Pharmaceutical Research

• • • This compound is used as an intermediate in the manufacture of fentanyl, as well as various related derivatives such as butyrylfentanyl, furanylfentanyl, benzylfentanyl and homofentanyl . It is an N-protected derivative of 4-anilinopiperidine which can be readily converted to fentanyl or related analogues in several straightforward synthetic steps .

Organic Synthesis

• • • 1-N-Boc-4-(Phenylamino)piperidine is an amino acid derivative widely employed as a reagent in organic synthesis . This compound exhibits remarkable versatility, finding applications in various fields .

Peptide and Protein Synthesis

• • • This compound is used in peptide and protein synthesis . It’s a versatile reagent that can be used in a variety of chemical reactions .

Drug Development

• • • It’s used in drug development . The compound can be used to create a variety of pharmaceuticals .

Scientific Research

• • • It’s used as a building block and laboratory chemical for research & development . It’s strictly not for human or animal use .

Illicit Drug Manufacture

• • It’s one of the precursors of the most common synthesis routes used in illicit fentanyl manufacture . Its possession, sale and importation are heavily regulated throughout much of the world .

1-Boc-4-(Phenylamino)piperidine, also known as tert-butyl 4-(phenylamino)piperidine-1-carboxylate, is a chemical compound characterized by the molecular formula C16H24N2O2 and a molecular weight of 276.4 g/mol. This compound features a piperidine ring with a phenylamino group and a tert-butoxycarbonyl protecting group. It is primarily utilized in synthetic organic chemistry, particularly as an intermediate in the production of various pharmaceutical compounds, including opioids and other bioactive molecules .

1-Boc-4-AP is a DEA Schedule I controlled substance in the United States due to its potential for conversion into fentanyl []. Fentanyl is a powerful synthetic opioid that is similar to morphine but is 50 to 100 times more potent []. It is a major public health concern due to its association with overdose deaths.

Safety Concerns:

• Possession or handling of 1-Boc-4-AP may be illegal without a proper license.
• Inhalation, ingestion, or skin contact with 1-Boc-4-AP can be harmful, although specific toxicity data is limited.
• Due to its structural similarity to fentanyl, it is possible that 1-Boc-4-AP may also have opioid-like effects, but this has not been well studied.

Involving peptide synthesis. Its phenylamino group enhances binding interactions with proteins and enzymes, facilitating the formation of peptide bonds. Additionally, it has been shown to modulate cellular processes such as signal transduction pathways, gene expression, and cellular metabolism by interacting with various kinases and phosphatases .

The synthesis of 1-Boc-4-(Phenylamino)piperidine typically involves the reaction of 4-anilinopiperidine with tert-butyl chloroformate under basic conditions. This method allows for high yields and purity of the final product. Various synthetic routes have been documented, including multiple steps involving intermediates like N-tert-butoxycarbonyl-4-piperidone  .

Example Synthetic Route:

• Combine N-tert-butoxycarbonyl-4-piperidone with aniline in dichloromethane.
• Add sodium triacetoxyborohydride followed by acetic acid.
• Stir the mixture at ambient temperature and then perform workup to isolate the product .

1-Boc-4-(Phenylamino)piperidine serves multiple applications in scientific research:

• Precursor in Drug Synthesis: It is a crucial intermediate in synthesizing fentanyl and its analogs, which are significant in pain management therapies.
• Analytical Reference Standard: Used for identifying and quantifying similar compounds in analytical chemistry.
• Forensic

Studies indicate that 1-Boc-4-(Phenylamino)piperidine interacts with various biomolecules, influencing their activity. Its ability to bind to enzyme active sites suggests potential inhibitory or activating effects on enzymatic reactions. The compound’s stability under certain conditions allows it to be used effectively in biochemical assays and drug development processes .

Several compounds share structural similarities with 1-Boc-4-(Phenylamino)piperidine, each exhibiting unique properties:

These compounds differ primarily in their functional groups and substituents, which influence their biological activity and reactivity profiles. 1-Boc-4-(Phenylamino)piperidine is unique due to its protective tert-butoxycarbonyl group, making it particularly useful as a stable precursor for further chemical modifications  .

Primary Synthetic Pathways

Reductive Amination of N-Boc-4-piperidone

The most widely employed method involves reductive amination of N-Boc-4-piperidone with aniline using sodium triacetoxyborohydride (STAB) as the reducing agent. In a representative procedure, N-Boc-4-piperidone (7 g) and aniline (3.3 g) are dissolved in dichloromethane (200 mL), followed by sequential addition of STAB (10.4 g) and glacial acetic acid (2.1 g) at ambient temperature [1]. The reaction completes within 2 hours, yielding 98% of 1-Boc-4-(Phenylamino)piperidine after aqueous workup [1]. STAB’s selectivity for imine reduction over competing carbonyl reduction ensures minimal side reactions, while acetic acid protonates the intermediate imine, enhancing electrophilicity for borohydride attack [5]. This method’s efficiency stems from the dichloromethane solvent, which solubilizes both polar (STAB) and nonpolar (aniline) components, facilitating homogeneous reaction conditions [1] [5].

Nucleophilic Substitution Approaches

Alternative routes involving nucleophilic substitution are less common due to steric hindrance at the piperidine ring’s 4-position. However, theoretical frameworks suggest that activating the piperidine nitrogen with a leaving group (e.g., mesylate) could enable phenylamine displacement. Such methods remain largely unexplored in practice, as reductive amination offers superior regioselectivity and milder conditions .

Protection-Deprotection Strategies

The tert-butoxycarbonyl (Boc) group in N-Boc-4-piperidone serves dual roles: it prevents unwanted side reactions at the piperidine nitrogen during reductive amination and enhances the substrate’s solubility in organic solvents [2]. Unlike Fmoc-protected analogs, the Boc group remains stable under the weakly acidic conditions of STAB-mediated reactions, obviating the need for mid-synthesis deprotection [4]. Post-synthesis, the Boc group can be selectively removed using trifluoroacetic acid (TFA) for further functionalization, though this falls outside the scope of synthesizing 1-Boc-4-(Phenylamino)piperidine itself [4].

Optimization of Reaction Conditions

Solvent Effects and Selection Criteria

Solvent polarity directly impacts reaction kinetics and yield. Dichloromethane, with a dielectric constant of 8.93, optimally balances the solubility of N-Boc-4-piperidone (logP ~1.8) and aniline (logP ~1.09) [1] [5]. Comparative studies with tetrahydrofuran (THF, ε = 7.52) show a 21% yield reduction due to incomplete imine formation, attributed to THF’s weaker stabilization of the protonated intermediate [5]. Ethyl ether, though nonpolar, aids in post-reaction extraction by partitioning hydrophilic byproducts into the aqueous phase [1].

Catalyst Systems and Their Influence

STAB’s superiority over alternative reductants like sodium cyanoborohydride (NaBH3CN) lies in its air stability and compatibility with acidic conditions. At stoichiometric ratios of 1.5:1 (STAB:substrate), conversion rates exceed 95%, while sub-stoichiometric amounts (0.8:1) result in 62% yields due to incomplete imine reduction [1] [5]. Acetic acid’s catalytic role is concentration-dependent: 1.2 equivalents relative to aniline maximize imine protonation without inducing Boc cleavage [1].

Temperature and Reaction Time Parameters

Ambient temperature (20–25°C) optimizes the trade-off between reaction rate and byproduct formation. Elevated temperatures (40°C) accelerate STAB decomposition, reducing effective hydride availability, while lower temperatures (0°C) prolong reaction times to 8+ hours without yield improvement [1] [5]. Time-course analyses reveal 90% conversion within 60 minutes, with diminishing returns thereafter due to equilibrium dynamics [5].

Industrial-Scale Production Methods

Process Engineering Considerations

Scaled-up synthesis (100+ kg batches) employs continuous flow reactors to mitigate exothermic risks during STAB addition. In a typical setup, N-Boc-4-piperidone and aniline are premixed in dichloromethane, then fed into a static mixer alongside STAB/acetic acid streams at 5 L/min . This approach reduces batch cycle times by 40% compared to stirred-tank reactors, while inline pH monitoring ensures optimal protonation states .

Yield Enhancement Strategies

Recycling mother liquors from crystallization steps recovers 12–15% of product otherwise lost. Implementing azeotropic drying (toluene/water) before STAB addition reduces hydrolytic side reactions, boosting yields from 98% to 99.2% [1] . Stoichiometric excesses are minimized via real-time FTIR monitoring of imine intermediates, lowering raw material costs by 18% .

Quality Control Methodologies

High-performance liquid chromatography (HPLC) with UV detection (λ = 254 nm) quantifies residual aniline (<0.1% specification). Nuclear magnetic resonance (NMR) spectroscopy (¹H, 400 MHz) confirms regioselectivity through characteristic Boc singlet at δ 1.45 ppm and phenylamino aromatic protons at δ 6.78–7.22 ppm [1]. X-ray powder diffraction (XRPD) ensures polymorphic consistency across batches, critical for downstream processing .