4-Amino-2-trifluoromethylpyridine
[CAS# 147149-98-2]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridine compound >> Aminopyridine
• Name: 4-Amino-2-trifluoromethylpyridine
• Synonyms: 2-(Trifluoromethyl)pyridin-4-amine
• Molecular Formula: C₆H₅F₃N₂
• Molecular Weight: 162.12
• CAS Registry Number: 147149-98-2
• EC Number: 802-901-1
• SMILES: C1=CN=C(C=C1N)C(F)(F)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Melting point: 58 - 62 ºC (Expl.)
• Boiling point: 230.7±40.0 ºC 760 mmHg (Calc.)^*
• Flash point: 93.3±27.3 ºC (Calc.)^*
• Index of refraction: 1.479 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS06;GHS07 Danger
• Hazard Statements: H301-H319
• Precautionary Statements: P264-P264+P265-P270-P280-P301+P316-P305+P351+P338-P321-P330-P337+P317-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2A	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335

Discovory and Applicatios

4-Amino-2-trifluoromethylpyridine was first prepared in the mid twentieth century during investigations into synthetic modifications of substituted pyridines conducted to support medicinal chemistry research. Its preparation was initially reported through electrophilic functionalisation routes developed as part of broader studies into the synthesis of trifluoromethyl substituted heteroaromatic compounds. The compound is a member of the trifluoromethyl pyridine family, which became an area of interest when the trifluoromethyl group was recognised as a stable and metabolically persistent substituent capable of significantly altering physicochemical properties of small molecules. These properties include increased lipophilicity, enhanced chemical stability and improved metabolic resistance. Such effects guided its adoption in the design of experimental pharmaceutical agents. The presence of an amino substituent positioned ortho to a trifluoromethyl group on a pyridine ring provided researchers with a reactive intermediate suitable for further functionalisation, making the compound a versatile building block for the synthesis of more complex derivatives for biological testing.

The early discovery work involving 4-amino-2-trifluoromethylpyridine focused mainly on its preparation and characterisation. Initially it attracted attention as a synthetic intermediate of interest due to the unique steric and electronic effects conferred by the trifluoromethyl group at position 2. Subsequent developments in nucleophilic substitution and transition metal catalysed coupling methods presented new synthetic opportunities involving this compound. Approaches such as palladium catalysed cross coupling began to incorporate 4-amino-2-trifluoromethylpyridine into diversified heterocyclic architectures. Improved synthetic strategies emerged to address the challenges associated with regioselective substitution on fluorinated pyridines, which included controlling reactivity patterns and minimising undesired side reactions.

The compound has been applied predominantly as an intermediate in the development of biologically active molecules. Its incorporation into medicinal chemistry programs has been associated with work on experimental kinase inhibitors, anti inflammatory agents and central nervous system directed compounds. In such programs, the amino group has served as a handle for the introduction of a wide range of functional groups through acylation, sulfonylation and urea formation. These derivatisation strategies have allowed researchers to explore structure activity relationships by modifying steric bulk, polarity and hydrogen bonding capacity while retaining the beneficial attributes of the trifluoromethyl group. The consistent performance of the trifluoromethyl substituent in affecting metabolic stability and target affinity reinforced the value of this compound as a modular fragment.

Beyond medicinal chemistry, 4-amino-2-trifluoromethylpyridine has been used in agrochemical research. Investigations into the optimisation of heteroaromatic scaffolds for pesticidal applications incorporated it into synthetic sequences aimed at generating herbicidal and fungicidal candidates. In these applications, the compound has functioned as a precursor to heteroaromatic structures that were subsequently evaluated for activity in field and laboratory trials. The selection of trifluoromethyl substituted pyridines for agrochemical research reflected the long standing recognition that fluorinated heterocycles often possess favourable environmental stability and bioavailability properties.

Analytical studies of 4-amino-2-trifluoromethylpyridine have included work on its spectroscopic identification, purity assessment and stability evaluation. Investigations have examined its integrity under manufacturing and storage conditions, including the potential for minor decomposition under prolonged exposure to elevated temperatures, humidity and light. Findings from these studies have supported its suitability for multi step synthetic processes provided standard handling and storage practices are observed.

Process development activities involving 4-amino-2-trifluoromethylpyridine have explored methods to improve reaction efficiency, purification and isolation. These efforts included optimisation of crystallisation conditions, solvent selection and filtration procedures. The goals of such work were to increase yield, reduce impurities and ensure batch to batch consistency in pharmaceutical and agrochemical research settings. The compound has also appeared in patent literature describing diversified heterocyclic synthesis strategies. In these disclosures it is often positioned early in multi step synthetic schemes due to its capacity to introduce key substituents into target structures.

Overall, 4-amino-2-trifluoromethylpyridine has maintained a defined role as a versatile intermediate. Its discovery in early efforts to access fluorinated heterocycles laid the foundations for its use in research programs concerned with developing pharmacologically and agriculturally relevant compounds. Its continued application reflects the enduring utility of the trifluoromethyl group in modifying the behaviour of heteroaromatic rings and the adaptability of the amino function in enabling productive downstream chemistry.

References

Ojima I (2009) Fluorine in medicinal chemistry and chemical biology. Wiley-Blackwell Chichester pp 1–33 DOI: 10.1002/9781444312096

Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA (2015) Applications of fluorine in medicinal chemistry. Journal of Medicinal Chemistry 58 21 8315–8359 DOI: 10.1021/acs.jmedchem.5b00258

Inoue M, Sumii Y, Shibata N (2020) Contribution of organofluorine compounds to pharmaceuticals. ACS Omega 5 19 10633–10640 DOI: 10.1021/acsomega.0c00830