4-Picolinic acid methyl ester – better known in purchasing departments as methyl isonicotinate and in the lab as methyl pyridine-4-carboxylate – is a small molecule with an outsized industrial role. It is the ester that turns into isoniazid, one of the four first-line antitubercular drugs, and it is the entry point to most of the pyridine-4-carboxamide family.
This guide covers what the compound is (CAS 2459-09-8), how it is produced, what the purity and water specifications actually protect against, the main synthetic routes out of it, and how to handle and store an ester that quietly hydrolyses if you let it.
What Is 4-Picolinic Acid Methyl Ester?
The molecule is a pyridine ring with a methyl ester at the 4-position, opposite the nitrogen. “Picolinic acid” is the historic name for pyridine-2-carboxylic acid and “isonicotinic acid” for the 4-isomer; the naming in this family is inconsistent across suppliers, which is why buying on CAS number rather than on name is the only safe approach.
At room temperature it is a colourless to light yellow liquid with a pyridine-type odour. It is miscible with most organic solvents and only sparingly soluble in water – a useful property, because it means the ester can be extracted from an aqueous reaction mass without excessive loss, while also meaning that any water present in the drum will slowly hydrolyse it at the interface.
Chemical Identity: CAS 2459-09-8
| Item | Detail |
|---|---|
| Chemical name | Methyl pyridine-4-carboxylate |
| Synonyms | Methyl isonicotinate; isonicotinic acid methyl ester; 4-picolinic acid methyl ester; 4-(methoxycarbonyl)pyridine |
| CAS Registry Number | 2459-09-8 |
| Chemical class | Heteroaromatic carboxylate ester (pyridine-4-carboxylate) |
| Appearance | Colourless to light yellow liquid |
| Purity (GC) | Min 98% |
| Water | Max 0.5% |
| Principal use | Pharmaceutical and agrochemical intermediate |
Note the naming trap: suppliers list this product as methyl isonicotinate, methyl 4-pyridinecarboxylate, 4-carbomethoxypyridine and 4-picolinic acid methyl ester – all the same CAS. Conversely, “methyl picolinate” without a positional number usually means the 2-isomer, a different compound with different reactivity. Confirm the CAS number on every quotation rather than trusting the name.
How It Is Produced
Two routes dominate industrial supply:
- Esterification of isonicotinic acid. Isonicotinic acid is dissolved or suspended in methanol with an acid catalyst (sulfuric acid, methanesulfonic acid or a solid acid resin) and refluxed; water is removed azeotropically to drive the equilibrium. The ester is then neutralised, washed and distilled. This is the standard route and the reason isonicotinic acid availability sets the market price of the ester.
- Alcoholysis of 4-cyanopyridine. 4-Cyanopyridine is treated with methanol and an acid or base to give the ester directly, with ammonia as the leaving group. This route is attractive where 4-cyanopyridine is cheap, and it is also used to make the corresponding amide under milder conditions.
Both routes converge on the same purification step – vacuum distillation – and both leave the same two specification parameters that buyers should watch: assay (unreacted acid or starting nitrile) and water.
Specifications and What They Protect
| Specification | Why it exists |
|---|---|
| Appearance: colourless to light yellow liquid | Colour drift indicates oxidation or iron contamination; darker lots often carry more acid |
| Purity min 98% (GC) | The remaining percent is typically isonicotinic acid, methanol or a positional isomer – all of which change the stoichiometry of the downstream reaction |
| Water max 0.5% | Hydrolysis control. Water converts ester back to acid, consumes hydrazine in the next step and shifts the assay |
The water figure deserves emphasis because it is the specification most often ignored in incoming inspection. A drum at 0.8% water is not “slightly wet”: it has already lost part of its active content, and the loss continues at the rate the storage temperature allows.
Reactions and Downstream Products
To isoniazid (isonicotinyl hydrazide)
The dominant use. The ester reacts with hydrazine hydrate in alcohol to give the hydrazide, which precipitates and is isolated by filtration. The reaction is fast and clean, which is why the ester route has stayed the industrial standard rather than being displaced by acid-chloride chemistry – it avoids thionyl chloride and the associated waste stream.
To isonicotinamide and N-substituted amides
Ammonia or primary amines convert the ester to the amide under mild conditions. Isonicotinamide and its derivatives are used as intermediates in their own right and as ligands.
To isonicotinic acid
Hydrolysis, deliberate or accidental, returns the acid. Deliberate hydrolysis is a normal production step when the acid is the target; accidental hydrolysis is the main storage failure mode.
To substituted pyridines
The pyridine nitrogen and the ester group can be functionalised independently – N-oxidation, alkylation, or Grignard addition to the ester – giving access to a wide range of 4-substituted pyridines used in agrochemicals and ligands.
Sourcing, Price Drivers and Supply Chain
Methyl isonicotinate is a second-tier intermediate: it is made from isonicotinic acid, which is itself made by oxidation of 4-methylpyridine or 4-cyanopyridine. That structure of the value chain explains most of the commercial behaviour of the product.
| Driver | Effect on the ester |
|---|---|
| Isonicotinic acid availability | Sets the floor price; a shortage of the acid moves the ester within weeks |
| Methanol cost and logistics | Minor on cost, significant on packaging and transport classification |
| Demand from antitubercular manufacturing | Isoniazid is a public-health commodity, so demand is large, stable and price-sensitive rather than cyclical |
| Environmental restrictions on chlorinated routes | Structural tailwind – ester chemistry replaces acid-chloride chemistry in more processes each year |
| Producer concentration | Supply comes from a limited number of fine-chemical producers, mostly in Asia; single-source dependence is a real procurement risk |
For procurement, three points matter more than the invoice price:
- Qualify two sources. The molecule is simple, but the impurity profile differs between producers and can change downstream crystallisation behaviour.
- Specify water and acid content, not only assay. Two lots both at 98% can behave differently if one carries 1.5% isonicotinic acid.
- Check the packaging grade. Esters shipped in reused drums occasionally pick up acidic residues that catalyse hydrolysis; new liners or dedicated containers avoid that.
Analytical Methods
Whether you are qualifying a supplier or monitoring a reaction, four methods cover the molecule:
| Method | Measured | Notes |
|---|---|---|
| GC with FID | Assay and organic impurities | Separates the 4-isomer from positional isomers; the standard release test |
| Karl Fischer titration | Water | The hydrolysis indicator; run on arrival as well as on release |
| Acid-base titration | Free isonicotinic acid | Fast, cheap, and the best single indicator of storage degradation |
| HPLC (reverse phase) | Trace impurities and downstream hydrazide purity | Used for the isoniazid step rather than for the ester itself |
A practical screening sequence on arrival: appearance, water by Karl Fischer, then assay. If water is out of specification, stand the drum aside and requalify rather than blending it into production – the acid content will follow.
Applications
| Sector | Role of the ester |
|---|---|
| Pharmaceutical intermediates | Hydrazide and amide synthesis; the isoniazid supply chain |
| Agrochemical intermediates | Pyridine-4-carboxamide and substituted pyridine herbicides/fungicides |
| Coordination chemistry | Ligand synthesis; pyridine-4-carboxylate linkers in MOF work |
| Fine chemicals | Building block for functional pyridines and quaternary pyridinium salts |
Documentation for Pharmaceutical Customers
Buyers in the pharmaceutical supply chain usually need more than a standard COA. The four documents asked for most often on this product are:
| Document | What it covers | When it matters |
|---|---|---|
| Residual solvent statement | Solvents used in manufacture, classified against ICH Q3C | Methanol and any esterification solvent must be declared if the intermediate enters a regulated process |
| Elemental impurity statement | Metal content against ICH Q3D risk assessment | Equipment contact and catalyst residues; relevant when the ester feeds an API step |
| TSE / BSE and allergen statement | Absence of animal-derived material | Standard requirement in most pharmaceutical vendor qualification packs |
| Impurity profile / method summary | Identified impurities and the analytical methods used | Needed to set specifications on the downstream hydrazide or amide |
An important distinction for buyers: this product is supplied as an industrial / fine-chemical grade with a standard COA. If your process requires a GMP-declared grade with a formal regulatory starting-material package, say so at enquiry stage – the documentation scope is agreed per market and per intended use rather than assumed from a generic datasheet.
Quality Control and Incoming Inspection
Three tests cover the specification, and a fourth catches the most common problem:
- Assay by GC – confirms the 98% minimum and flags positional isomers, which co-elute differently from the 4-isomer.
- Water by Karl Fischer – the hydrolysis marker; test on arrival, not only on manufacture.
- Appearance and colour – a simple visual check that catches oxidation and metal contamination.
- Acid content (titration) – not always on the datasheet, but the fastest way to know how much of the batch has already hydrolysed.
Handling and Storage
| Item | Practice |
|---|---|
| Containers | Stainless steel or HDPE; keep sealed and headspace dry |
| Temperature | Ambient storage is adequate; avoid hot locations, which accelerate hydrolysis and colour drift |
| Moisture | Use dry equipment when transferring; do not leave drums open in humid weather |
| Incompatibility | Strong acids and bases (hydrolysis), strong oxidisers (ring oxidation) |
| Personal protection | Gloves, eye protection, local exhaust ventilation – the odour is a useful warning at low concentrations |
| Shelf life | Re-test water and assay if a drum has been open or stored warm for an extended period |
Packaging and Supply
| Item | Detail |
|---|---|
| Standard pack | 200 kg drum (PE or stainless steel) |
| Bulk pack | 1000 kg IBC on request |
| Documents | COA per batch (appearance, assay, water), SDS in English, packing list, shipping documents |
| Samples | Available for route development and analytical method work |
Frequently Asked Questions
Is 4-picolinic acid methyl ester the same as methyl picolinate? Not necessarily. “Methyl picolinate” alone usually means the 2-isomer. This product is the 4-isomer, CAS 2459-09-8.
What purity do I need for hydrazide synthesis? 98% min with water below 0.5% is the standard starting point; the hydrazine charge is calculated on the actual assay, so a lot at 96% will under-react if you use the nominal figure.
Can it be shipped as a non-hazardous product? Classification depends on the current SDS and on the destination’s transport rules; documentation is provided per shipment rather than assumed.
How does it compare with the acid chloride route? The ester route avoids thionyl chloride handling and the associated acidic waste, at the cost of a slightly higher molecular weight per reactive group.
Is it suitable for pharmaceutical use? The product is supplied as an industrial/fine-chemical grade with a standard COA; additional documentation for pharmaceutical use is arranged at enquiry stage for the specific market.
Contact PolyBlueChem for specifications, samples, COA and quotations.