3-Methylfentanyl
[CAS# 42045-86-3]

Identification

• Classification: Organic raw materials >> Heterocyclic compound >> Piperidines
• Name: 3-Methylfentanyl
• Synonyms: N-[3-methyl-1-(2-phenylethyl)piperidin-4-yl]-N-phenylpropanamide
• Molecular Formula: C₂₃H₃₀N₂O
• Molecular Weight: 350.50
• CAS Registry Number: 42045-86-3
• SMILES: CCC(=O)N(C1CCN(CC1C)CCC2=CC=CC=C2)C3=CC=CC=C3

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 472.8±38.0 ºC 760 mmHg (Calc.)^*
• Flash point: 184.5±19.1 ºC (Calc.)^*
• Index of refraction: 1.572 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Controlled Substance: DEA Drug Code Number: 9813

Discovory and Applicatios

3-Methylfentanyl is a synthetic opioid analgesic that belongs to the fentanyl family, a class of potent μ-opioid receptor agonists. It is structurally derived from fentanyl by the introduction of a methyl group at the 3-position of the piperidine ring, which significantly enhances its potency. Like fentanyl, 3-methylfentanyl acts primarily through binding to μ-opioid receptors in the central nervous system, leading to strong analgesic and sedative effects. However, the presence of the additional methyl group substantially increases its receptor affinity and intrinsic activity, making it several times more potent than fentanyl.

The compound was first synthesized in the 1970s as part of structure-activity relationship studies designed to explore how chemical modifications of fentanyl influence pharmacological properties. Researchers identified 3-methylfentanyl as a particularly potent derivative, with a range of stereoisomers that showed significant differences in analgesic activity. The cis-(+)-isomer is reported to be the most active form, with some studies indicating that its analgesic potency can exceed that of fentanyl by over an order of magnitude. This high potency has made 3-methylfentanyl a compound of interest in both pharmacological research and forensic toxicology.

Although never approved for clinical use, 3-methylfentanyl has occasionally appeared on the illicit drug market. Its extreme potency presents substantial risks, including a high potential for overdose and death, even at very low doses. Illicit synthesis and distribution of 3-methylfentanyl and related analogs became more prominent in the 1980s and 1990s, particularly in certain regions where it was associated with clusters of opioid-related fatalities. The substance has since been classified as a controlled substance in many countries due to its abuse potential and public health threat.

In laboratory settings, 3-methylfentanyl is synthesized through multi-step organic reactions involving the manipulation of the phenethylpiperidine core. Synthesis generally begins with an anilino-nitrile or related intermediate, which is then methylated at the 3-position of the piperidine ring. Subsequent steps include acylation with a propionyl chloride derivative to install the propionamide moiety critical for opioid activity. Enantioselective or diastereoselective methods may be employed to control the stereochemistry, as different isomers exhibit varying pharmacological profiles.

Analytical identification of 3-methylfentanyl in forensic or clinical toxicology samples requires high-sensitivity techniques due to its low effective concentration. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) are commonly employed. Standard reference materials are crucial for accurate detection and quantification. Distinguishing between isomers of 3-methylfentanyl is particularly important for understanding potency and for identifying specific analogs in forensic investigations.

The compound's extreme potency and small therapeutic window necessitate stringent regulation. Exposure, whether accidental or intentional, can lead to profound respiratory depression, unconsciousness, and death. Consequently, 3-methylfentanyl has been placed under Schedule I or equivalent classifications in many jurisdictions, indicating no accepted medical use and a high potential for abuse.

In summary, 3-methylfentanyl is a potent synthetic opioid with a history rooted in analgesic research but is best known today for its implications in illicit drug use and overdose fatalities. Its development highlighted the importance of molecular modifications on opioid receptor interactions and served as a critical example of the challenges posed by designer opioids.

References

1981. The Bogus Drug: Three Methyl & Alpha Methyl Fentanyl Sold as �China White�. Journal of Psychoactive Drugs, 13(1).
DOI: 10.1080/02791072.1981.10471455

1991. (+)-Cis-3-methylfentanyl and its analogs bind pseudoirreversibly to the mu opioid binding site: Evidence for pseudoallosteric modulation. Neuropharmacology, 30(5).
DOI: 10.1016/0028-3908(91)90006-w

2017. An LC�MS-MS Method for the Analysis of Carfentanil, 3-Methylfentanyl, 2-Furanyl Fentanyl, Acetyl Fentanyl, Fentanyl and Norfentanyl in Postmortem and Impaired-Driving Cases. Journal of Analytical Toxicology, 41(6).
DOI: 10.1093/jat/bkx052