120702-26-3Relevant academic research and scientific papers
PYRAZOLE DERIVATIVES AS ANTI-PLATELET AND ANTI-THROMBOTIC AGENTS
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Page/Page column 56, (2010/11/30)
This invention relates to novel compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof wherein Y, R1 through R9, and X1 through X7 are as defined in the specification, pharmaceutical compositions containing said compounds useful as P2Y1 antagonists, and to methods of treating thromboembolic disorders.
The Mechanism of RuO4-Mediated Oxidations of Ethers: Isotope Effects, Solvent Effects and Substituent Effects
Bakke, Jan M.,Froehaug, Astrid E.
, p. 615 - 622 (2007/10/02)
The mechanism of the RuO4-mediated oxidation of ethers to esters has been investigated.Oxidation of cyclopropylmethyl methyl ether gave methyl cyclopropanecarboxylate.No rearranged products were observed.On RuO4 oxidation of benzyl methyl ether and p-methoxybenzyl methyl ether in CCl4 with NaIO4 as stoichiometric oxidant, no chlorinated products were observed.A series of 4-substituted benzyl methyl ethers was oxidized with RuO4-NaIO4.A correlation of the rate of the reaction with Hammett ?-values gave a ρ of -1.7, indicating only a moderate charge separation in the transition state (TS).Benzyl methyl ether (1) was oxidized in a series of acetone-water mixtures.From these experiments, a Grunwald-Winstein m-value of 0.11 was obtained, indicating a non-polar TS for the reaction.PhCHDOCH3 (2) and PhCD2OCH3 (3) were oxidized and two deuterium isotipe effects, one of 6.1+/-0.4 and another of 1.3+/-0.1 were obtained.If one assumes a one-step reaction mechanism, the value of 1.3 would be a large α-secondary isotope effect, indicating a change in the hybridization of the benzylic carbon during the reaction. α-Methylbenzyl methyl ether (4) was oxidized at a seventh of the rate of 1, despite the fact that 4 would have given a more stable carbocation than 1.These conflicting pieces of evidence are difficult to rationalise with a hydride or hydrogen abstraction mechanism.Instead it is proposed that the reaction proceeds by either a concerted reaction or by a reversible oxidative addition of the ether to RuO4 followed by a slow concerted step to give the product.
Reactions of Substituted 1-Phenylethyl Carbocations with Alcohols and Other Nucleophilic Reagents
Richard, John P.,Jencks, William P.
, p. 1373 - 1383 (2007/10/02)
Selectivities of a series of substituted 1-phenylethyl carbocations toward alcohols and other nucleophiles have been determined by product analysis.The 1-(4-dimethylamino)phenyl)ethyl carbocation exhibits a high selectivity in its reactions with alcohols , with KEtOH/KTFE = 140 and βnuc = 0.5.The selectivity for activation-limited reactions with alcohols decreases progressively with increasing reactivity of the carbocation, in contrast to the behavior expected from the N+ scale of reactivity.A sharper drop in selectivity for carbocations that react faster than ca. 109 S-1 is attributed to an approach to limiting rate constants for the more reactive alcohol.The limiting selectivity of kEtOH/kTFE = 2 for carbocations with ks ca. 1011 S-1 may represent reaction from a pool of solvent molecules in which there is a modest charge-dipole interaction between the alcohol and carbocation.The relatively low reactivity of water corresponds to that expected for an alcohol of pKa ca. 13.This is ascribed to an imbalance between charge development and solvation of the transition state compared with H3O+.Substituted acetate anions react with the 1-(4-methoxyphenyl)ethyl carbocation with βnuc = 0.13.The selectivity decreases with increasing cation reactivity as the carboxylate ions approach limiting rate constants of ca. 5 * 108 M-1 s-1.This relatively low limit is attributed to a requirement for desolvation of basic oxygen anions before reaction.A dependence of solvent selectivity on the leaving group shows that the 1-(4-methylphenyl)ethyl carbocation reacts with solvent, in part, through an ion pair.Azide ion reacts from a pool that can be described by an equilibrium constant of Kas = 0.3 M-1.Styrene formation from this carbocation is catalyzed by a leaving carboxylate ion and by added buffers, wih β = 0.14.The equilibrium constant for the formation of a reactive base-cation pair is ca. 0.04 M-1.Rate constants for collapse of the ion pair, to form ester, and for proton removal, to form 4-methylstyrene, were estimated to be approximately 1.6 * 1010 s-1 and 6 * 107 s-1, respectively.The rate constants for deprotonation and for hydration of the styrene give the acid dissociation constant of the carbocation to form 4-methylstyrene, pKA = -11.2.
Concerted Bimolecular Substitution Reactions of 1-Phenylethyl Derivatives
Richard, John P.,Jencks, William P.
, p. 1383 - 1396 (2007/10/02)
Substituted 1-phenylethyl derivatives with ?+ > -0.08 exhibit bimolecular substitution reactions with azide ion in 20percent acetonitrile in water.The reactions with 1-phenylethyl chlorides follow a Hammett correlation with ρ = -2.9, compared with ρ = -5.6 (r+ = 1.15) for solvolysis.Swain-Scott correlations give values of s = 0.46 and 0.22 for 1-(4-nitrophenyl)ethyl chloride and tosylate, respectively; there are large positive deviations for azide ion and water and negative deviations for cyanide ion.The value of βnuc is 0.09 for reactions of substituted acetates with the chloride.The reactions exhibit ''synergism'' between the nucleophile and leaving group that favors the bimolecular reaction with Me2S, Br- > Cl- > OTs- leaving groups.The bimolecular reaction with azide follows the Grunwald-Winstein Y correlation with m = 0.8 in methanol-water mixtures.Bimolecular reactions with less reactive nucleophiles in the series N3-, CN-, AcO-, and ROH appear at progressively larger ? values, as the carbocation becomes less stable.It is concluded that these reactions are SN2 displacements that proceed through an open, ''exploded'' transition state that closely resembles a carbocation.Specific salt effects are small in water but are significant in acetonitrile-water mixtures and could be mistaken for normal or induced common ion rate depressions.No evidence was obtained for nucleophilic assistance to the formation of a carbocation intermediate.Concurrent SN1 and SN2 pathways occur in the reactions with solvent and azide of dimethylsulfonium ion, 1-(4-fluorophenyl)ethyl chloride, 1-(3-methoxyphenyl)ethyl chloride, and, probably, 1-(3-nitro-4-methoxyphenyl)ethyl chloride.Crude estimates of the lifetime of the carbocation intermediate in the presence of the nucleophile are consistent with the hypothesis that the concerted reactions are enforced by the absence of a significant lifetime of the carbocation in the presence of the nucleophile and that stepwise mechanisms are followed when the intermediate has a significant lifetime; the change from a stepwise to a concerted mechanism occurs when the intermediate ceases to have a lifetime in the presence of a nucleophile.
