(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate
[CAS# 376608-71-8]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: (1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate
• Synonyms: (alphaR)-alpha-Hydroxybenzeneacetic acid compd. with (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine; Ticagrelor impurity E
• Molecular Formula: C₉H₉F₂N.C₈H₈O₃
• Molecular Weight: 321.32
• CAS Registry Number: 376608-71-8
• EC Number: 619-507-9
• SMILES: C1[C@H]([C@@H]1N)C2=CC(=C(C=C2)F)F.C1=CC=C(C=C1)[C@H](C(=O)O)O

Properties

• Flash point: 218.5 °C - closed cup (Expl.)

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319
• Safety Statements: P264-P264+P265-P280-P302+P352-P305+P351+P338-P321-P332+P317-P337+P317-P362+P364

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate is a chiral cyclopropylamine derivative paired with a mandelate counterion. The molecule features a 3,4-difluorophenyl-substituted cyclopropane core in the (1R,2S) configuration, which is protonated to form the ammonium cation. The counterion, (2R)-hydroxy(phenyl)ethanoate (mandelate), is a chiral carboxylate that provides crystallinity and optical resolution, making this compound useful for enantiomeric purification and as a chiral building block in pharmaceutical chemistry.

The discovery of this type of cyclopropanaminium mandelate salts originates from the development of chiral resolution techniques for amine-containing drugs. Cyclopropylamine derivatives are common scaffolds in medicinal chemistry due to their rigidity, metabolic stability, and ability to interact with biological targets. The use of chiral mandelate counterions allows the separation of enantiomers via salt formation, exploiting differences in solubility between diastereomeric salts to obtain optically pure compounds.

In synthetic applications, the (1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium cation serves as a key intermediate for the preparation of active pharmaceutical ingredients (APIs) with stereochemically defined pharmacophores. The difluorophenyl substitution can influence receptor binding affinity, metabolic stability, and lipophilicity, which are important considerations in drug design. The cyclopropane ring imparts conformational rigidity, reducing the flexibility of the molecule and often enhancing selectivity for biological targets.

The mandelate counterion not only facilitates chiral resolution but also improves the handling properties of the compound. As a crystalline solid, the salt is more stable and easier to purify than the free amine. It can be converted back to the free base under mild conditions, allowing subsequent reactions such as acylation, alkylation, or coupling with other molecular fragments in synthetic sequences. This approach is widely used in the synthesis of CNS-active agents, enzyme inhibitors, and other bioactive molecules where stereochemistry is critical.

The stereochemistry of both the cyclopropylamine and the mandelate ion is important for both physical and biological properties. Enantiomerically pure salts can influence the pharmacokinetics, pharmacodynamics, and toxicity of the derived compounds. Researchers exploit this feature in drug development, using chiral salts to isolate desired enantiomers and improve drug efficacy and safety.

Preparation of the salt generally involves combining the optically active mandelic acid with the cyclopropylamine in an appropriate solvent, leading to formation of the crystalline ammonium mandelate. Control over temperature, solvent choice, and crystallization conditions is essential to achieve high enantiomeric excess and yield. The resulting salt can be analyzed using chiral chromatography and other spectroscopic techniques to confirm stereochemical purity and structural integrity.

Overall, (1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-hydroxy(phenyl)ethanoate is a valuable chiral compound in pharmaceutical chemistry. Its rigid cyclopropane core, difluorophenyl substitution, and mandelate counterion combine to provide a stable, optically pure intermediate that facilitates the synthesis of stereochemically defined bioactive molecules, contributing to drug discovery and development efforts.