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Acetylfentanyl was first synthesized in the 1970s but has become more widely recognized in recent years due to its emergence as a designer drug. It is classified under the category of synthetic opioids, which also includes other analogs like carfentanil and furanylfentanyl. The structural formula of acetylfentanyl can be represented as C22H28N2OC22​H28​N2​O, with a molecular weight of approximately 348.48 g/mol.

Methods of Synthesis

Acetylfentanyl can be synthesized through various chemical reactions involving precursor compounds. One common method involves the reaction of 4-anilino-N-phenethylpiperidine (ANPP) with acetic anhydride or acetyl chloride. The general reaction can be summarized as follows:

This method typically requires careful control of reaction conditions, including temperature and time, to maximize yield and purity.

Technical Details

The synthesis process often involves the use of solvents such as dichloromethane or ethanol and may require purification steps such as recrystallization or chromatography to isolate acetylfentanyl from byproducts. Analytical techniques like thin-layer chromatography (TLC) or high-performance liquid chromatography (HPLC) are commonly used to monitor the reaction progress and assess product purity. Buy Acetylfentanyl Cas 3258-84-2

Structure and Data

The molecular structure of acetylfentanyl features a piperidine ring, an aniline group, and an acetyl moiety. Its structural representation is crucial for understanding its pharmacological properties: Buy Acetylfentanyl Cas 3258-84-2

• Molecular Formula: C22H28N2OC22​H28​N2​O
• Molecular Weight: 348.48 g/mol
• IUPAC Name: N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide

The compound exhibits a three-dimensional configuration that influences its binding affinity to opioid receptors.

Reactions Involving Acetylfentanyl

Acetylfentanyl undergoes various chemical reactions, particularly metabolic transformations when introduced into biological systems. The primary metabolic pathways include:

1. N-Dealkylation: This process leads to the formation of noracetylfentanyl, which retains some opioid activity.
2. Hydroxylation: Hydroxylation at different positions on the phenethyl moiety can produce various metabolites that may exhibit different pharmacological effects.

These reactions are critical for understanding both the therapeutic potential and toxicity associated with acetylfentanyl use.

Process and Data

Acetylfentanyl exerts its analgesic effects primarily through agonistic action on the mu-opioid receptors in the central nervous system. The mechanism involves:

Studies have shown that acetylfentanyl has a potency significantly greater than morphine, making it particularly dangerous in terms of overdose risk.

Physical Properties

• Appearance: Acetylfentanyl typically appears as a white crystalline solid.
• Solubility: It is soluble in organic solvents like ethanol and chloroform but poorly soluble in water.
• Melting Point: The melting point ranges between 100°C to 105°C.

Chemical Properties

• Stability: Acetylfentanyl is stable under normal conditions but may degrade under extreme temperatures or in the presence of strong acids or bases.
• Reactivity: It can react with oxidizing agents and undergo hydrolysis in aqueous environments.

These properties are essential for both handling in laboratory settings and understanding its behavior in biological systems.

Scientific Uses

While acetylfentanyl has no accepted medical applications due to safety concerns, it is utilized in scientific research primarily for:

1. Analytical Chemistry: Developing methods for detecting synthetic opioids in biological samples, including urine and plasma.
2. Toxicology Studies: Investigating the pharmacokinetics and metabolic pathways of synthetic opioids to understand their effects on human health.
3. Forensic Science: Assisting law enforcement agencies in identifying substances involved in overdose cases.

Research continues into the properties and effects of acetylfentanyl as part of broader efforts to combat the opioid crisis and improve safety protocols for handling synthetic drugs.

Optimized Synthesis Protocols for Acetylfentanyl and Fentanyl Analogues

The synthesis of acetylfentanyl follows a streamlined three-step pathway that maximizes yield and purity while minimizing side products. This protocol, optimized by Valdez et al., begins with the alkylation of 4-piperidone monohydrate hydrochloride with 2-(bromoethyl)benzene in acetonitrile, using cesium carbonate as a base catalyst. This reaction yields N-phenethyl-4-piperidone (13) with 88% efficiency—a significant improvement over earlier methods that used dimethylformamide (DMF) and achieved only 72% yields [3]. The second step involves reductive amination of intermediate 13 with aniline, where sodium triacetoxyborohydride (STAB) and acetic acid in dichloromethane facilitate near-quantitative conversion (91%) to the critical precursor 4-anilino-N-phenethylpiperidine (14) [3]. The final acylation step employs acetic anhydride (or acetyl chloride) with N,N-diisopropylethylamine (Hünig’s base) to form acetylfentanyl in 98% yield. This route enables gram-scale production (73–78% overall yield) and is adaptable to analogs like thiofentanyl and acetylthiofentanyl (Fig. 3) [3] [8].

Table 1: Optimization of Acetylfentanyl Synthesis Steps

Alkylation and Acylation Strategies in Piperidine-Based Opioid Synthesis

Alkylation selectivity is paramount for constructing the fentanyl backbone. The phenethyl side chain must be introduced at the piperidine nitrogen without O-alkylation byproducts. Cesium carbonate’s mild basicity (pKa ≈ 8) in acetonitrile selectively deprotonates the piperidine N–H group, enabling efficient N-alkylation while suppressing enolization. Replacing bromoalkyl precursors with mesylates (e.g., 2-(thiophen-2-yl)ethyl methanesulfonate for thiofentanyl) further boosts yields to 90% due to superior leaving-group kinetics [3].

In the acylation phase, nucleophilicity modulation of the secondary amine in intermediate 14 is critical. Hünig’s base (N,N-diisopropylethylamine) scavenges HCl without inducing premature hydrolysis, while polar aprotic solvents (dichloromethane) stabilize the tetrahedral intermediate. Acetic anhydride outperforms acetyl chloride in acylation efficiency (98% vs. 95%) due to its slower hydrolysis rate, reducing acid waste [3].

Table 2: Solvent and Leaving Group Effects on Alkylation

Yield Optimization in Reductive Amination and Acyl Transfer Reactions

Reductive amination efficiency hinges on iminium ion stabilization and hydride source selection. Acetic acid protonates the Schiff base intermediate (N-(phenethyl)-N-(phenylimino)piperidine), generating a cationic iminium species that resists enolization. Sodium triacetoxyborohydride (STAB) delivers hydrides selectively to iminium ions at ambient temperature, achieving 91% conversion to 14. By contrast, sodium cyanoborohydride (NaBH₃CN) requires elevated temperatures (80°C) to attain 85% yields, while unmodified sodium borohydride (NaBH₄) causes over-reduction of ketone starting material, lowering yields to 68% [3].

Acyl transfer to 14 is optimized by electrophile reactivity tuning. Acetyl chloride reacts vigorously but requires stoichiometric base to neutralize HCl. Acetic anhydride’s balanced electrophilicity allows controlled exothermic acylation, minimizing N-oxide formation. Solvent screening revealed dichloromethane’s superiority over pyridine; the latter induces solvolysis, reducing yields to 80% [3].

Salt Formation and Physicochemical Stabilization of Acetylfentanyl Derivatives

Acetylfentanyl’s tertiary amine is converted to pharmaceutically compatible salts to enhance stability, crystallinity, and handling. Hydrochloride salts form by bubbling HCl gas through an anhydrous ether solution of freebase acetylfentanyl, yielding a crystalline solid with >99% conversion. Citrate salts are synthesized by reacting acetylfentanyl with citric acid in ethanol, generating a water-soluble triester salt. Both processes achieve near-quantitative yields (98–99%) and suppress degradation pathways like N-dealkylation or ester hydrolysis (Fig. 3) [3] [4].

Physicochemical analyses confirm superior stability of salt forms:

• Hydrochloride salts exhibit a sharp melting point (187–189°C), indicating high crystallinity.
• Citrate salts display hygroscopicity below 40% RH, facilitating storage.
• Freebase acetylfentanyl decomposes above 150°C, while salts remain stable to >180°C [3].

Table 3: Characteristics of Acetylfentanyl Salts