Drug Chemistry
What type of drug is fentanyl? Define that drug
opioid
drug that ats in your body by primarily binding to opioid receptors in your body and thus preventing pain
What is the name for the 'one-pot' fentanyl synthesis process?
Gupta
What type of chemical reaction is the formation of 4-NPP from NPP?
What is getting reduced?
the ketone on the NPP is reduced to an amine
What is the lab hazard of sodium borohydride (NaBH4)?
violently water-reactive
When was fentanyl first prepared? Why was it prepared?
Early 60s, as a replacement for the opioidmeperidine (Demerol)
What are the most common forms of fentanyl encountered?
citrate, oxalate, hydrochloride
What type of organic reaction mechanism is the formation of NPP from 4-piperidone and phenethyl bromide? What is the nucleophile and what is the electrophile?
SN2 --> backside attack
nucleophile comes in and leaving groups leaves in a single step
nucleophile: N atom on the 4-piperidone
electrophile: alpha-carbon on the bromine
How does the Siegfried method differ from the Gupta method?
Siegfried: 4-piperidone+phenethylbromide --> NPP + aniline -> reductive amination --> 4-ANPP
Gupta: does not go through NPP; 4-piperidone + aniline --> 4-AP --> phenethyl bromide (tacks on the phenyl group at the end rather than the other way around)
What is the lab hazard of propionyl chloride?
violently water-reactive
How long on average does it take to make a batch of fentanyl via. the Siegfried method?
How long does the NPP synthesis take?
How long does the condensation step of 4-ANPP synthesis take?
55 hours
-NPP reflux goes for 12-15 hours
-the condensation step (first step) of 4-ANPP reaction goes at RT for 24 hours
What is salting out? How does it work? Where in the fentanyl process is it typically used?
by adding a saturated salt (brine) solution after the acid-base extraction, the more salt in the aqueous layer the more it forces the salt out of the aqueous layer and into the solid precipitate form, thus increasing the yield
-this is used after the acid-base extraction from 4-ANPP to 4-ANPP hydrochloride, to force the salt to precipitate out
What are the main precursors for NPP synthesis?
4-piperidone
phenethyl bromide
accessory: acetonitrile, potassium carbonate, PEG
What is the purpose of the molecular sieves added in the synthesis of NPP --> 4-ANPP?
Since the first step to form the imine intermediate is a condensation reaction and forms water as a byproduct, the addition of the molecular sieves shifts equilibrium towards the desired products, significantly improving the yield and purity of the 4-ANPP
What are the main colorimetric detection reagents used in fentanyl detection?
There aren't any common colorimetric agents used. Instead, test strips are used, which are rapid lateral flow chromatographic immunoassays
About how many neurons are in the human brain?
Around 86 billion
Does fentanyl have high or low lipophilicity? What does that mean for a drug in relation to the BBB and how quickly it can exert its effects?
High (due to the benzene and alkyl groups)
A hydrophilic drug easily dissolves in blood but struggles to cross membranes (like the lipid bilayer responsible for passing things into the brain), whereas a lipophilic drug can easily cross these barriers into the brain, organs, and tissues, but doesn't dissolve well in the blood
Having a high lipophilicity means that once they enter the bloodstream, they typically have a rapid onset of action --> potent
What is the purpose of the PEG in NPP synthesis?
phase-transfer catalyst, facilitates the mixing of the aqueous and organic layers; oxygen on ether in PEG complexes with the cations of the K2CO3 and prevents it from ion-pairing with the deprotonated N in 4-piperidone
What is the purpose of the pyridine added in the final step reaction of fentanyl synthesis 4-ANPP --> fentanyl?
Why is pyridine a good choice?
to act as a base, to neutralize the HCl formed as a byproduct in the reaction, shifts
-soluble in DCM, other organic solvents
-strong enough to neutralize HCl but weaker than 4-ANPP so it doesn't compete with 4-ANPP for the propionyl chloride, doesn't deprotonate the protonated 4-ANPP prematurely
How does the fentanyl test strip immunoassay work?
They rely on antibody–antigen binding: antibodies specific to fentanyl (and some analogs) recognize and bind to it if present in the sample. Fentanyl test strips are competitive immunoassays, meaning that fentanyl in the sample competes with fentanyl immobilized on the test line for antibody binding.
If fentanyl is present, you only see one line, because the antibodies (which are tagged with colored particles) 'stick' to the fentanyl and so when it moves up the line, the binding sites of the antibodies are already taken up with fentanyl so they can't bind with the fentanyl-protein conjugates on the test line, so you only see one colored line at the start.
If fentanyl is not present, nothing is holding the fentanyl back from moving up the strip and binding with the test line (the antibodies find the 'fentanyl' on the test line and bind with it, bringing its colored particles with it) so you see two lines. The line is visible because you have MANY gold nanoparticles allllll lined up, scattering light and creating a visible line
What is the physical appearance of NPP hydrochloride and NPP freebase?
both are pale to dark yellow solids
In the context of drug chemistry, describe why a drug's pKa is important
In drug chemistry, the pKa of a compound is crucial because it determines how much of the drug exists in its ionized (charged) versus unionized (neutral) form at physiological pH, which directly affects its absorption, distribution, and ability to cross biological membranes. Only the unionized form of a drug can easily pass through the lipid-rich cell membranes and the blood–brain barrier, while the ionized form stays in aqueous environments like blood plasma. Knowing a drug’s pKa allows chemists and pharmacologists to predict how it will behave in different parts of the body, how well it will be absorbed orally, how it will partition between tissues and blood, and how changes in pH (for example, in the stomach, urine, or brain) will influence its bioavailability and pharmacological effect.
What is the purpose of the K2CO3 or CsCO3 we use in the NPP synthesis step? There are 2 main reasons
1. 'Activate' N on the 4-piperidone so that it is more nucleophilic and more susceptible to nucleophilic attack
2. Neutralize HBr side product so that we don't re-protonate the N after we have deprotonated it so that we essentially quench its reactivity
how does narcan/naloxone work to treat fentanyl overdose? can you pre-treat with narcan?
Narcan (naloxone) works by competitively binding to μ-opioid receptors in the brain — the same receptors that fentanyl and other opioids activate to cause pain relief and, in overdose, dangerous respiratory depression. Naloxone has a very high receptor affinity but does not activate the receptor (it’s a pure antagonist), so when it’s given, it rapidly displaces fentanyl molecules that are occupying those receptor sites. This reverses opioid effects like slowed breathing and sedation, allowing normal respiration to resume. Because fentanyl binds tightly and lasts longer in the body, naloxone may need to be repeated or given as a continuous infusion to outcompete it until the fentanyl is cleared. In short, Narcan rescues breathing by kicking fentanyl off the receptors and blocking them from being reactivated.
What is the fentanyl test strip limit of detection?
200 ng/mL
What specific receptors does fentanyl target? What is the mechanism of action?
mu-opioid receptors in the CNS
-potent agonist of MORs. Binding by fentanyl results in inhibition of the enzyme responsible for making cAMP, which results in opening K channels and closing Ca channels. This causes hyperpolarization of the neuron, which causes a reduction in neurotransmitters involved in transmitting pain signals