Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

Abstract

Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests.

Synthesis of 3‐O‐Carboxyalkyl Morphine Derivatives and Characterization of Their Acid‐Base Properties

“…We have recently investigated N ‐carboxymethyl opioid compounds, [19] where we showed that the basicity of the carboxylate site is smaller by several orders of magnitude than that of the amino site, thus K 2 values of the dibasic 3‐ O ‐carboxymethyl compounds characterize almost exclusively the protonation of the carboxylate sites, with K 2 practically equal to .…”

“…Non‐linear parameter fitting with Origin 8 provided the protonation constants from the volume differences [27] . The method of measurements was identical to our previous work [19] …”

“…For the analysis of NMR titration curves of proton chemical shifts versus pH, the software Origin Pro 8 (OriginLab Corp., Northampton, MA, USA) was used [26] . Titrations were carried out the same way as in our previous publication [19] …”

“…[17,18] Our research team has recently published the synthesis and characterization of acid-base properties of N-carboxyalkyl and N-acetylglycine morphine derivatives. [19] The purpose of the recent work was to extend our studies for the synthesis of 3-Ocarboxymethyl derivatives. These functionalized compounds contain basic tertiary nitrogen and free carboxylic groups, so we intended to determine their ionization constants, too.…”

“…Our research team has recently published the synthesis and characterization of acid‐base properties of N ‐carboxyalkyl and N ‐acetylglycine morphine derivatives [19] . The purpose of the recent work was to extend our studies for the synthesis of 3‐ O ‐carboxymethyl derivatives.…”