Page column 51
(2014/06/11)
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- Aminoalkyl-1,1-bis(phosphinic acids): Stability, acid-base, and coordination properties
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Four geminal bis(phosphinic acids), namely, aminomethylbis(H-phosphinic acid) (H2L1) and 4-aminobutyl-1-hydroxy-1,1-bis(R-phosphinic acid) with R = H (H2L2), Me (H2L3) and CH2CH2COOH (H4L4), were studied. Their acid-base properties and coordination ability towards Cu2+, Ni2+ and Zn2+ ions were studied by potentiometry, UV/Vis spectroscopy and NMR spectroscopy. The amine group in H2L1 has a lower protonation constant (log Ka = 6.79) than those found for other studied bisphosphinates (log Ka = 10.75-11.05) with distant amine groups. The structure of [Ca(H2L2-O,O')(HL2-O,O')]Cl revealed an octahedral arrangement of the metal coordination sphere and a linear polymeric structure, which forms through eight-membered Ca(-O-P-O-)2Ca rings. The structure of [Cu(HL3-O,O')2(H2O)]·5H2O shows two chelating bisphosphinate groups in an equatorial O4 environment. The structure of [Cu(H0.5L3-O,O')(NO3)0.5]·2.25H2O shows two different coordination environments, one is an elongated tetragonal pyramid, and the other is a trigonal bipyramid with a bidentate nitrate ion. Four geminal bisphosphinates were synthesized, and their acid-base properties and coordination behaviour with Cu2+, Zn2+ and Ni2+ ions were studied. The compounds show lower amine basicity and complex stability constants than those of analogous bisphosphonates. In the solid-state structures of the Ca2+ and Cu2+ complexes, the bisphosphinates are coordinated in O,O'-chelating mode.
- David, Tomá?,Procházková, Soňa,Kotek, Jan,Kubí?ek, Vojtěch,Hermann, Petr,Luke?, Ivan
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p. 4357 - 4368
(2015/03/30)
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- Methylene-bis[(aminomethyl)phosphinic acids]: Synthesis, acid-base and coordination properties
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Three symmetrical methylene-bis[(aminomethyl)phosphinic acids] bearing different substituents on the central carbon atom, (NH2CH 2)PO2H-C(R1)(R2)-PO 2H(CH2NH2) where R1 = OH, R 2 = Me (H2L1), R1 = OH, R 2 = Ph (H2L2) and R1,R2 = H (H2L3), were synthesized. Acid-base and complexing properties of the ligands were studied in solution as well as in the solid state. The ligands show unusually high basicity of the nitrogen atoms (log K1 = 9.5-10, log K2 = 8.5-9) if compared with simple (aminomethyl)phosphinic acids and, consequently, high stability constants of the complexes with studied divalent metal ions. The study showed the important role of the hydroxo group attached to the central carbon atom of the geminal bis(phosphinate) moiety. Deprotonation of the hydroxo group yields the alcoholate anion which tends to play the role of a bridging ligand and induces formation of polynuclear complexes. Solid-state structures of complexes [H 2NC(NH2)2][Cu2(H-1L 2)2]CO3·10H2O and Li 2[Co4(H-1L1)3(OH)] ·17.5H2O were determined by X-ray diffraction. The complexes show unexpected geometries forming dinuclear and cubane-like structures, respectively. The dinuclear copper(ii) complex contains a bridging μ2-alcoholate group with the -O-P(O)-CH 2-NH2 fragments of each ligand molecule chelated to the different central ion. In the cubane cobalt(ii) complex, one μ3-hydroxide and three μ3-alcoholate anions are located in the cube vertices and both phosphinate groups of one ligand molecule are chelating the same cobalt(ii) ion while each of its amino groups are bound to different neighbouring metal ions. All such three metal ions are bridged by the alcoholate group of a given ligand.
- David, Tomá?,Procházková, Soňa,Havlí?ková, Jana,Kotek, Jan,Kubí?ek, Vojtěch,Hermann, Petr,Luke?, Ivan
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p. 2414 - 2422
(2013/03/29)
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- Synthesis and reactivity of alkoxy(trimethylsiloxy)phosphines and their derivatives
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Convenient procedures for the synthesis of new alkoxy(trimethylsiloxy) phosphines and their derivatives starting from the available alkyl hypophosphites and N-trimethylsilyl succinimide are proposed. Some properties of these new phosphines such as nucleophilic substitution of the trimethylsiloxy group at trivalent phosphorus, the Arbuzov reaction, and addition of PH and POSi fragments to multiple carbon-carbon bonds are presented.
- Prishchenko, Andrey A.,Livantsov, Mikhail V.,Novikova, Olga P.,Livantsova, Ludmila I.,Petrosyan, Valery S.
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experimental part
p. 138 - 145
(2012/07/13)
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- 1-hydroxy-1,1-bis(H-phosphinates): Synthesis, stability, and sorption properties
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A synthesis of 1-hydroxy-1,1-bis(H-phosphinates) from acylchlorides is described. Solid-state structures of two bis(phosphinates) determined by X-ray diffraction showed variations in the Pi-C distances. The compounds show negligible sorption on hydroxyapatite and an intermediate chemical stability in aqueous solution. The hydrolysis occurs in acidic as well as alkaline media. Hydrolysis rates of four derivatives show the lowest stability for aromatic derivatives as a result of the electron-withdrawing effect. Main products of hydrolysis are 1-hydroxy-(H-phosphinates) and phosphorous acid.
- David, Tomas,Kreckova, Pavlina,Kotek, Jan,Kubicek, Vojtech,Lukes, Ivan
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experimental part
p. 195 - 201
(2012/07/03)
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- Application of bis(trimethylsilyl) phosphonite in the efficient preparation of new heterocyclic -aminomethyl- H -phosphinic acids
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A simple, reproducible, and efficient preparation of new heterocyclic -aminomethyl-H-phosphinic acids is reported. The synthetic protocol is based on the application of bis(trimethylsilyl) phosphonite, as an efficient phosphorous nucleophile, in the reaction with the corresponding heterocyclic imines. Subsequent methanolysis of the addition intermediates leads to the expected heterocyclic -aminomethyl-H-phosphinic acids in fair to good yields. Additionally, acidic hydrolysis of benzhydrylamino derivatives allows the efficient preparation of free -aminomethyl-H-phosphinic acids in good yields and high purity after simple crystallization. Georg Thieme Verlag Stuttgart New York.
- Olszewski, Tomasz K.,Boduszek, Bogdan
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experimental part
p. 437 - 442
(2011/04/22)
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- A virtual screening hit reveals new possibilities for developing group III metabotropic glutamate receptor agonists
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(R)-PCEP (3-amino-3-carboxypropyl-2′-carboxyethyl phosphinic acid, 1), a new metabotropic glutamate receptor 4 (mGlu4R) agonist, was discovered in a previously reported virtual screening. The (S)-enantiomer and a series of derivatives were synthesized and
- Selvam, Chelliah,Oueslati, Nadia,Lemasson, Isabelle A.,Brabet, Isabelle,Rigault, Delphine,Courtiol, Tiphanie,Cesarini, Sara,Triballeau, Nicolas,Bertrand, Hugues-Olivier,Goudet, Cyril,Pin, Jean-Philippe,Acher, Francine C.
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experimental part
p. 2797 - 2813
(2010/08/06)
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- A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric68GA tracers for positron emission tomography
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For application in positron emission tomography (PET), PrP9, a N,N′,N″-trisubstituted triazacyclononane with methyl(2-carboxyethyl) phosphinic acid pendant arms, was developed as 68Ga3+ complexing agent. The synthesis is short and inexpensive. GaIII and FeIII complexes of PrP9 were characterized by single-crystal X-ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The GaIII complex possesses a high thermodynamic stability (log K[GaL]=26.24) and a high degree of kinetic inertness. 68Ga labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO2based 68Ge/68Ga generator (typically consisting of 0.1M HCl) can be directly used for labeling purposes. The rate of 68Ga activity incorporation at pH 3.3 and 20°C is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.
- Notni, Johannes,Hermann, Petr,Havlickova, Jana,Kotek, Jan,Kubicek, Vojtech,Plutnar, Jan,Loktionova, Natalia,Riss, Patrick Johannes,Roesch, Frank,Lukes, Ivan
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experimental part
p. 7174 - 7185
(2010/09/16)
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- PROCESS FOR THE SYNTHESIS OF ALKYL PHOSPHINIC ACIDS BY INITIATION OF AN AMINE AND AN AMINEOXIDE
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The present invention relates toa new process for the synthesis of alkyl phosphinic acids, and more particularly to a coupling reaction between an alkylhalide and a hypophosphorous acid derivative in the presence of an amine and an amineoxide.
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Page/Page column 13-17
(2009/01/20)
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- PROCESS FOR THE SYNTHESIS OF ALKYL PHOSPHINIC ACIDS BY INITIATION OF AN AMINE AND AN AMINEOXIDE
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The present invention relates to a new process for the synthesis of alkyl phosphinic acids, and more particularly to a coupling reaction between an alkylhalide and a hypophosphorous acid derivative in the presence of an amine and an amineoxide.
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Page/Page column 11-15
(2009/01/20)
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- A method of synthesis of phosphinic acids on the basis of hypophosphites: VII. Synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid
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A method of synthesis of pseudo-γ-aminobutanoyl peptides and other phosphinic analogs of γ-aminobutyric acid from hypophosphites is suggested. Silyl phosphonites formed by in situ addition of bis-(trimethylsilyl) hypophosphite to the corresponding α-substituted acrylates, styrene, or vinyl phosphonate used as unsaturated components in the synthesis react in situ with N-(ω-bromoalkyl)phthalimides by an Arbuzov reaction scheme, affording ω-(phthalimido)alkylphosphinic acids possessing β-substituted β-(alkoxycarbonyl)ethyl, β-phenylethyl, or β- (diethoxyphosphinoyl)ethyl substituents. Acid hydrolysis of these reaction products gives the target aminophosphinic acids: phosphinic analogs of γ-aminobutyric acid.
- Ragulin
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experimental part
p. 1655 - 1661
(2009/02/06)
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- Synthesis and pharmacological evaluation of novel γ-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors
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We have previously demonstrated that the prototypical GABAB receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABAB agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABAB agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABAB agonists devoid of classical GABAB agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.
- Alstermark, Christer,Amin, Kosrat,Dinn, Sean R.,Elebring, Thomas,Fjellstr?m, Ola,Fitzpatrick, Kevin,Geiss, William B.,Gottfries, Johan,Guzzo, Peter R.,Harding, James P.,Holmén, Anders,Kothare, Mohit,Lehmann, Anders,Mattsson, Jan P.,Nilsson, Karolina,Sundén, Gunnel,Swanson, Marianne,Von Unge, Sverker,Woo, Alex M.,Wyle, Michael J.,Zheng, Xiaozhang
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experimental part
p. 4315 - 4320
(2009/05/30)
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- NEW PROCESS FOR THE PREPARATION OF ALKYL PHOSPHINIC ACIDS
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The present invention relates to a new process for the synthesis of alkyl phosphinic acids, and more particularly to a coupling reaction between an alkylhalide and a hypophosphorous acid derivative by a radical initiated reaction. The invention also relat
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Page/Page column 15; 16; 16-17; 19-20
(2008/06/13)
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- Shortcut to Fmoc-protected phosphinic pseudodipeptidic blocks
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(Chemical Equation Presented) A three-component condensation reaction of Fmoc-carbamate, aldehydes, and alkylphosphinic acids provides a new, direct, and efficient method for synthesizing Fmoc-protected phosphinic pseudodipeptidic blocks, directly usable
- Matziari, Magdalini,Yiotakis, Athanasios
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p. 4049 - 4052
(2007/10/03)
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- Design, modelling, synthesis and biological evaluation of peptidomimetic phosphinates as inhibitors of matrix metalloproteinases MMP-2 and MMP-8
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Three novel peptidomimetic phosphinate inhibitors have been synthesized and evaluated as inhibitors of matrix metalloproteinases MMP-2 and MMP-8. Their IC50 values are in the micromolar range, and one of them showed to be the most effective inh
- Bianchini, Gianluca,Aschi, Massimiliano,Cavicchio, Giancarlo,Crucianelli, Marcello,Preziuso, Serena,Gallina, Carlo,Nastari, Adele,Gavuzzo, Enrico,Mazza, Fernando
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p. 4740 - 4749
(2007/10/03)
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- A method for preparing phosphinic acids from hypophosphites: III. Synthesis of α-hydroxy phosphinic acids
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A one-pot method is proposed for preparing unsymmetrical α-hydroxy phosphinic acids from ammonium hypophosphite. Bis(trimethylsilyl) phosphonites formed in situ on addition of bis(trimethylsilyl) hypophosphite to activated unsaturated compounds are brough
- Rozhko,Ragulin
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p. 1087 - 1090
(2007/10/03)
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- Synthesis of Azole Nucleoside 5′-Monophosphate Mimics (P1Ms) and Their Inhibitory Properties of IMP Dehydrogenases
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IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5′-MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not ass
- Wang, Guangyi,Sakthivel, Kandasamy,Rajappan, Vasanthakumar,Bruice, Thomas W.,Tucker, Kathleen,Fagan, Patrick,Brooks, Jennifer L.,Hurd, Tiffany,Leeds, Janet M.,Cook, P. Dan
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p. 317 - 337
(2007/10/03)
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- Synthesis of phosphinic acids on the basis of hypophosphites: IV. Synthesis of pseudo-γ-glutamylglycine and its enantiomers
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A new method for construction of pseudopeptide molecules is proposed, exemplified by the synthesis of [3-amino-3-(hydroxycarbonyl)propyl][2- (hydroxycabonyl)ethyl]phosphinic acid (I) (pseudo-γ-glutamylglycine), starting from ammonium hypophosphite. Enzyma
- Ragulin
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p. 1177 - 1181
(2007/10/03)
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- Synthesis of New Arylhydroxymethylphosphinic Acids and Derivatives
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The synthesis of a new series of arylhydroxymethylphosphinic acid derivatives is described. The protected compounds were prepared by a palladium(0) catalysed arylation of ethyl benzyloxymethylphosphinate with aryl halides. Subsequent hydrogenolysis of the
- Cristau,Herve,Loiseau,Virieux
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p. 2216 - 2220
(2007/10/03)
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- Synthesis of novel 3'-methylene H-phosphonate thymidines
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The synthesis of novel 5'-DMT- and 5'-MMT-protected 3'-methylene H-phosphonate thymidines 1-6, having methoxy, fluoro, hydrogen, and methoxyethoxy substituents at the 2'-position is reported. (C) 2000 Elsevier Science Ltd.
- An,Wang,Cook
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p. 7813 - 7816
(2007/10/03)
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- DHPMP: A novel Group I specific metabotropic glutamate receptor agonist
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The synthesis and preliminary pharmacological evaluation of (RS)-amino(3,5-dihydroxyphenyl)methylphosphinic acid (DHPMP) is reported. DHPMP has been identified as possessing Group I specific metabotropic agonist activity.
- Boyd, E. Andrew,Alexander, Stephen P. H.,Kendall, David A.,Loh Jr., Vincent M.
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p. 2137 - 2140
(2007/10/03)
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- Synthesis of γ-Keto-substituted Phosphinic Acids from Bis(trimethylsilyl)phosphonite and α,β-Unsaturated Ketones
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Mono- and di-substituted phosphinic acids have been synthesised in high yield by addition of silyl phosphonites to α,β-unsaturated ketones, and conveniently purified via their adamantanammonium salts. Key Words: Bis(trimethylsilyl)phosphonite (BTSP); Phosphinic Acids; 1,4 Michael-type Addition; Adamantanammonium Phosphinates.
- Boyd, E. Andrew,Regan, Andrew C.,James, Keith
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p. 813 - 816
(2007/10/02)
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