4-Methoxymethylfentanyl
[CAS# 60618-49-7]

Identification

• Classification: Organic raw materials >> Heterocyclic compound >> Piperidines
• Name: 4-Methoxymethylfentanyl
• Synonyms: N-[4-(methoxymethyl)-1-(2-phenylethyl)piperidin-4-yl]-N-phenylpropanamide
• Molecular Formula: C₂₄H₃₂N₂O₂
• Molecular Weight: 380.52
• CAS Registry Number: 60618-49-7
• SMILES: CCC(=O)N(C1=CC=CC=C1)C2(CCN(CC2)CCC3=CC=CC=C3)COC

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 492.1±35.0 ºC 760 mmHg (Calc.)^*
• Flash point: 251.4±25.9 ºC (Calc.)^*
• Index of refraction: 1.565 (Calc.)^*

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

Discovory and Applicatios

4-Methoxymethylfentanyl is a synthetic opioid analgesic structurally related to fentanyl, distinguished by the substitution of a methoxymethyl group at the 4-position of the aniline ring. This modification alters both its lipophilicity and receptor binding characteristics, often resulting in changes to potency, onset, and duration of action. As a member of the fentanyl analog class, 4-methoxymethylfentanyl acts as a μ-opioid receptor agonist, producing typical opioid effects such as analgesia, euphoria, sedation, and respiratory depression.

The compound was originally synthesized in the context of structure-activity relationship studies aimed at improving the pharmacological profiles of fentanyl derivatives. Researchers examined how modifications at various positions on the molecule could influence opioid receptor affinity and selectivity. The methoxymethyl group was introduced to explore changes in the electronic and steric environment around the aromatic ring, which plays a critical role in receptor interaction.

Although 4-methoxymethylfentanyl was not developed for therapeutic use, it has surfaced in illicit drug markets. Like other non-pharmaceutical fentanyl analogs, its emergence has been associated with opioid overdose cases, some of them fatal. The potency of 4-methoxymethylfentanyl is not precisely established in humans, but based on animal models and structural similarity, it is presumed to be several times more potent than morphine and possibly comparable to or greater than fentanyl. This high potency increases the risk of accidental overdose, especially when mixed with other opioids or recreational drugs without precise dosing control.

In chemical synthesis, the preparation of 4-methoxymethylfentanyl involves derivatization of the fentanyl core. Key steps include the N-alkylation of an aniline precursor and introduction of the methoxymethyl group through etherification or related methods. The final compound contains the essential propionamide moiety for opioid activity and retains the phenethylpiperidine backbone characteristic of fentanyl analogs. Control of stereochemistry is less critical for this analog compared to others with asymmetric centers, but purity remains essential due to its high pharmacological activity.

Forensic and toxicological laboratories monitor the appearance of such analogs using techniques like gas chromatography-mass spectrometry (GC-MS) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Analytical challenges include low concentration detection, structural similarity to other analogs, and the need for reference standards. Accurate identification is critical for tracking trends in synthetic opioid distribution and for diagnosing overdose cases.

Due to its potential for abuse and lack of accepted medical use, 4-methoxymethylfentanyl has been placed under regulatory control in several countries. The scheduling of such substances typically follows outbreaks of poisonings or law enforcement seizures. Regulatory bodies often classify these compounds under generic legislation covering fentanyl analogs to prevent the emergence of new variants designed to evade existing laws.

In recent years, the proliferation of fentanyl analogs like 4-methoxymethylfentanyl has contributed significantly to the global opioid crisis. Their high potency, ease of synthesis, and illicit distribution have posed serious public health challenges. Efforts to combat the spread of these substances include international collaboration on scheduling, rapid forensic detection, and public awareness campaigns aimed at reducing exposure risks. Despite these measures, the continual development of new analogs underscores the need for ongoing vigilance in opioid monitoring and control.

References

1992. Pharmacological profiles of fentanyl analogs at mu, delta and kappa opiate receptors. European Journal of Pharmacology, 213(2).
DOI: 10.1016/0014-2999(92)90685-w

2000. Molecular docking reveals a novel binding site model for fentanyl at the mu-opioid receptor. Journal of Medicinal Chemistry, 43(3).
DOI: 10.1021/jm9903702

1976. Arzneimittel-Forschung. Drug Research, 26(1548).
PMID: 12771