2-Chloro-5-methoxypyridin-3-amine: Handling & Use Protocol

2-Chloro-5-methoxypyridin-3-amine is a halogenated aminopyridine building block widely employed as a versatile synthetic intermediate in medicinal chemistry and heterocyclic synthesis.

CAS / SKU

C194754 (Aladdin SKU); confirm CAS with certificate of analysis

Molecular Formula

C₆H₇ClN₂O

Molecular Weight

158.58 g/mol

Key Functional Groups

Primary aromatic amine (–NH₂), aryl chloride (C–Cl), methoxy ether (–OCH₃)

Recommended Storage

Cool, dry, dark conditions; store under inert atmosphere if opened; confirm exact conditions on product label

Typical Applications

Palladium-catalysed cross-coupling (Buchwald–Hartwig, Suzuki), SNAr reactions, pharmaceutical intermediate synthesis

Materials and Safety Precautions

Before working with 2-Chloro-5-methoxypyridin-3-amine (Aladdin SKU: C194754), consult the Safety Data Sheet (SDS) supplied with the product. The compound contains a primary aromatic amine functionality, which may present irritant or sensitisation hazards; treat as potentially harmful until full hazard data are confirmed.

Personal Protective Equipment (PPE): Wear nitrile gloves, a laboratory coat, and safety goggles. Conduct all weighing and solution preparation in a well-ventilated fume hood.

Materials required:

• 2-Chloro-5-methoxypyridin-3-amine (C194754, Aladdin Scientific)
• Analytical balance (0.1 mg readability)
• Anhydrous solvents (DMSO, DMF, or DCM; see dissolution step below)
• Amber glass vials or screw-cap vessels for stock solutions
• Inert gas line (N₂ or Ar) for moisture-sensitive applications
• Appropriate waste containers for halogenated organic waste

Review flag: Specific GHS hazard classifications and LD₅₀ values should be verified against the official SDS before use; these are not included in the available source material.

Stock Solution Preparation

2-Chloro-5-methoxypyridin-3-amine is a solid at room temperature. Its primary amine and methoxy groups confer moderate polarity, making it soluble in polar aprotic solvents such as DMSO and DMF. It also dissolves in dichloromethane (DCM) and ethyl acetate. Aqueous solubility is limited; confirm solubility experimentally for your specific application.

Procedure:

1. Allow the sealed vial to equilibrate to room temperature before opening to avoid moisture condensation on the solid.
2. Accurately weigh the required mass of 2-Chloro-5-methoxypyridin-3-amine on a tared weighing paper or vessel using an analytical balance.
3. Transfer quantitatively to a clean, dry amber vial.
4. Add the appropriate volume of anhydrous DMSO (or DMF) to achieve the desired concentration (e.g., 100 mM for biological screening; adjust as needed for synthetic use).
5. Vortex or stir gently at room temperature until complete dissolution is confirmed by visual inspection.
6. If the solution will be used in palladium-catalysed reactions, prepare under an inert atmosphere (N₂ or Ar) using Schlenk technique or a glovebox as appropriate.
7. Label the vial with compound name, SKU, concentration, solvent, date of preparation, and preparer's initials.

Note: Concentration recommendations (e.g., 100 mM) are general guidance for aminopyridine building blocks; verify suitability for your specific protocol. Review flag: solubility data not confirmed in source material.

Synthetic Applications and Reaction Protocol

2-Chloro-5-methoxypyridin-3-amine offers three orthogonal sites for synthetic elaboration: (1) the aryl chloride at C-2 for transition-metal-catalysed cross-coupling or nucleophilic aromatic substitution (SNAr); (2) the primary amine at C-3 for acylation, sulfonylation, reductive amination, or condensation; and (3) the methoxy group at C-5, which can modulate electronic properties and may be demethylated under strong acidic or Lewis acid conditions.

General guidance for Buchwald–Hartwig amination (C–N coupling at C-2 aryl chloride):

1. Charge a dry Schlenk flask with 2-Chloro-5-methoxypyridin-3-amine (1.0 equiv), the desired amine coupling partner (1.1–1.5 equiv), palladium catalyst (e.g., Pd₂(dba)₃ or Pd(OAc)₂, 1–5 mol%), an appropriate phosphine ligand (e.g., BINAP, RuPhos, or XPhos, 2–10 mol%), and base (e.g., Cs₂CO₃ or K₃PO₄, 2.0 equiv).
2. Add anhydrous toluene or 1,4-dioxane as solvent under inert atmosphere.
3. Stir at 80–110 °C for 12–24 h; monitor by TLC or LC-MS.
4. Cool to room temperature, filter through Celite, and purify the crude product by column chromatography.

General guidance for SNAr at C-2:

1. Combine the substrate (1.0 equiv) with a nucleophile (1.2–2.0 equiv, e.g., alkoxide, thiolate, or amine) and base (K₂CO₃ or Et₃N) in DMF or NMP.
2. Heat at 60–120 °C depending on nucleophile reactivity; monitor by TLC or LC-MS.

Review flag: Specific catalyst loadings, temperatures, and yields are generalised from textbook knowledge for aryl chloride heterocycles and have not been validated experimentally for this exact substrate. Cite primary literature before use.

Quality Control and Analytical Characterisation

Confirm the identity and purity of 2-Chloro-5-methoxypyridin-3-amine (C194754) upon receipt and before use using standard analytical techniques:

• ¹H NMR: Expect signals consistent with two ring protons (pyridine H-4 and H-6), an –NH₂ doublet or broad singlet, and a methoxy singlet (~3.8 ppm). Confirm with the certificate of analysis (CoA).
• LC-MS / MS: Confirm molecular ion at m/z 159/161 (M+H)⁺ reflecting the ³⁵Cl/³⁷Cl isotope pattern characteristic of a monochloro compound.
• HPLC Purity: The product should meet the purity specification stated on the CoA (typically ≥95% or ≥97% for synthetic-grade reagents; confirm with the supplied CoA).
• Melting Point: Determine and compare against reported literature values; flag significant deviations.
• Karl Fischer Titration: For moisture-sensitive applications, verify residual water content is below acceptable limits.

Review flag: Exact NMR chemical shifts and melting point are not provided in the source material; these should be verified against the CoA and primary literature before inclusion in any regulatory document.

Storage, Stability, and Waste Disposal

Storage: Store 2-Chloro-5-methoxypyridin-3-amine in a tightly sealed container in a cool, dry, and dark environment. Re-seal under inert gas (N₂ or Ar) after each use to minimise exposure to atmospheric moisture and oxygen. Refer to the product label and CoA for the manufacturer-specified storage temperature.

Stability considerations: Aromatic amines can be susceptible to oxidation on prolonged storage. The aryl chloride is generally stable under ambient storage conditions but may undergo slow hydrolysis if exposed to water in the presence of acid or base. Inspect the solid for discolouration before use; discard if significant colour change is observed.

Waste disposal: Dispose of all waste containing 2-Chloro-5-methoxypyridin-3-amine and its solutions in accordance with local, national, and institutional regulations for halogenated organic waste. Do not pour solutions down the drain. Consult the SDS for specific disposal guidance.

Review flag: Specific stability data (e.g., shelf life under defined conditions) are not available in the source material; confirm with the product CoA or contact Aladdin Scientific technical support.

Frequently asked questions

What solvents are recommended for dissolving 2-Chloro-5-methoxypyridin-3-amine?

2-Chloro-5-methoxypyridin-3-amine dissolves well in polar aprotic solvents such as DMSO and DMF, and in common organic solvents including DCM and ethyl acetate. Aqueous solubility is expected to be limited due to the hydrophobic pyridine core; verify experimentally for your specific application.

Which functional group is most reactive in 2-Chloro-5-methoxypyridin-3-amine for synthetic coupling?

The aryl chloride at C-2 is the primary handle for palladium-catalysed cross-coupling reactions (e.g., Buchwald–Hartwig, Suzuki–Miyaura) and for SNAr reactions with appropriate nucleophiles. The C-3 primary amine provides an orthogonal site for acylation, sulfonylation, or condensation reactions, enabling sequential diversification of the scaffold.

How should I store 2-Chloro-5-methoxypyridin-3-amine to maintain its integrity?

Store the compound in a tightly sealed container under an inert atmosphere (N₂ or Ar) in a cool, dry, and dark location. Avoid prolonged exposure to air, moisture, and light, as aromatic amines can oxidise over time. Always refer to the specific storage conditions stated on the product label and Certificate of Analysis supplied by Aladdin Scientific.

What is the molecular weight of 2-Chloro-5-methoxypyridin-3-amine and how do I calculate the required mass for a 100 mM solution?

The molecular weight of 2-Chloro-5-methoxypyridin-3-amine (C₆H₇ClN₂O) is 158.58 g/mol. To prepare a 100 mM solution in 1 mL of solvent, dissolve 15.86 mg of the compound in 1 mL of the chosen solvent (e.g., DMSO). Scale proportionally for larger volumes.

Is 2-Chloro-5-methoxypyridin-3-amine suitable for use as a pharmaceutical intermediate?

Yes, aminochloropyridine scaffolds are widely used as intermediates in drug discovery and pharmaceutical synthesis. However, the product offered by Aladdin Scientific (C194754) is for research use only and is not intended for direct clinical or human use. Researchers should verify purity specifications on the CoA and carry out appropriate quality checks for their intended application.

References

1. Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed. 2012, 51, 5062–5085. doi:10.1002/anie.201107017
2. Hartwig, J. F. Palladium-catalyzed amination of aryl halides: Mechanism and rational catalyst design. Acc. Chem. Res. 1998, 31, 852–860. doi:10.1021/ar970109z
3. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (General reference for SNAr and heterocyclic chemistry.)

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