6-Amino-4-fluoronicotinonitrile
[CAS# 1708974-11-1]

Identification

• Classification: Organic raw materials >> Nitrile compound
• Name: 6-Amino-4-fluoronicotinonitrile
• Molecular Formula: C₆H₄FN₃
• Molecular Weight: 137.11
• CAS Registry Number: 1708974-11-1
• EC Number: 888-602-7
• SMILES: C1=C(C(=CN=C1N)C#N)F

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 302.7±42.0 ºC 760 mmHg (Calc.)^*
• Flash point: 136.9±27.9 ºC (Calc.)^*
• Index of refraction: 1.562 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS06 Danger
• Hazard Statements: H301-H311-H331
• Precautionary Statements: P261-P262-P264-P270-P271-P280-P301+P316-P302+P352-P304+P340-P316-P321-P330-P361+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Acute toxicity	Acute Tox.	3	H331
Acute toxicity	Acute Tox.	3	H311

• Transport Information: UN 3439

Discovory and Applicatios

The chemical substance 6-amino-4-fluoronicotinonitrile is a functionalized pyridine derivative, valued in organic chemistry as a key intermediate, particularly in pharmaceutical and agrochemical synthesis. Its discovery and applications are well-documented in the literature, rooted in the development of substituted pyridines and fluorinated heterocyclic chemistry.

The origins of this compound are linked to the study of pyridine derivatives, which have been explored since the 19th century for their presence in natural products and utility as synthetic scaffolds. Nicotinonitrile, a pyridine with a cyano group at the 3-position, has been a versatile building block since the early 20th century due to the reactivity of the nitrile group. The introduction of fluorine and amino groups to pyridine rings gained prominence in the mid-20th century, driven by the pharmaceutical industry’s need for electron-deficient, polar heterocycles. Fluorine, recognized for enhancing metabolic stability and lipophilicity, and amino groups, valued for their versatility in forming amides or heterocycles, were incorporated using advances in regioselective halogenation and amination techniques during the 1960s and 1970s. The specific placement of an amino group at the 6-position and fluorine at the 4-position of nicotinonitrile emerged in the late 20th century to create intermediates for bioactive molecules.

Synthetically, 6-amino-4-fluoronicotinonitrile is typically prepared through a multi-step process. A common route starts with 4,6-dichloronicotinonitrile, where the pyridine core and nitrile group are pre-installed. The 4-position is selectively fluorinated by nucleophilic aromatic substitution using a fluoride source, such as potassium fluoride, under controlled conditions. The 6-position is then aminated by reacting the chloro intermediate with ammonia or an amine equivalent, often under elevated temperature or catalytic conditions to ensure regioselectivity. Alternatively, the synthesis may begin with 4-fluoro-6-hydroxynicotinonitrile, where the hydroxyl group is converted to an amine via a Buchwald-Hartwig amination or a related transformation. These methods rely on well-established heterocyclic and fluorination chemistry protocols, ensuring high yields and purity.

The primary application of 6-amino-4-fluoronicotinonitrile is as a synthetic intermediate in pharmaceutical chemistry. The pyridine core is a privileged scaffold in drugs targeting cancer, inflammation, and infectious diseases, due to its ability to engage in hydrogen bonding and π-interactions. The 6-amino group serves as a handle for forming amides, amines, or heterocycles, while the 4-fluorine enhances metabolic stability and lipophilicity. The 3-cyano group is a versatile moiety, enabling hydrolysis to carboxylic acids, reduction to amines, or cyclization to form additional heterocycles. This compound is frequently used in the synthesis of kinase inhibitors, antimicrobial agents, and receptor modulators, where the combination of polar and electron-withdrawing groups optimizes pharmacokinetic properties and target affinity.

In addition to pharmaceuticals, the compound is employed in agrochemical synthesis, particularly for developing pesticides and herbicides, where fluorinated pyridines are valued for their bioactivity and environmental stability. In academic research, it serves as a model compound for studying regioselective functionalization, the electronic effects of fluorine and amino groups, and nitrile reactivity. Its synthesis has contributed to the refinement of fluorination and amination techniques.

The significance of 6-amino-4-fluoronicotinonitrile lies in its role as a multifunctional intermediate that combines the biological relevance of pyridine with the synthetic versatility of amino, fluoro, and cyano groups. Its development reflects progress in regioselective heterocyclic synthesis and fluorinated chemistry. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical, agrochemical, and chemical research.