2-[(4-Fluorophenyl)sulfonyl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one
[CAS# 272786-64-8]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrazines
• Name: 2-[(4-Fluorophenyl)sulfonyl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one
• Synonyms: DM 232; Unifiram
• Molecular Formula: C₁₃H₁₅FN₂O₃S
• Molecular Weight: 298.33
• Protein Sequence: v
• CAS Registry Number: 272786-64-8
• SMILES: C1CC(=O)N2C1CN(CC2)S(=O)(=O)C3=CC=C(C=C3)F

Properties

• Solubility: Very slightly soluble (0.42 g/L) (25 °C), Calc.^*
• Density: 1.47±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Boiling point: 479.5±55.0 °C 760 mmHg (Calc.)^*
• Flash point: 243.8±31.5 °C (Calc.)^*
• Index of refraction: 1.628 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2014 ACD/Labs)

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P280-P301+P312-P302+P352-P305+P351+P338

Discovery and Applications

2-[(4-Fluorophenyl)sulfonyl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one is a synthetic compound that incorporates a fused bicyclic system derived from hexahydropyrrolo[1,2-a]pyrazine and a fluorinated arylsulfonyl moiety. The compound is of interest due to its structural similarity to bioactive molecules that modulate proteolytic enzymes or act as intermediates in drug discovery pipelines.

The hexahydropyrrolo[1,2-a]pyrazine core is commonly observed in biologically active compounds, especially those designed to mimic natural substrates or transition states of enzymes. The rigidity and defined conformation of this bicyclic ring system allow for targeted interactions with protein active sites. Furthermore, the ketone at the 6-position (i.e., the lactam) can serve as a hydrogen bond acceptor, which enhances binding to biological targets.

The presence of a sulfonyl group attached to a para-fluorophenyl ring introduces both electron-withdrawing and lipophilic properties. The fluorine atom enhances metabolic stability and modulates the electronic characteristics of the aromatic ring, often improving binding affinity to target receptors or enzymes. The sulfonyl group acts as a key pharmacophoric element in many inhibitors, particularly for serine and cysteine proteases, by engaging in polar interactions with amino acid residues in enzyme pockets.

Derivatives of this compound type have been explored in the context of protease inhibition, neuropharmacology, and peptide-mimetic drug development. Their rigid structure and favorable pharmacokinetic properties make them attractive scaffolds for lead optimization. For instance, similar fused heterocycles with sulfonyl substitutions have been investigated for use as dipeptidyl peptidase IV (DPP-IV) inhibitors or as antagonists of neuropeptide receptors.

Although no widely commercialized drugs are known to be based directly on this compound, it continues to serve as a valuable intermediate in medicinal chemistry for the synthesis of more complex analogs with potential therapeutic benefits. Current synthetic strategies focus on efficient construction of the fused ring system followed by selective sulfonylation with substituted arylsulfonyl chlorides under mild conditions, often utilizing base-mediated coupling in polar aprotic solvents.

The continued exploration of 2-[(4-Fluorophenyl)sulfonyl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one derivatives in drug discovery underscores the utility of this scaffold in developing novel therapeutics with enhanced specificity and improved metabolic profiles.

References


Manetti D, Ghelardini C, Bartolini A, Dei S, Galeotti N, Gualtieri F, Romanelli MN, Teodori E (2000) Molecular Simplification of 1,4-Diazabicyclo[4.3.0]nonan-9-ones Gives Piperazine Derivatives That Maintain High Nootropic Activity. Journal of Medicinal Chemistry 43 22 4169–4176 DOI: 10.1021/jm000972h


Manetti D, Ghelardini C, Bartolini A, Bellucci C, Dei S, Galeotti N, Gualtieri F, Romanelli MN, Scapecchi S, Teodori E (2000) Design, synthesis, and preliminary pharmacological evaluation of 1,4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents. Journal of Medicinal Chemistry 43 8 1417–1428 DOI: 10.1021/jm991170t


Martino MV, Guandalini L, Di Cesare Mannelli L, Menicatti M, Bartolucci G, Dei S, Manetti D, Teodori E, Ghelardini C, Romanelli MN (2017) Piperazines as nootropic agents: New derivatives of the potent cognition-enhancer DM235 carrying hydrophilic substituents. Bioorganic & Medicinal Chemistry 25 10 2719–2730 DOI: 10.1016/j.bmc.2017.02.019