The Half Decent Pharmaceutical Chemistry Blog

Tonight, we wait for a response from the coroner.

Good evening and welcome to this hypnotic episode of Saturday Night Synthesis. Following the death of Hollywood’s next iconic actor Heath Ledger for what seems to be an accidental overdose of prescription benzodiazepines mixed with opiates (so Mr. Ledger was another depressed and hopeless junky), a lot of attention turned to drugs such as diazepam (whose commercial name is very iconic and popular, too: Valium). I was kind of disappointed when I read both excellent Kyle’s posts on this tragic episode (because, no matter what’s your opinion on someone, death is always a tragedy. End of the story…) and realised I hadn’t felt the need to link to any of my posts. How can you blog about drugs and not quote any half-decent post?! How is this legally possible?

Well, it doesn’t really matter because that made me reflect on one thing: I’ve talked about benzos from different points of view but, strangely, never described the synthesis of one of them. Generally speaking, they all start with the same synthesis of a crucial bit: the phenyl-methanone.
Therefore, once you’ve seen the synthesis of one of them, you’ve seen everything. I mean, each benzodiazepine might have unquestionably cool steps in its synthesis, but the overall process is rather conserved. Diazepam, though, serves as the ideal molecule to describe some general features of these glamorous drugs. In fact, it’s the typical benzodiazepine: great in relieving anxiety state and reliable to promote the onset of sleep.
It’s the most lipid-soluble and, as a result, the quickest to reach the central nervous system. It undergoes the classic biotransformation pathway: metabolised by hepatic enzymes, it’s dealkylated and hydroxylated during the so-called phase I, and the resulting metabolite is turned into a glucuronide, easily excreted in the urine. On the other hand, phase I yields two metabolites which retain activity: Desmethyl-diazepam and Oxazepam.
Benzodiazepines are remarkably safer than barbiturates, but, although you won’t die, their (ab)use isn’t trouble-free at all. First, there is physical dependence, which often leads to abstinence syndrome, characterised by anxiety, insomnia, excitability and convulsions. Then, there is the usual list of adverse effects, which is far from being reassuring: impaired judgement, lethargy, loss of self-control and, eventually, coma. Theoretically, one could even choose benzos to commit suicide, but, in that case, my opinion about junkies and drug-abusers will just be confirmed: it’s stupid to select benzodiazepines (unless enhancing their central, sedative effect with alcohol, but that’s a different story), because this would require a jolly massive amount of tablets even the most depressed individual would be unable to swallow.
The (relative) safety of these molecules helps explain why they have quickly and entirely replaced barbiturates as sedative-hypnotic drugs of choice in clinical practice.

Let’s go back to the synthesis: is it any good? It is. It begins with the nicest Friedel-Crafts acylation I’ve ever seen on this weekly show: it involves two moles of each substrate (4-chlorobenzamine and benzoyl chloride) and yields unstable Schiff bases, easily hydrolysed by the addition of acid.

 

This is the common step in the synthesis of any benzodiazepine. The proper mechanism to obtain diazepam (to be performed while listening to The Who’s “My Generation”: “I hope I die before I get old”) begins with the activation of the primary amine with tosyl chloride and continues with the methylation of this function in the presence of sodium and, predictably, dimethyl sulphate.
To add the extra carbons required for the cycloheptane, an amide is formed by adding a reactive chloroacetyl chloride.
Hexamine is finally used to slowly release ammonia and yield our benzodiazepine.

Rest in peace…