Methodologies for the Chemical Synthesis of the Benzofuran (B130515) Core Structure

The benzofuran core, a fused benzene (B151609) and furan (B31954) ring system, is a significant heterocyclic scaffold found in numerous natural products and pharmacologically active compounds.  Various synthetic methodologies have been developed for its construction, reflecting its importance in chemical research.

Common approaches to synthesizing the benzofuran core include cyclization reactions of appropriately substituted precursors. For instance, the cyclization of ortho-alkynylphenols is a known method.  Transition metal-catalyzed reactions, particularly palladium-catalyzed cross-coupling reactions, are powerful tools for forming substituted benzofuran structures.  Copper-promoted hydration/annulation reactions starting from 2-fluorophenylacetylene derivatives have also been reported.

Other methodologies involve oxidative cyclization of ortho-alkenylphenols, sometimes catalyzed by palladium.  Acid-catalyzed cyclization of aryl ether substrates, such as acetals, is another popular synthetic route for constructing the benzofuran scaffold.  This method typically involves protonation of the substrate, followed by elimination and nucleophilic addition to form the cyclic structure.  Regioselectivity can be a challenge in these cyclization reactions, and factors like the properties of oxonium ion intermediates influence the product ratio.  Catalyst-free synthesis using hydroxyl-substituted aryl alkynes and sulfur ylides has also been explored.

Various catalysts, including those based on nickel, copper, palladium, and rhodium, have been employed to facilitate benzofuran synthesis, offering efficient routes and noteworthy yields depending on the specific reaction and substrates.  Base-mediated cyclizations, such as the potassium tert-butoxide-catalyzed intramolecular cyclization of ortho-bromobenzylvinyl ketones, represent transition-metal-free alternatives for core synthesis.

Synthetic Pathways and Derivatization Strategies to Aminoalkylbenzofuran Analogues, Including 6-EAPB

The synthesis of aminoalkylbenzofuran analogues like 6-APB and its N-ethyl derivative, this compound, typically involves the functionalization of the benzofuran core. The synthetic preparation of 5-APB and 6-APB was documented as part of research programs aimed at developing selective receptor agonists.

A reported synthetic route for 6-APB involves starting with 3-bromophenol (B21344).  This precursor undergoes reaction with bromoacetaldehyde (B98955) diethylacetal in the presence of a base like sodium hydride to yield a diethyl acetal (B89532) intermediate.  Heating this acetal with polyphosphoric acid facilitates cyclization, resulting in a mixture of bromobenzofuran structural isomers, specifically 4-bromo-1-benzofuran and 6-bromo-1-benzofuran.  These isomers can be separated, for instance, by silica (B1680970) gel column chromatography.

To arrive at the aminoalkyl structure, the separated bromobenzofuran isomer (e.g., 6-bromo-1-benzofuran for 6-APB synthesis) is typically converted to its corresponding propanone derivative.  This propanone then undergoes reductive amination to yield the target aminoalkylbenzofuran, such as 6-APB.  this compound, being an N-ethyl analogue of 6-APB, would involve a similar synthetic strategy but with the introduction of an ethyl group onto the amine nitrogen during or after the reductive amination step. This could potentially be achieved by using ethylamine (B1201723) or through subsequent N-alkylation of the primary amine of 6-APB.

Research into the synthesis of metabolites of compounds like 5-APB and 6-APB also provides insights into derivatization strategies. For example, the synthesis of a 5-APB metabolite involved methylation, formylation, Aldol-type condensation, reduction, and hydrolysis reactions starting from 2-hydroxyphenylacetic acid.  While this pertains to metabolic pathways, the chemical transformations involved (methylation, reduction, etc.) are relevant derivatization strategies in synthetic chemistry.

Case studies in the synthesis of aminoalkylbenzofurans using specific precursors, such as 1-(6-Benzofuranyl)-2-propanone, have demonstrated enhanced yields and selectivity for desired products in research settings.

Identification and Characterization of Synthetic By-products and Impurities Relevant to Research Sample Purity

Ensuring the purity of synthesized compounds is critical for accurate research findings. Synthetic processes for benzofuran derivatives, including aminoalkylbenzofurans like this compound, can yield various by-products and impurities. Identifying and characterizing these is essential for assessing research sample purity.

Impurities in chemical synthesis can arise from incomplete reactions, side reactions, or impurities present in the starting materials or reagents.  Characterization of impurities is typically performed using a range of analytical techniques.

Techniques commonly employed for the identification and characterization of synthetic by-products and impurities include:

Chromatography: High-performance liquid chromatography (HPLC) is widely used for separating and quantifying impurities.  Orthogonal chromatographic methods with different separation principles are often employed for comprehensive impurity profiling.

Mass Spectrometry (MS): Coupled with chromatography (e.g., LC-MS, GC-MS), mass spectrometry is invaluable for determining the molecular weight and fragmentation pattern of impurities, aiding in their structural elucidation.  High-resolution mass spectrometry (HRMS) provides accurate mass data for determining elemental composition.

Nuclear Magnetic Resonance (NMR) Spectroscopy: ¹H and ¹³C NMR spectroscopy provide detailed structural information about impurities.

Infrared (IR) Spectroscopy: IR spectroscopy can help identify functional groups present in impurities.

Research on the synthesis of other drug compounds containing benzofuran cores, such as darifenacin (B195073) hydrobromide or dronedarone (B1670951) hydrochloride, highlights the importance of identifying and characterizing process-related impurities using techniques like LC-MS/MSn, NMR, and IR.  Plausible mechanisms for the formation of these impurities are often proposed based on the synthetic route.

For aminoalkylbenzofurans, potential impurities could include unreacted starting materials, intermediates from incomplete reactions (e.g., the propanone precursor), isomers formed during cyclization or other steps, and by-products from side reactions (e.g., over-alkylation if N-alkylation is used).  Studies on the metabolism of 6-APB have identified various metabolites resulting from phase I and phase II transformations, such as ring hydroxylation, ring cleavage, oxidation, reduction, and glucuronidation.  While metabolites are not synthetic impurities, the analytical techniques used to identify and characterize them (e.g., GC-MS and LC-(HR)-MSn) are directly applicable to the analysis of synthetic impurities.

The characterization of impurities is crucial for establishing the purity of research samples and ensuring that observed biological or chemical effects are attributable to the target compound, this compound, rather than contaminants.

In Vitro and Ex Vivo Neurotransmitter Transporter Interaction Studies

Studies employing in vitro and ex vivo methods, such as assays using human embryonic kidney (HEK) cells transfected with human transporters and experiments with rat brain synaptosomes, have been instrumental in characterizing the interaction of benzofurans with monoamine transporters. These studies assess compounds’ affinity for transporters, their ability to inhibit neurotransmitter uptake, and their capacity to induce neurotransmitter release.

Receptor Binding and Functional Agonism Investigations

Beyond their interactions with monoamine transporters, benzofuran compounds have been investigated for their activity at various neurotransmitter receptors, particularly serotonin receptors.

Comparative Preclinical Pharmacology with Structural Analogues (e.g., 6-APB, 5-EAPB, 6-MAPB, MDMA, MDA)

Preclinical pharmacological studies compare the effects of this compound to its structural analogues, such as 6-APB, 5-EAPB, 6-MAPB, MDMA, and MDA, to understand its relative potency and mechanism of action.

Research indicates that benzofuran compounds, including 5-APB and 6-APB, act as potent substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT).  They inhibit neurotransmitter uptake at these transporters in a dose-dependent manner.  Compared to MDA and MDMA, 5-APB and 6-APB have been found to be more potent at evoking transporter-mediated release.  For example, 6-APB was reported to be 10-fold more potent than MDA at DAT-mediated release and 4.5 times more potent than MDA at SERT-mediated release in rat brain synaptosomes.

While 5-APB and 6-APB show relatively low DAT:SERT inhibition ratios, consistent with greater serotonergic versus dopaminergic activity similar to MDMA, some studies suggest they can be more selective for inhibiting DAT.

5-EAPB, a structural isomer of this compound, has also been evaluated. One study reported that 5-EAPB exhibited a reduction in the magnitude of norepinephrine and dopamine release while maintaining 5-HT releasing properties compared to 5-APB.  5-EAPB was also found to be more potent at the DAT compared with MDMA and MDA in one study.

6-MAPB and 5-MAPB, N-methylated analogues, are also potent substrate-type releasers at DAT, NET, and SERT, and have been shown to be more potent than MDMA at these transporters.

In addition to transporter interactions, comparative studies highlight differences in receptor affinities. While 5-APB and 6-APB are agonists at 5-HT2A and 5-HT2B receptors, unlike MDMA which is not a 5-HT2B agonist, most benzofurans are partial 5-HT2A agonists similar to MDMA.  6-APB also shows affinity for the 5-HT2C and 5-HT1A receptors.

The preclinical data collectively suggest that this compound and its analogues share similarities with MDMA and MDA in their ability to interact with monoamine transporters, acting as releasers. However, there are notable differences in potency and receptor profiles, particularly concerning 5-HT2B and potentially adrenergic receptors and TAAR1.

Data Table: Comparative In Vitro Potencies (EC50 nM) for Monoamine Release in Rat Brain Synaptosomes

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