2-Chloro-4-pivalamidonicotinic Acid: Properties & Applications

2-Chloro-4-pivalamidonicotinic acid is a halogenated, amide-functionalized pyridine-carboxylic acid that serves as a versatile synthetic building block for the preparation of pharmaceutical intermediates and biologically active heterocyclic compounds.

Chemical Name

2-Chloro-4-pivalamidonicotinic acid

SKU

C165490

Core Scaffold

Pyridine-3-carboxylic acid (nicotinic acid) with C-2 chloro and C-4 pivalamido substituents

Functional Groups

Carboxylic acid, pivalamido (tertiary amide), aryl chloride

Compound Class

Halogenated heteroaromatic carboxylic acid

Primary Use

Pharmaceutical synthesis intermediate and research reagent

Chemical Structure and Key Structural Features

2-Chloro-4-pivalamidonicotinic acid is built on a pyridine-3-carboxylic acid (nicotinic acid) core. Three distinct structural modifications differentiate it from the parent scaffold:

• C-2 Chloro substituent: An aryl chloride at the 2-position of the pyridine ring activates the ring toward nucleophilic aromatic substitution (SNAr) reactions, providing a site for further diversification through coupling chemistry or displacement reactions.
• C-4 Pivalamido group: A tert-butyl carbonyl amide (pivalamido) at the 4-position introduces steric bulk and acts as a directing/protecting group for the amine nitrogen. The pivalamido (trimethylacetamido) moiety is widely used in medicinal chemistry as a protecting group for primary amines because it is stable under many reaction conditions yet removable under acidic or basic hydrolysis.
• C-3 Carboxylic acid: The free carboxylic acid enables amide coupling reactions, esterification, and serves as a handle for further elaboration of the molecular framework.

Together, these three orthogonal reactive handles make 2-Chloro-4-pivalamidonicotinic acid a synthetically rich starting material for convergent multi-step synthesis.

Role as a Pharmaceutical Intermediate

Substituted nicotinic acid derivatives are extensively represented in drug discovery pipelines and approved pharmaceuticals. The pyridine ring is a privileged scaffold in medicinal chemistry owing to its metabolic stability, favorable aqueous solubility relative to benzene analogues, and capacity to engage in hydrogen-bonding interactions with biological targets.

2-Chloro-4-pivalamidonicotinic acid combines several attributes that are valued in drug discovery:

• The C-2 chloride can be displaced by amines, alcohols, or organometallic reagents (e.g., via Buchwald-Hartwig, Suzuki-Miyaura, or Ullmann-type coupling conditions) to produce a diverse library of analogues in a single transformation.
• After constructing the desired core, the pivalamido group can be hydrolyzed to reveal a free amine at C-4, which may be reacted further or tested directly in biological assays.
• The carboxylic acid at C-3 is amenable to standard peptide-coupling reagents (HATU, EDC, DCC) for attachment to amines, enabling rapid generation of amide libraries.

This combination of reactivity and selectivity is particularly relevant for the synthesis of kinase inhibitors, antiviral agents, and other target classes in which substituted azine carboxylic acids appear as key pharmacophoric elements.

Handling, Storage, and Safety Considerations

As with most halogenated aromatic carboxylic acids and amide reagents, standard laboratory safety practices should be observed when working with 2-Chloro-4-pivalamidonicotinic acid:

• Personal Protective Equipment (PPE): Use appropriate gloves (nitrile or equivalent), safety glasses, and a lab coat. Work in a well-ventilated area or fume hood to avoid inhalation of dust or aerosols.
• Storage: Store in a tightly sealed container in a cool, dry location away from incompatible materials such as strong oxidizers, strong bases, and strong acids. Consult the product-specific Safety Data Sheet (SDS) for detailed storage temperature recommendations.
• Disposal: Dispose of waste in accordance with local, regional, and national regulations governing halogenated organic waste streams.
• Stability: The pivalamido group is generally robust under ambient conditions; however, prolonged exposure to strongly acidic or basic aqueous conditions may lead to hydrolysis. Keep the reagent dry to preserve purity.

Always consult the current SDS provided by Aladdin Scientific (SKU C165490) before use for the most authoritative hazard and handling information.

Purity, Specifications, and Quality Assurance

Research reproducibility depends critically on reagent quality. Aladdin Scientific supplies 2-Chloro-4-pivalamidonicotinic acid (SKU C165490) as a research-grade reagent. Key specification considerations for end users include:

• Purity assessment: High-performance liquid chromatography (HPLC) is the standard method for assessing purity of this class of compound. Users should confirm the purity certificate provided with each lot prior to use in critical assays or scale-up reactions.
• Structural confirmation: Nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS) are definitive tools for confirming the identity and structural integrity of 2-Chloro-4-pivalamidonicotinic acid.
• Lot-to-lot consistency: For regulated research (e.g., IND-enabling studies), verify lot-specific Certificates of Analysis (CoA) to ensure consistency across experiments.
• Moisture sensitivity: Carboxylic acids can absorb moisture. Weighing should be performed promptly, and unused material should be resealed immediately.

For specific purity grades, available quantities, and current pricing, please contact Aladdin Scientific directly or visit the product page for SKU C165490.

Frequently asked questions

What reactions can be performed using the carboxylic acid group of 2-Chloro-4-pivalamidonicotinic acid?

The free carboxylic acid at the 3-position can participate in amide bond-forming reactions using standard coupling reagents such as HATU, EDC, or DCC, enabling attachment to primary or secondary amines. It can also be converted to esters, acid chlorides, or reduced to the corresponding alcohol, providing multiple options for molecular elaboration.

How can the C-2 chloro group be utilized in cross-coupling chemistry?

The aryl chloride at C-2 is competent for palladium-catalyzed cross-coupling reactions, including Suzuki-Miyaura (with aryl boronic acids), Buchwald-Hartwig (with amines), and Negishi couplings (with organozinc reagents). It can also be displaced by nucleophiles under SNAr conditions when the pyridine ring is sufficiently electron-deficient.

How is the pivalamido protecting group removed to reveal the free amine?

The pivalamido group is typically cleaved by hydrolysis under acidic conditions (e.g., concentrated HCl or H2SO4 in water or aqueous dioxane) or under strongly basic conditions (e.g., KOH or NaOH in aqueous alcohol at elevated temperature). The bulky tert-butyl group makes it more resistant to hydrolysis than acetamide, so forcing conditions may be required.

What storage conditions are recommended for 2-Chloro-4-pivalamidonicotinic acid?

The compound should be stored in a tightly closed container in a cool, dry environment away from strong oxidizers, strong acids, and strong bases. Consult the Aladdin Scientific Certificate of Analysis and Safety Data Sheet (SKU C165490) for lot-specific recommended storage temperatures.

Is 2-Chloro-4-pivalamidonicotinic acid suitable for use as a kinase inhibitor intermediate?

The substituted nicotinic acid scaffold is well-represented among kinase inhibitor pharmacophores. The orthogonal reactive handles on this compound—aryl chloride, pivalamido, and carboxylic acid—allow efficient construction of diversified analogues relevant to kinase inhibitor programs. However, specific biological activity data for this compound itself should be verified in primary literature or internal assay data before proceeding.

References

1. Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822–5880. (General reference on pyridine-based medicinal chemistry scaffolds.) doi:10.1021/acs.jmedchem.8b00035
2. Roughley, S. D.; Jordan, A. M. The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451–3479. (Covers amide coupling and cross-coupling reactions as key synthetic transformations.) doi:10.1021/jm200187y
3. Aladdin Scientific Product Page: 2-Chloro-4-pivalamidonicotinic acid, SKU C165490. (Primary source for product specifications and safety information.)

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.