N-[3-(Aminocarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetamide
[CAS 489408-02-8]

Identification

• Classification: Chemical reagent >> Organic reagent >> Amide
• Name: N-[3-(Aminocarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetamide
• Synonyms: HBT1; 2-[[2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide
• Molecular Formula: C₁₆H₁₇F₃N₄O₂S
• Molecular Weight: 386.39
• CAS Registry Number: 489408-02-8
• SMILES: CC1=CC(=NN1CC(=O)NC2=C(C3=C(S2)CCCC3)C(=O)N)C(F)(F)F

Properties

• Solubility: Insoluble (2.7E^-3 g/L) (25 °C), Calc.^*
• Density: 1.58±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Boiling point: 531.9±50.0 °C 760 mmHg (Calc.)^*
• Flash point: 275.5±30.1 °C (Calc.)^*
• Index of refraction: 1.661 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501

Discovery and Applications

N-[3-(Aminocarbonyl)-4,5,6,7-tetrahydrobenzo[b]thien-2-yl]-5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetamide is a highly functionalized heteroaromatic acetamide composed of two main fused-ring heterocyclic systems connected through an acetamide linker. The structure contains a tetrahydrobenzothiophene-derived fragment on one side and a substituted pyrazole ring on the other, with multiple electron-withdrawing and hydrogen-bonding functional groups distributed across the molecule.

The tetrahydrobenzo[b]thiophene portion consists of a partially saturated benzothiophene system. Benzothiophene is a fused bicyclic structure combining a benzene ring and a thiophene ring, where sulfur is incorporated into a five-membered heteroaromatic ring. In this molecule, the “4,5,6,7-tetrahydro” designation indicates partial saturation of the benzene portion, reducing aromaticity and increasing conformational flexibility. At the 3-position of this fragment, an aminocarbonyl substituent (–CONH₂) is present, introducing an amide functionality capable of both hydrogen bond donation and acceptance.

The second major fragment is a pyrazole ring substituted at multiple positions. Pyrazole is a five-membered aromatic heterocycle containing two adjacent nitrogen atoms. In this compound, the pyrazole is substituted at the 3-position with a trifluoromethyl group (–CF₃) and at the 5-position with a methyl group (–CH₃). The trifluoromethyl group is strongly electron-withdrawing due to the high electronegativity of fluorine, significantly influencing the electronic distribution of the ring and increasing lipophilicity. The methyl group contributes weak electron donation through inductive effects and increases hydrophobic character.

The two heterocyclic systems are connected via an acetamide linker, specifically through an N-acetylated pyrazole nitrogen. The acetamide functional group contains a carbonyl group bonded to nitrogen, forming a resonance-stabilized amide bond. This bond restricts rotation due to partial double-bond character and contributes to conformational rigidity in the central portion of the molecule.

The molecule contains multiple heteroatoms, including nitrogen, oxygen, sulfur, and fluorine, creating a highly polarized chemical environment. The amide groups and carbonyl oxygen atoms serve as hydrogen bond acceptors, while the amide NH groups can act as hydrogen bond donors. The pyrazole nitrogen atoms may also participate in protonation or coordination interactions depending on the chemical environment.

From a physicochemical standpoint, the compound combines both hydrophobic and polar regions. The aromatic and heteroaromatic ring systems, along with the trifluoromethyl and methyl substituents, contribute significant hydrophobic character. In contrast, the amide and aminocarbonyl groups introduce polarity and hydrogen bonding capability. This balance typically leads to moderate to low water solubility and higher compatibility with organic phases.

The trifluoromethyl substituent plays a particularly important role in modulating physicochemical properties. It increases metabolic stability, enhances lipophilicity, and strongly influences electron density in the adjacent pyrazole ring through inductive effects. Such groups are commonly used in medicinal chemistry to tune binding affinity, permeability, and stability profiles.

The tetrahydrobenzothiophene fragment introduces conformational flexibility relative to fully aromatic systems. Partial saturation reduces π-conjugation and allows the molecule to adopt multiple low-energy conformations, which can influence molecular recognition and packing behavior in the solid state.

Chemically, the most reactive sites are expected to be the amide bonds (subject to hydrolysis under strong conditions), the aminocarbonyl group, and the heteroatoms in the pyrazole and thiophene systems, which may participate in protonation or coordination chemistry. The carbon–fluorine bonds in the trifluoromethyl group are generally highly stable under normal chemical conditions.

Without verified literature specific to this compound, no statements can be made regarding biological activity or application. Based on structural analysis alone, it is best described as a multifunctional heteroaromatic acetamide featuring fused sulfur-containing ring systems, a trifluoromethyl-substituted pyrazole, and multiple amide functionalities that collectively generate a strongly polarized, conformationally mixed molecular framework.

References

2018. HBT1, a Novel AMPA Receptor Potentiator with Lower Agonistic Effect, Avoided Bell-Shaped Response in In Vitro BDNF Production. The Journal of Pharmacology and Experimental Therapeutics.
DOI: https://pubmed.ncbi.nlm.nih.gov/29298820