- Ion-molecule reactions of O,S-dimethyl methylphosphonothioate: Evidence for intramolecular sulfur oxidation during VX perhydrolysis
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(Chemical Equation Presented) The alkaline perhydrolysis of the nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) was investigated by studying the ion-molecule reactions of HOO- with O,S-dimethyl methylphosphonothioate in a modified linear ion-trap mass spectrometer. In addition to simple proton transfer, two other abundant product ions are observed at m/z 125 and 109 corresponding to the S-methyl methylphosphonothioate and methyl methylphosphonate anions, respectively. The structure of these product ions is demonstrated by a combination of collision-induced dissociation and isotope-labeling experiments that also provide evidence for their formation by nucleophilic reaction pathways, namely, (i) SN2 at carbon to yield the S-methyl methylphosphonothioate anion and (ii) nucleophilic addition at phosphorus affording a reactive pentavalent intermediate that readily undergoes internal sulfur oxidation and concomitant elimination of CH3SOH to yield the methyl methylphosphonate anion. Consistent with previous solution phase observations of VX perhydrolysis, the toxic P-O cleavage product is not observed in this VX model system and theoretical calculations identify P-O cleavage to be energetically uncompetitive. Conversely, intramolecular sulfur oxidation is calculated to be extremely exothermic and kinetically accessible explaining its competitiveness with the facile gas phase proton transfer process. Elimination of a sulfur moiety deactivates the nerve agent VX and thus the intramolecular sulfur oxidation process reported here is also able to explain the selective perhydrolysis of the nerve agent to relatively nontoxic products.
- McAnoy, Andrew M.,Williams, Jilliarne,Paine, Martin R. L.,Rogers, Michael L.,Blanksby, Stephen J.
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- Synthesis and in vivo antitumor evaluation of an orally active potent phosphonamidate derivative targeting IDO1/IDO2/TDO
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Targeting Trp-Kyn pathways has been identified as an attractive approach for the cancer immunotherapies. In this study, a novel phosphonamidate containing compound was designed, synthesized and evaluated for its inhibitory activity against key dioxygenase
- Feng, Xi,Shen, Pei,Wang,Li,Bian, Jinlei
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- Asymmetric synthesis of a cyclopropanecarboxylic acid derivative–the potential agonist/antagonist of GABA receptors
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The synthesis of enantiomerically pure (1S,2S,S P)-1-[hydroxy(methyl)phosphonyl]-2-aminocyclopropanecarboxylic acid (1) (a potential agonist/antagonist of GABA receptors) was accomplished in six steps based on optically inactive methyl 2-[metho
- Krysiak, Jerzy,Mikina, Maciej,Rzewnicka, Aneta,Sobczak, Agata,?urawiński, Remigiusz,Sieroń, Les?aw
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- HEADGROUP LIPID COMPOUNDS AND COMPOSITIONS FOR INTRACELLULAR DELIVERY OF THERAPEUTIC AGENTS
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The application relates to lipids of Formula (A-1) and compositions involving the same. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) include such a lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) further including therapeutic and/ or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.
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Paragraph 00402
(2021/04/01)
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- Discovery of phosphonamidate IDO1 inhibitors for the treatment of non-small cell lung cancer
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Targeting indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as an attractive approach for the development of cancer immunotherapy. In this study, a series of phosphonamidate ester containing compounds were designed, synthesized and evaluated for their inhibitory activities against IDO1. Among them, compounds 16, 17, and 26 with good IDO1 inhibitory (HeLa IDO1 IC50 = 10–21 nM, hIDO1 IC50 = 78–121 nM) activities were selected for further investigation and showed good physicochemical properties. Furthermore, based on comparable PK profile and excellent IDO2/TDO inhibitory potency, representative compound 16 was selected for further bio-evaluation and characterized with good efficacy in suppressing lung metastasis (77% inhibition rate) of Lewis cells in vivo. Thus, compound 16 could be a potential and efficacious agent for further evaluation.
- Du, Qianming,Feng, Xi,Wang, Yinuo,Xu, Xi,Zhang, Yan,Qu, Xinliang,Li, Zhiyu,Bian, Jinlei
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- New method for synthesizing substituted phosphinate
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The invention discloses a new method for synthesizing substituted phosphinate. The method comprises the step of generating the substituted phosphinate by reducing halogenated phosphonate under the effect of a reducing agent. The optimal preparation method for the substituted phosphinate is screened through a large number of experiments according to the invention; the whole process is reasonably designed; the technological operation is simple and efficient; especially, the optimal reaction conditions are screened, including reaction solvent, reaction temperature, reaction time and optimal reaction pH value; the reaction yield is obviously increased; the yield reaches up to 85-95%; the side reaction is less; the production cost is greatly lowered; the industrial production can be realized; and the method has a wide application prospect.
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Paragraph 0052; 0055-0056
(2017/12/27)
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- Chemical synthesis and molecular recognition of phosphatase-resistant analogues of phosphatidylinositol-3-phosphate
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The remodeling of phosphatidylinositol polyphosphates in cellular membranes by phosphatases and kinases orchestrates the signaling by these lipids in space and time. To provide chemical tools to study the changes in cell physiology mediated by these lipids, three new metabolically stabilized (ms) analogues of phosphatidylinositol-3-phosphate (Ptdlns(3)P) were synthesized. We describe herein the total asymmetric synthesis of 3-methylphosphonate, 3-(monofluoromethyl)phosphonate and 3-phosphorothioate analogues of Ptdlns(3)P. From differentially protected D-myo-inositol key intermediates, a versatile phosphoramidite reagent was employed in the synthesis of Ptdlns(3)P analogues with diacylglyceryl moieties containing dioleoyl, dipalmitoyl, and dibutyryl chains. In addition, we introduce a new phosphorylation reagent, (monofluoromethyl)phosphonyl chloride, which has general applications for the preparation of "pKa-matched" monofluorophosphonates. These ms-Ptdlns(3)P analogues exhibited reduced binding activities with 15N-labeled FYVE and PX domains, as significant 1H and 15N chemical shift changes in the FYVE domain were induced by titrating ms-Ptdlns(3)P analogues into membrane-mimetic dodecylphosphocholine micelles. In addition, the Ptdlns(3)P analogues with dioleoyl and dipalmitoyl chains were substrates for the 5-kinase enzyme PIKfyve; the corresponding phosphorylated ms-PI(3,5)P2 products were detected by radio-TLC analysis.
- Xu, Yong,Lee, Stephanie A.,Kutateladze, Tatiana G.,Sbrissa, Diego,Shisheva, Assia,Prestwich, Glenn D.
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p. 885 - 897
(2007/10/03)
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- A convenient two-step one-pot synthesis of phosphonamidates
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Phosphonamidates are formed in high yield from a one-pot sequential reaction of a phosphonyl dichloride with an alcohol and then an amine in the presence of catalytic 1H-tetrazole. Undesired disubstitution of the phoshphonyl dichloride by the alcohol or the amine is minimal due to the presence of tetrazole.
- Mlodnosky, Karyn L.,Holmes, H. Michael,Lam, Vinh Q.,Berkman, Clifford E.
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p. 8803 - 8806
(2007/10/03)
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- Convenient "one-pot" synthesis of chlorophosphonates, chlorophosphates and chlorophosphoramides from the corresponding benzyl esters
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Selective monodeprotection of alkyl phosphonate, phosphate and phosphoramide benzyl esters using quinuclidine and chlorination of the subsequent salts allows preparation of various alkyl phosphonochloridates, monochlorophosphates and monochlorophosphoramides in a convenient "one-pot" procedure.
- Saady, Mourad
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p. 4785 - 4786
(2007/10/02)
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- ORGANIC PHOSPHORUS COMPOUNDS 90. A CONVENIENT, ONE-STEP SYNTHESIS OF ALKYL- AND ARYLPHOSPHONYL DICHLORIDES
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N,N-Disubstituted formamides such as dimethylformamide, N-formylpyrrolidine, N-formylpiperidine etc. and also pyridine and hexamethylphosphonic acid triamide catalyze the chlorination of phosphonates with thionyl chloride to give phosphonyl dichlorides in high yield.Thus RP(O)Cl2, R=CH3, C2H5, n-C12H25, C6H5, have been isolated in better than 90 per cent yield.The procedure is less satisfactory for the production of 2-chloroethylphosphonyl dichloride.Only a 34 per cent yield was realized.The chlorination proceeds very likely through the intermediate formation of the halfesters, RP(O)(OR)Cl since these could be isolated under favorable circumstances.
- Maier, Ludwig
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p. 465 - 470
(2007/10/02)
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- ORGANOPHOSPHORUS CHEMISTRY. ESTER-CHLORIDE CONVERSION UNDER MILD CONDITIONS AT PHOSPHORUS
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The use of triphenylphosphine dichloride as a mild reagent for the replacement of a single ester linkage by a chloride in phosphonate diesters is described.The conversion has also been accomplished using a tertiary phosphine which is polymer-bound.
- Ylagan, Lourdes,Benjamin, Anat,Gupta, Amar,Engler, Robert
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p. 285 - 290
(2007/10/02)
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- A PRACTICAL SYNTHESIS OF (+/-)-PHOSPHINOTHRICINE
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A practical synthesis of (+/-)-phosphinothricine from trimethyl phosphite is described.
- Minowa, Nobuto,Fukatu, Shunzo,Niida, Taro,Takada, Masao,Sato, Kikumasa
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p. 2391 - 2392
(2007/10/02)
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- PHOTOLYSIS OF SOME UNSYMMETRICAL PHOSPHINIC AZIDES IN METHANOL. RELATIVE MIGRATORY APTITUDES OF ALKYL GROUPS AND PHENYL IN THE CURTIUS-LIKE REARRANGEMENT.
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When an alkylphenylphosphinic azide RPhP(O)N3 (R=Me, Et, Pri or But) is photolysed in MeOH either the alkyl or phenyl group can migrate from P to N in the Curtius-like rearrangement.The composition of the product shows that migration of the alkyl group R is preferred.However, the preference is not great and decreases as R changes But->Pri->Et->Me-> (approx. migratory aptitudes relative to Ph: 2.1, 1.7, 1.3, 1.2 respectively), probably because the Ph-P bond is better able to assume the correct conformation for Ph migration when R is less bulky.For t-butylmethylphosphinic azide there is very little preference for migration of But relative to Me.Small amounts of unrearranged products such as ButPhP(O)NHOMe and ButPhP(O)NH2 are generally produced in the photolyses, together with the methyl phosphinates RPhP(O)OMe (major product when R=Me) resulting from (non-photochemical) solvolysis of the azide.
- Harger, Martin J. P.,Westlake, Sally
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p. 3073 - 3078
(2007/10/02)
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- Preparation of 3-substituted cephalosporins
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There is described a process for preparing an enamine of formula (IX): STR1 where R2 is a carboxylic acid protecting group and R3 is the residue of a carboxylic acid derived acyl group and where R5 and R6 are the same or different C1-4 alkyl or C7-10 aralkyl groups; or taken together with the adjacent nitrogen atom form a heterocyclic ring containing from 4 to 8 carbon atoms and optionally a further heteroatom selected from oxygen and nitrogen; by reacting a compound of formula (XII): STR2 with an amine of formula HNR5 R6, the reactant of formula (XII) being prepared by reaction of an appropriate enol derivative with a phosphorus reagent. The enamines of formula (IX) are useful in the preparation of 3-hydroxycephalosporins.
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- Derivatives of cis-epoxy-1,2-propyl-phosphonic acid and drugs containing in particular as active ingredients derivatives of cis-epoxy-1,2-propylphosphonic acid in dextrorotatory form
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New asymmetrical derivatives of cis-epoxy-1,2-propylphosphonic acid, corresponding to the formula: STR1 in which: M(+) and M'(+), which are identical or different, are chosen from the hydrogen ion and the inorganic or organic cations, A is chosen from: The straight or branched alkyl and alkoxy radicals having 1 to 8 carbon atoms and being able to comprise at least one substitutent constituted by an epoxy bridge or chosen from the alkoxy radicals having 1 to 5 carbon atoms, alkoxycarbonyl whose alkyl radical comprises from 1 to 5 carbon atoms, amino, alkylamino, nitrile, The aryl, aralkyl, arylkoxy radicals which are substituted or not, Said products being useful particularly as drugs.
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- Condensation reactions giving rise to P-P bonded compounds
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The room-temperature condensation of CH3P(OCH3)2 with an equimolar amount of (C6H5)2PCl leads to the new compound (C6H5)2P-P(O)(CH3)OCH3, whereas the related reaction between CH3PCl2 and (C6H5)2POCH3 leads first to exchange of the chloro and methoxyl groups followed by slow self-condensation of the resulting CH3P(OCH3)Cl molecules. When CH3P(OCH3)2 is combined with an excess of (C6H5)2PCl, the product is found to react further with this excess reagent to give (C6H5)2P-P(C6H5) 2. Furthermore, the room-temperature reaction of CH3P(OCH3)2 with C6H5PCl2 leads to condensation products apparently based on the combination of the C6H5(CH3O)P- end group with CH3P(O)6H5P(O)3(CH3O)P(O)- group. The new compound (C6H5)2P-P(O)(OCH2) 2C(CH3)2 was obtained by reaction of (C6H5)2POCH3 with (CH3)2C(CH2O)2PCl, whereas, also at room temperature, only exchange of chloro for methoxyl group was observed in the reaction between o-C6H4O2PCl and (C6H5)2POCH3. At 140°, the reagents underwent exchange and condensation to give what appeared to be a P-O-P bridged structure, [C6H4O2P]2O.
- Abraham, Kuzhikalail M.,Van Wazer, John R.
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p. 1099 - 1103
(2007/10/05)
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