PhD Scientific Days 2025

Poster Session II. - G: Pharmaceutical Sciences and Health Technologies

Synthesis of aminoalkyl normorphine haptens and their hippuric acid derivatives

Name of the presenter

Simon Balázs

Institute/workplace of the presenter

Department of Pharmaceutical Chemistry, Semmelweis University

Authors

Balázs Simon¹, Sándor Hosztafi¹

1: Department of Pharmaceutical Chemistry, Semmelweis University

Text of the abstract

Introduction:
The abuse of opiod analgetics and their derivatives is a long-standing problem, leading to numerous deaths and loss of quality of life worldwide. Therapeutic options are limited against this problem, but a promising option could be vaccination against drugs of abuse. This requires the design of hapten-type molecules, which can be used to effect a response from the immune system against the othervise not immunogenic small molecules.
Aims:
We aimed to snythetise and characterize new normorphine derivatives, which in theory could be used as haptens, posessing a primary amine substituent. We then aimed to react these compounds with hippuric acid as a model reaction to present their ability to be used in peptide synthesis-like reactions.
Methods:
First we prepared the needed nor-opiate derivatives using 1-chloroethyl chloroformate, dichloroethane and methanol. Then we reacted the acquired nor-compounds with the appropriate trifluoroacetic acid protected bromoalkylamine in either N,N-dimethyl formamide or acetonitrile. After coloumn chromatography, the deprotection of the amines was performed using 10% aquous NaOH solution. The free amines were reacted with hippuric acid in the presence of HATU, and DIPEA. Characterisation of the new compounds were performed with NMR spectroscopy, LC-MS, and melting point analysis.
Results:
We synthetised 16 noropiate derivatives, and characterised them. For the codeine derivatives, protonation constants were also measured. With the synthesis of the hippuric acid derivatives, we confirm that the newly snythetised N-aminopropyl and N-aminoethyl noropiates can possibly be used as new haptens in reaction conditions typical of peptide synthesis. We trialed different alkylating reagents and synthetic equivalents, e.g. phthalimides as a protecting group, BOC as a protecting group, or cyano groups as synthetic equivalents, as reducing them with LiALH4 leads to the desired amine derivatives. The used synthetic pathway produced the desired amine derivatives in 35 to 65% yield over two steps, while the following amidation step usually reached 75-85% yield.
Conclusion:
we developed a synthetic pathway to new aminoalkyl normorphine derivatives, which can be useful intermediates towards amide derivatives, and can be used as haptens in possible vaccine applications.
Funding:
no outside funding was received.