129967-45-9Relevant articles and documents
Stereocontrolled glycoside and glycosyl ester synthesis. Neighboring group participation and hydrogenolysis of 3-(2′-benzyloxyphenyl)-3,3- dimethylpropanoates
Crich, David,Cai, Feng
, p. 1613 - 1615 (2008/02/03)
Equation presented The 2-O[3-(2′-benzyloxyphenyl)-3,3- dimethylpropanoate] and 2-O-[3-(2′-benzyloxy-4′,6′- dimethylphenyl)-3,3-dimethylpropanoate] esters enable the synthesis of a range of β-glucosides and α-mannosides through neighboring participation in excellent yield, and are removed by hydrogenolysis in concert with the cleavage of benzyl esters in the presence of other esters making them particularly well suited to the stereocontrolled synthesis of glycosyl esters.
Application of the 'trimethyl lock' to Ganciclovir, a pro-prodrug with increased oral bioavailability
Dillon, Michael P.,Cai, Haiying,Maag, Hans
, p. 1653 - 1656 (2007/10/03)
The synthesis and oral bioavailability of two potential prodrugs of Ganciclovir (1) based on the 'trimethyl lock' is described. The mono-3-(2'-Acetoxy-4'6'-dimethylphenyl)-3,3-dimethylpropanoic ester (2) showed a four-fold increase in oral bioavailability over the parent drug in rats.
The Lactonization of 2'-Hydroxyhydrocinnamic Acid Amides: A Potential Prodrug for Amines
Amsberry, Kent L.,Borchardt, Ronald T.
, p. 5867 - 5877 (2007/10/02)
The lactoniaztion of two hydroxy amides - 4-methoxyaniline 3-(2'-hydroxyphenyl)-3,3-dimethylpropionic acid amide (2b) and 4-methoxyaniline 3-(2'-hydroxy-4',6'-dimethylphenyl)-3,3-dimethylpropionic acid amide (3b) - was studied over a pH range of 1-8.Due to the slowness of its reaction, a third hydroxy amide - 4-methoxyaniline 3-(2'-hydroxyphenyl)propionic acid amide (1b) - was investigated only at pH values of 7.5 and 10.The lactonization of 2b and 3b, which was found to be subject to general catalysis by buffer components, was observed to be catalyzed concurrently but not concertedly by both the acidic and basic forms of the buffer.The buffer-independent pH rate profiles for the lactonization of 2b and 3b were found to obey the equation k0 = kH++> + kH2O + kOH-->, indicating that the reaction is also subject to specific catalysis by hydronium and hydroxide ions.A Broenstedt analysis of the rate constants for buffer catalysis gave α and β values of 0.30 +/- 0.02 and 0.54 +/- 0.04, respectively, for 3b.The rate constants for the accelerated lactonization of 1b at 50, 70, and 90 deg C and pH 10 were used to calculate values of 14.7 +/- 0.8 kcal/mol and -9.5 +/- 2.3 eu for the activation parameters, ΔH(excit.) and ΔS(excit.), respectively.Comparison of the observed rates of lactonization at pH 7.5 and 30 deg C for the three hydroxy amides allowed an estimate of the extent of rate enhancement provided by addition of a partial or total "trimethyl lock" for the hydroxy amide lactonization reaction under near physiological conditions.The order of reactivity of the three hydroxy amides was found to be 3b >> 2b > 1b with rate enhancement factors of 2.5E4, 44, and 1, respectively.This study was begun with the objective of generating a hydroxy amide of very high reactivity at physiological pH for development into amine prodrug forms. 3b, which exhibited a half-life of 65 s at pH 7.5, has been chosen for further development as an amine prodrug.
