437-38-7

Usage

Uses

Used in Pain Management:
Fentanyl is used as an analgesic for the management of acute and chronic pain. It is particularly effective in cases where other opioids are not sufficient or when rapid pain relief is required.
Used in Anesthesia:
Fentanyl is used as an adjunct in anesthesia to provide analgesia and sedation during surgical procedures. Its rapid onset and short duration of action make it an ideal choice for this application.
Used in Palliative Care:
Fentanyl is used in palliative care to manage severe pain in patients with terminal illnesses, such as cancer. It can be administered through transdermal patches, providing a slow and steady release of the drug over an extended period.
Used in Breakthrough Pain:
Fentanyl is used as a treatment for breakthrough pain, which is a sudden increase in pain that occurs despite ongoing pain management. New buccal/transmucosal preparations have been developed for rapid-onset breakthrough pain, aiming to provide relief within approximately 10 minutes.
Used in Drug Delivery Systems:
Fentanyl's lipophilic nature and large volume of distribution make it an ideal candidate for drug delivery systems. Various formulations, such as transdermal patches and buccal tablets, have been developed to improve its bioavailability and therapeutic outcomes.

Originator

Fentanyl,Janssen,W. Germany,1963

Manufacturing Process

To the stirred solution of 5 parts of N-(4-piperidyl)propionanilide, 6.85 parts sodium carbonate, 0.05 part potassium iodide in 120 parts hexone is added portionwise a solution of 3.8 parts β-phenylethyl chloride in 24 parts 4- methyl-2-pentanone. The mixture is stirred and refluxed for 27 hours. The reaction mixture is filtered while hot, and the filtrate is evaporated. The oily residue is dissolved in 160 parts diisopropyl ether and the solution is filtered several times until clear, then concentrated to a volume of about 70 parts. The residue is then cooled for about 2 hours at temperatures near 0°C to yield N- [1-(β-phenylethyl)-4-piperidyl]propionanilide, melting at about 83° to 84°C as described in US Patent 3,141,823.The starting material is prepared by reacting 1-benzyl-4-piperidone with aniline, reducing the condensation product with lithium aluminum hydride, reacting the product thus obtained with propionic anhydride, then hydrogen.

Therapeutic Function

Narcotic analgesic

Hazard

Toxic.

Clinical Use

Fentanyl (Sublimaze) and its related phenylpiperidine derivatives are extremely potent drugs.They are used as adjuncts to anesthesia, and fentanyl may be given transdermally as an analgesic and as an oral lozenge for the induction of anesthesia, especially in children who may become anxious if given IV anesthesia. Fentanyl is 80 to 100 times as potent as morphine. Sufentanil (Sufenta) is 500- to 1,000-fold more potent than morphine, while alfentanil (Alfenta) is approximately 20 times more potent than morphine. Their onset of action is usually less than 20 minutes after administration. Dosage is determined by the lean body mass of the patient, since the drugs are lipophilic and tend to get trapped in body fat, which acts as a reservoir, prolonging their half-life. In addition, redistribution of the drugs from the brain to fat stores leads to a rapid offset of action. Droperidol, a neuroleptic agent, is generally administered in combination with fentanyl for IV anesthesia. Fentanyl transdermal patches are available for analgesia in chronic pain and for postsurgical patients. The use of the patch is contraindicated, however, for patients immediately after surgery because of the profound respiratory depression associated with its use. The patches must be removed and replaced every 3 days. The onset of action of transdermal fentanyl is slower than that of oral morphine. Thus, patients may require the use of oral analgesics until therapeutic levels of fentanyl are achieved. Fentanyl lozenges have been used to induce anesthesia in children and to reduce pain associated with diagnostic tests or cancer in adult patients. However, all of the adverse side effects associated with morphine are produced with far greater intensity, but shorter duration, by fentanyl in the patch, the lozenge, or IV administration. Given the abuse liability of fentanyl, controversy exists as to the ethics of marketing a lollipop lozenge form. Sufentanil is much more potent than fentanyl and is indicated specifically for long neurosurgical procedures. In such patients, sufentanil maintains anesthesia over a long period when myocardial and cerebral oxygen balance are critical.

Side effects

In addition to all of the adverse effects and contraindications previously described for morphine, the following contraindications apply specifically to these drugs. They are contraindicated in pregnant women because of their potential teratogenic effects. They also can cause respiratory depression in the mother, which reduces oxygenation of fetal blood, and in the newborn; the incidence of sudden infant death syndrome (SIDS) in the newborn is also increased. Cardiac patients need to be monitored closely when receiving these drugs because of their bradycardiac effects (which can lead to ectopic arrhythmias), and hypotensive effects resulting from prolonged vasodilation. In addition, the drugs stiffen the chest wall musculature, an effect reversed by naloxone.

Safety Profile

Poison by intraperitoneal routes. Human systemic effects by intravenous route: somnolence, respiratory depression. When heated to decomposition it emits toxic fumes of NOx.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: metabolism increased by rifampicin. Antidepressants: possible CNS excitation or depression (hypertension or hypotension) in patients also receiving MAOIs (including moclobemide) - avoid concomitant use; possibly increased sedative effects with tricyclics. Antifungals: concentration increased by triazoles. Antihistamines: increased sedative effects with sedating antihistamines. Antipsychotics: enhanced hypotensive and sedative effects. Antivirals: concentration increased by ritonavir; increased risk of ventricular arrhythmias with saquinavir - avoid. Cytotoxics: use crizotinib with caution. Dopaminergics: avoid with selegiline. Sodium oxybate: enhanced effect of sodium oxybate - avoid concomitant use

Metabolism

Fentanyl is metabolised in the liver by N-dealkylation and hydroxylation via the cytochrome P450 isoenzyme CYP3A4. Metabolites and some unchanged drug are excreted mainly in the urine. The short duration of action is probably due to rapid redistribution into the tissues rather than metabolism and excretion. The relatively longer elimination half-life reflects slower release from tissue depots.The main metabolites of fentanyl, which are excreted in the urine, have been identified as 4-N-(N-propionylanilino) piperidine and 4-N-(Nhydroxypropionylanilino) piperidine; 1-(2-phenethyl)- 4-N-(N-hydroxypropionylanilino) piperidine is a minor metabolite. Fentanyl has no active or toxic metabolites.

Upstream product

• 39742-60-4 1-(2-phenylethyl)-4-piperidinone 
• 41979-39-9 4-piperidone hydrochloride 
• 60-12-8 2-phenylethanol 
• 1609-66-1 Norfentanyl 
• 57958-48-2 N-(1-phenethylpiperidin-4-ylidene)aniline 
• 79-03-8 propionyl chloride 
• 24775-76-6 4-anilino-N-(phenethyl)-4-piperidine bis hydrochloride 
• 74-85-1 ethene 
• 201230-82-2 carbon monoxide 
• 21409-26-7 (1-Phenethyl-piperidin-4-yl)-phenyl-amine 
• 622-24-2 2-phenylethyl chloride 
• 62-53-3 aniline 
• 122-78-1 phenylacetaldehyde 
• 1474-02-8 N-(1-benzyl-4-piperidinyl)-N-phenylpropionamide 

Downstream Products

• 1195983-47-1 Fentanyl methiodide 
• 1863-07-6 fentanyl citrate 
• 1443-54-5 fentanyl hydrochloride 
• 1254229-85-0 N-([2-⁽²⁾H]-1-(2-phenylethyl)-4-piperidinyl)aniline 
• 1254229-86-1 C₂₂H₂₇⁽²⁾HN₂O 
• 85893-37-4 fentanyl N-oxide 
• 122861-38-5 N-<1-(2-phenylethyl)-4-piperidyl>-N-phenylthiopropanamide 

Relevant academic research and scientific papers

A structural study of fentanyl by DFT calculations, NMR and IR spectroscopy

N-(1-(2-phenethyl)-4-piperidinyl-N-phenyl-propanamide (fentanyl) is synthesized and characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The geometry optimization is performed using the B3LYP and M06 density functionals with 6-311?+?G(d) and 6-311++G(d,p) basis sets. The complete assignments are performed on the basis of the potential energy distribution (PED) of the all vibrational modes. Almost a nice correlation is found between the calculated 13C chemical shifts and experimental data. The frontier molecular orbitals and molecular electrostatic potential of fentanyl are also obtained.

Evaluation of agonistic activity of fluorinated and nonfluorinated fentanyl analogs on μ-opioid receptor using a cell-based assay system

The agonistic activity of fluorinated and nonfluorinated fentanyl analogs on μ-opioid receptor was investigated using a cell-based assay system. Based on the activity, fentanyl analogs were ranked as follows: fentanyl>isobutyrylfentanyl≈butyrylfentanyl≈methoxyacetylfentanyl>acetylfentanyl. However, among the fentanyl analogs fluorinated on the Nphenyl ring, 2-fluoro analogs and 3-fluoro analogs showed the strongest and weakest activities, respectively. These results suggest that the 2-fluorinated isomers of fentanyl analogs are more likely to cause poisoning.

Metabolism of fentanyl and acetylfentanyl in human-induced pluripotent stem cell-derived hepatocytes

To evaluate the capability of human-induced pluripotent stem cell-derived hepatocytes (h-iPS-HEP) in drug metabolism, the profiles of the metabolites of fentanyl, a powerful synthetic opioid, and acetylfentanyl, an N-acetyl analog of fentanyl, in the cells were determined and analyzed. Commercially available h-iPSHEP were incubated with fentanyl or acetylfentanyl for 24 or 48 h. After enzymatic hydrolysis, the medium was deproteinized with acetonitrile, then analyzed by LC/MS. Desphenethylated metabolites and some hydroxylated metabolites, including 4′-hydroxy-fentanyl and β-hydroxy-fentanyl, were detected as metabolites of fentanyl and acetylfentanyl in the medium. The main metabolite of fentanyl with h-iPS-HEP was the desphenethylated metabolite, which was in agreement with in vivo results. These results suggest that h-iPSHEP may be useful as a tool for investigating drug metabolism.

Palladium-catalyzed hydroaminocarbonylation of alkenes with amines promoted by weak acid

The weak acid has been identified as an efficient basicity-mask to overcome the basicity barrier imparted by aliphatic amines in the Pd-catalyzed hydroaminocarbonylation, which enables both aromatic and aliphatic amines to be applicable in the palladium-catalyzed hydroaminocarbonylation reaction. Notably, by using this protocol, the marketed herbicide of Propanil and drug of Fentanyl could be easily obtained in a one-pot manner.

An efficient, optimized synthesis of fentanyl and related analogs

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73-78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.

Methods For Preparing Fentanyl And Fentanyl Intermediates

A method and an intermediate are provided for preparing fentanyl. Aniline and 1-phenylethyl-4-piperidone are reacted with a borane complex, in a lower C1-C4 alcoholic solvent, in the presence of an alkanoic acid. The reaction mixture is then treated with a hydrohalic acid to precipitate 4-anilino-N-phenethyl-4-piperidine (ANPP) as the bis-hydrohalide salt in high yield and purity. This ANPP salt may be directly treated with propionyl halide to produce fentanyl, or the ANPP salt may be converted to the free base of ANPP and similarly treated with propionyl halide to produce fentanyl.

Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl) propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a popular narcotic analgesic agent that is clinically used worldwide. However, fentanyl and its several analogs have caused abuse and fatalities in humans due to overdosing and narrow therapeutic index. The present study reports the synthesis and comparative bioefficacy of fentanyl and its four analogs, viz., N-(1-propyl-4-piperidinyl)propionanilide (1), N-(1-(2-phenoxyethyl)-4- piperidinyl)propionanilide (2), N-(1-(3-phenoxypropyl)-4-piperidinyl) propionanilide (3) and N-(1-(2-cyanoethyl)-4-piperidinyl)propionanilide (4), where the phenethyl chain of fentanyl was replaced by different functional groups, viz., alkyl, ethereal, and nitrile moieties. The median lethal dose (LD50) of the compounds was determined by three different routes and all the analogs were found to be safer than fentanyl. Observational assessment on spontaneous activities of the central nervous system, peripheral nervous system, and autonomic nervous system revealed that all the analogs were similar to fentanyl. Further, the neurotoxic effects of all the analogs were reversed by naloxone hydrochloride (opioid antagonist), confirming that their effects were mediated through opioid receptors. Antinociceptive activity was displayed by all the compounds and their median effective dose (ED50) and analgesic potency ratio were more or less similar to fentanyl. The lowest ED50 (23.7) and the highest potency ratio (1.18) was observed in the case of 2. However, the maximum therapeutic index was afforded by 4. The study indicates the promising role of some new opioid analgesics.

Synthesis of amides from imines using Et3SiH/Zn system

A simple and efficient approach for the synthesis of amides by the reaction of imines and acyl chlorides in the presence of Et3SiH/Zn system in THF at ambient temperature is reported. Mild reaction conditions, good yields of products, short reaction time and operational simplicity are the advantages of this procedure. Copyright

A new method for the synthesis of amides from imines

An efficient and straightforward method for the synthesis of amides by the reaction of imines and anhydrides in the presence of Et3SiH/Zn is reported. Mild reaction conditions, good yields of products, short reaction times, and operational simplicity are advantages of this procedure.