Norfentanyl
[CAS# 1609-66-1]

Identification

• Classification: Analytical chemistry >> Analytical reagent >> Ion chromatography reagent
• Name: Norfentanyl
• Synonyms: N-Phenyl-N-4-piperidinylpropionamide; N-Piperidin-4-yl-N-phenylpropionamide; NSC 89293
• Molecular Formula: C₁₄H₂₀N₂O
• Molecular Weight: 232.32
• CAS Registry Number: 1609-66-1
• EC Number: 216-543-3
• SMILES: CCC(=O)N(C1CCNCC1)C2=CC=CC=C2

Properties

• Solubility: Slightly soluble (7.4 g/L) (25 °C), Calc.^*
• Density: 1.075±0.06 g/cm³ (20 °C 760 Torr), Calc.^*
• Melting point: 92 °C^**
• Boiling point: 359.8±35.0 °C 760 mmHg (Calc.)^*
• Flash point: 171.4±25.9 °C (Calc.)^*
• Index of refraction: 1.558 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2014 ACD/Labs)

^** NL 6506574 1965.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Skin corrosion	Skin Corr.	1B	H314
Serious eye damage	Eye Dam.	1	H318
Specific target organ toxicity - single exposure	STOT SE	3	H335
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Skin sensitization	Skin Sens.	1B	H317

Discovery and Applications

Norfentanyl is a key metabolite of fentanyl, a potent synthetic opioid analgesic widely used in clinical anesthesia and pain management. Chemically, norfentanyl is the N-dealkylated form of fentanyl, produced primarily in the liver through enzymatic metabolism mediated by cytochrome P450 enzymes, particularly CYP3A4. The structural change involves the removal of the N-phenethyl group from the piperidine nitrogen, yielding a secondary amine while preserving the central piperidine ring and the anilide moiety.

The formation of norfentanyl represents a major biotransformation pathway during fentanyl metabolism. Following administration of fentanyl, norfentanyl is detected in plasma and urine as an inactive or minimally active metabolite, lacking significant affinity for the μ-opioid receptor. Its presence serves primarily as a biomarker of fentanyl exposure rather than a contributor to the drug’s analgesic or toxic effects.

Norfentanyl is not pharmacologically active in therapeutic or toxicological contexts, but its role is crucial in forensic and clinical toxicology. It is often used as an indicator of recent fentanyl use in biological specimens, especially in urine drug testing. Detection of norfentanyl, particularly in the absence of fentanyl itself, may indicate prior drug administration due to the parent compound's relatively short half-life and the metabolite's longer persistence in the body.

The analytical detection of norfentanyl is commonly performed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which provides high sensitivity and specificity. Immunoassay-based methods have also been developed for initial screening. These tests are essential tools in workplace drug monitoring, post-mortem toxicological evaluations, and compliance testing in opioid dependency treatment programs.

Because of its structural similarity to fentanyl and other analogs, norfentanyl also plays a role in the synthesis of modified fentanyl derivatives. While it lacks intrinsic pharmacological effects, its amine functionality can serve as a synthetic handle for chemical transformations. However, the conversion of norfentanyl into active opioid analogs is not typically favored in illicit synthesis due to its reduced potency and the complexity of reintroducing high-affinity side chains.

In legal and regulatory frameworks, norfentanyl is generally not a controlled substance by itself due to its lack of activity, but its presence is considered significant in forensic investigations and drug enforcement. It is routinely monitored in samples associated with opioid overdoses, suspected drug abuse, or clinical pharmacokinetic studies.

Norfentanyl has also been used in pharmacokinetic modeling and simulation studies to understand fentanyl metabolism, disposition, and elimination. Its concentration-time profiles can help determine dosing regimens, predict metabolic clearance, and assess individual variability in drug metabolism among different populations, including those with hepatic impairment or genetic polymorphisms affecting CYP3A4 activity.

As the opioid crisis has expanded, monitoring of fentanyl and its metabolites, including norfentanyl, has become a vital component of public health surveillance. Comprehensive toxicological panels that include norfentanyl assist in tracking patterns of fentanyl abuse, identifying cases of accidental or intentional exposure, and informing strategies for prevention and treatment of opioid-related harm.

References

1996. Identification of Human Liver Cytochrome P-450 3A4 as the Enzyme Responsible for Fentanyl and Sufentanil N-Dealkylation. Anesthesia and Analgesia, 82(1).
DOI: 10.1097/00000539-199601000-00031

2020. Determination of Morphine, Fentanyl and Their Metabolites in Small Sample Volumes Using Liquid Chromatography Tandem Mass Spectrometry. Journal of Analytical Toxicology, 44(2).
DOI: 10.1093/jat/bkz104

2024. Performance of a Norfentanyl Immunoassay in Specimens with Low Concentrations of Fentanyl and/or Norfentanyl. The Journal of Applied Laboratory Medicine, 9(5).
DOI: 10.1093/jalm/jfae036