Investigations into naloxone-based degradation products in Suboxone® sublingual film

In the field of drug development, knowing the chemical composition of a pharmaceutical product is important to develop a process that will avoid the formation of unwanted compounds. The isolation and the chemical synthesis of impurities provides useful information.
Naloxone is an opioid derivative present in Suboxone® sublingual film. It has been demonstrated that naloxone-related impurities are formed during the storage of this pharmaceutical product. However, these compounds are unknown and therefore, synthesising them is the key to confirm their structure.
In this instance, the semi-synthesis of these impurities was attempted. Analysis showed that the majority of the impurities are oxidation products: Alcohols, carboxylic acid or lactones, alpha-hydroxy ketones, and products of rearrangements. In total, 17 impurities were found and needed to be prepared.
Various compounds were targeted. The benzylic oxidation of naloxone was first attempted. This compound is known as a naloxone-related impurity in Suboxone® sublingual film. Chapter II relates of the synthesis of the desired impurity following a literature procedure, and our attempts to obtain the desired product using other methods.
The second chapter of this report relates of the oxidation of the cyclohexanone ring of naloxone, in order to prepare a di-carboxylic acid, alpha-hydroxy ketone and lactone. A synthetic route to the dicarboxylic acid was designed. The key oxidation step – the dihydroxylation of an alkene – required a deallylation followed by the Boc protection of the amine. The diol is also an intermediate to the synthesis of the alpha-hydroxy ketone. The preferred route towards this compound involved the mono-protection followed by the oxidation of the diol. However, some work still needs to be done to provide the desired compound.
Another targeted impurity was a lactone, formed by Baeyer-Villiger oxidation of the parent ketone. However, the main reaction that seemed to happen was the oxidation of the basic nitrogen to form the corresponding N-oxide.
Finally, Chapter IV contains the initial work towards the opening of the furan ring, in order to form two alpha-hydroxyketone products. To this end, the formation of an alkene followed by oxidation was the attempted strategy. The opening of the E ring using a stepwise Wolff-Kishner approach provided the desired alkene between positions 5 and 6.