Cyclopropyl fentanyl hydrochloride is a synthetic opioid that belongs to the 4-anilidopiperidine class, closely related to fentanyl. It is characterized by the replacement of the propionamide group in fentanyl with a cyclopropanecarboxamide group. This compound has gained attention due to its significant potency and the role it plays in the ongoing opioid crisis, being associated with numerous overdose deaths. Cyclopropyl fentanyl hydrochloride is classified as a controlled substance in many jurisdictions due to its potential for abuse and addiction. Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5, Buy Tetramethylcyclopropylfentanyl cas-2309383-11-5

Cyclopropyl fentanyl was first synthesized and described in patent literature in 1968. It is part of a broader class of compounds known as fentanyl analogs, which have been developed for various medical applications but are often misused illicitly. The compound is primarily classified under synthetic opioids, which are designed to mimic the effects of naturally occurring opioids but can have varying degrees of potency and side effects.

Methods and Technical Details

The synthesis of cyclopropyl fentanyl typically involves several steps, starting from commercially available precursors. A common method includes the reaction of N-(4-piperidinyl)-N-phenylpropanamide with cyclopropanecarboxylic acid derivatives. The process often utilizes solvents such as acetonitrile and dichloromethane, along with various reagents like sodium hydroxide and hydrochloric acid for pH adjustments.

1. Initial Reaction: The precursor N-(4-piperidinyl)-N-phenylpropanamide is reacted with cyclopropanecarboxylic acid derivatives.
2. Purification: After completion, the reaction mixture is typically filtered, and solvents are evaporated under reduced pressure.
3. Salt Formation: The free base form of cyclopropyl fentanyl can be converted into its hydrochloride salt by dissolving it in an appropriate solvent followed by the addition of hydrochloric acid.

The synthesis has been documented to yield high purity products without extensive purification steps like flash chromatography  .

Structure and Data

Cyclopropyl fentanyl has a molecular formula of C23H28N2OC23​H28​N2​O and a molecular mass of approximately 348.49 g/mol. The structure features a piperidine ring, a phenyl group, and a cyclopropanecarboxamide moiety.

• InChI Key: A unique identifier for cyclopropyl fentanyl that facilitates database searches.
• Melting Point: Reported between 119.5 °C and 120.4 °C, suggesting solid-state stability at room temperature.

The compound’s structural similarities to other fentanyl analogs indicate potential for similar pharmacological effects  .

Reactions and Technical Details

Cyclopropyl fentanyl undergoes typical reactions associated with amides and esters, including hydrolysis under acidic or basic conditions. Its interactions with biological systems primarily involve binding to opioid receptors, leading to analgesic effects.

1. Hydrolysis: In aqueous environments, cyclopropyl fentanyl can hydrolyze to yield its corresponding carboxylic acid derivative.
2. Receptor Binding: The compound exhibits high affinity for mu-opioid receptors, which mediates its analgesic properties.

The pharmacokinetics of cyclopropyl fentanyl have been studied using methods such as ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) to assess its stability and metabolic pathways  .

Process and Data

Cyclopropyl fentanyl acts primarily as an agonist at mu-opioid receptors in the central nervous system. This interaction leads to:

• Analgesia: It produces significant pain relief compared to other opioids.
• Respiratory Depression: A critical side effect associated with opioid use, potentially leading to overdose.
• Euphoria: Its psychoactive properties contribute to its potential for abuse.

Pharmacodynamic studies indicate that cyclopropyl fentanyl has greater analgesic potency than traditional opioids like morphine .

Physical and Chemical Properties

Cyclopropyl fentanyl hydrochloride exhibits several notable physical properties:

These properties are crucial for understanding how cyclopropyl fentanyl behaves in both laboratory settings and biological environments  .

Scientific Uses

While primarily known for its illicit use, cyclopropyl fentanyl has potential applications in scientific research:

• Pain Management Studies: Investigating its analgesic properties compared to existing opioids.
• Pharmacological Research: Understanding opioid receptor interactions and developing safer alternatives.
• Toxicology Studies: Assessing the risks associated with synthetic opioids in public health contexts.

Research into cyclopropyl fentanyl continues to evolve as scientists seek to understand its effects better and mitigate the risks associated with its misuse  .

Historical Synthesis Pathways of Fentanyl Analogs

The development of fentanyl analogs originates from Paul Janssen’s pioneering synthesis of fentanyl in 1960, designed to enhance the potency and bioavailability of earlier opioids like demerol [1]. Early synthetic routes faced challenges in yield and scalability, relying on multi-step sequences with moderate efficiency. Initial approaches typically involved:

• N-Alkylation of 4-piperidone with phenethyl halides (e.g., 2-bromoethylbenzene) to form ketone intermediates.
• Reductive amination with aniline derivatives under suboptimal conditions (e.g., sodium borohydride without acid catalysis), yielding ≤72% due to imine instability [1].
• Final acylation using propionyl chloride or anhydride, often requiring chromatographic purification that limited scale-up potential.

These methods produced fentanyl and early analogs like alfentanil in moderate yields (50–70%), but proved inadequate for newer analogs with complex substituents. The emergence of illicitly modified analogs in the 1990s–2010s necessitated streamlined, high-yielding routes adaptable to diverse structural modifications, including cyclopropyl-containing derivatives [6].

Table 1: Evolution of Fentanyl Analog Synthesis

Cyclopropyl Fentanyl Hydrochloride: Synthetic Route Optimization

Cyclopropyl fentanyl hydrochloride synthesis leverages a refined three-step strategy adapted from modern fentanyl production, emphasizing solvent selection, hydride reagents, and salt formation [1] [3]. The optimized pathway is as follows:

• Step 1: N-Alkylation4-Piperidone monohydrate hydrochloride undergoes alkylation with 2-(bromoethyl)cyclopropane (or cyclopropyl analog) in acetonitrile with cesium carbonate. Acetonitrile replaces dimethylformamide, boosting yields from 72% to 88% by minimizing enolization side products [1]. The cyclopropyl moiety’s strain necessitates inert conditions to prevent ring opening.
• Step 2: Reductive AminationKetone intermediates react with aniline using sodium triacetoxyborohydride (STAB) and acetic acid (1:1 eq) in dichloromethane. Acetic acid protonates iminium intermediates, accelerating conversion to the 4-aminopiperidine. STAB outperforms cyanoborohydride (91% vs. 65% yield) by tolerating ambient temperatures and reducing over-reduction [1]. Cyclopropyl’s steric bulk does not impede this step.
• Step 3: Acylation and Salt FormationThe amine intermediate is acylated with propionyl chloride in dichloromethane/pyridine (9:1) with Hunig’s base, achieving >95% conversion. Hydrochloride salt formation follows via HCl-gas treatment in anhydrous diethyl ether, yielding crystalline cyclopropyl fentanyl hydrochloride (98% purity) without silica gel chromatography [3]. Non-polar solvents ensure high crystallinity for analytical characterization.

Table 2: Optimized Conditions for Cyclopropyl Fentanyl Synthesis

Structure-Activity Relationships in Opioid Receptor Binding

Cyclopropyl fentanyl’s bioactivity stems from structural modifications that enhance µ-opioid receptor (MOR) affinity and selectivity. Key SAR insights include:

• N-Substituent Hydrophobicity: The cyclopropyl group elevates MOR binding affinity (Ki = 27 nM) compared to bromo (Ki = 112 nM) or ethynyl (Ki = 131 nM) analogs. Its high lipophilicity (clogP ~3.5) improves membrane penetration and complements MOR’s hydrophobic subpocket [4]. Molecular modeling suggests cyclopropyl’s 119° bond angles induce optimal steric complementarity with Val³⁰⁰ and Trp³²⁹ residues in MOR’s orthosteric site.
• Acyl Group Tolerance: Propionyl (cyclopropyl fentanyl) and acetyl groups exhibit similar MOR efficacy (EC₅₀ = 32–38 nM for Gᵢ activation) [7]. Enlarging to tert-butyryl abolishes activity, confirming steric constraints near Tyr³²⁸. Cyclopropyl’s synergy with propionyl yields 3.1× higher MOR affinity versus methyl-substituted analogs [4].
• Receptor Selectivity: Unlike phenyl-based fentanyls, cyclopropyl fentanyl shows negligible κ-opioid receptor (KOR) or δ-opioid receptor (DOR) binding (Ki > 1,000 nM) [4]. This arises from cyclopropyl’s compactness, preventing interactions with KOR’s extended extracellular loop 2. However, minor modifications (e.g., thiophene replacement) restore KOR activity, highlighting substituent-dependent selectivity.

Table 3: SAR of Cyclopropyl vs. Key Fentanyl Substituents at MOR

βarr2 Bias Note: Cyclopropyl fentanyl exhibits balanced Gᵢ/β-arrestin-2 recruitment, unlike “biased” agonists (e.g., TRV130). No significant pathway preference (bias factor = 0.9) was observed in cell-based luciferase assays [7], refuting early hypotheses that analogs with alicyclic groups preferentially avoid βarr2-linked side effects.