2-Ethoxybenzamidine hydrochloride
[CAS# 18637-00-8]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Amine
• Name: 2-Ethoxybenzamidine hydrochloride
• Molecular Formula: C₉H₁₃ClN₂O
• Molecular Weight: 200.66
• CAS Registry Number: 18637-00-8
• EC Number: 606-080-9
• SMILES: CCOC1=CC=CC=C1C(=N)N.Cl

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H332-H335
• Precautionary Statements: P261-P280-P305+P351+P338

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Acute toxicity	Acute Tox.	4	H302

Discovory and Applicatios

2-Ethoxybenzamidine hydrochloride is an organic compound classified as an amidine derivative, specifically a benzamidine substituted at the 2-position with an ethoxy group. Its molecular structure features a benzene ring bearing an amidine functional group (–C(=NH)NH₂) attached directly to the aromatic ring, and an ethoxy substituent (–OCH₂CH₃) located ortho to the amidine. The compound is isolated as its hydrochloride salt, formed by protonation of the amidine moiety, which enhances solubility and stability.

The benzamidine core is well recognized in organic chemistry and pharmaceutical science for its strong basicity and ability to form stable interactions with biological targets, including enzymes and receptors. Amidines are known for their role as protease inhibitors, receptor agonists or antagonists, and as building blocks in medicinal chemistry. Substitution at the 2-position by an ethoxy group modifies the electronic and steric environment of the benzamidine, potentially influencing its reactivity and binding characteristics.

Synthesis of 2-ethoxybenzamidine hydrochloride typically involves the functionalization of 2-ethoxybenzonitrile or related precursors. One common synthetic approach is the Pinner reaction, in which nitriles are converted to amidines through reaction with alcoholic hydrogen chloride followed by treatment with ammonia or amines. This process introduces the amidine functionality while preserving the ethoxy substituent on the aromatic ring. Subsequent isolation as the hydrochloride salt involves protonation of the amidine nitrogen atoms under acidic conditions.

Chemically, 2-ethoxybenzamidine hydrochloride exhibits properties characteristic of amidine salts. The protonated amidine group confers strong basicity and ionic character, resulting in enhanced water solubility relative to the free base. The ethoxy substituent, being an electron-donating group, affects the electron density of the aromatic ring and the amidine group, potentially altering the compound’s nucleophilicity and interaction with electrophiles.

Applications of 2-ethoxybenzamidine hydrochloride are primarily found in medicinal chemistry and enzymology. Amidines are widely studied as inhibitors of serine proteases, including trypsin and thrombin, due to their ability to mimic the transition state of peptide bond hydrolysis. The ortho-ethoxy substituent may modulate binding affinity and selectivity by engaging in additional interactions or affecting the compound’s conformation. Consequently, this compound and related derivatives serve as valuable scaffolds for designing enzyme inhibitors and pharmacologically active molecules.

In synthetic organic chemistry, 2-ethoxybenzamidine hydrochloride can be utilized as a reagent or intermediate for constructing heterocyclic systems or amidine-containing compounds. The presence of both the ethoxy group and amidine functionality allows for selective reactions, enabling the preparation of diverse derivatives with potential biological activity.

Analytical characterization includes nuclear magnetic resonance (²H and ³C NMR) spectroscopy, which confirms the presence of aromatic protons, ethoxy methylene and methyl groups, and amidine protons. Infrared (IR) spectroscopy identifies characteristic absorption bands corresponding to amidine N–H stretches and aromatic C–O stretches. Elemental analysis and mass spectrometry support the determination of molecular composition and purity.

Physically, 2-ethoxybenzamidine hydrochloride is typically obtained as a crystalline solid, soluble in polar solvents such as water, methanol, and ethanol due to its ionic nature. It is stable under standard laboratory storage conditions and can be handled safely with standard precautions for amidine salts.

In summary, 2-ethoxybenzamidine hydrochloride is a hydrochloride salt of a 2-ethoxy-substituted benzamidine, combining amidine’s basic and biological properties with the electron-donating ethoxy group on the aromatic ring. It serves as a significant compound in medicinal chemistry as a protease inhibitor scaffold and as an intermediate in synthetic organic chemistry for preparing bioactive molecules.

References

2004. Vardenafil hydrochloride. Pharmaceutical Substances.
URL: https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-22-0010