1-Methyl-4-piperidinemethanol CAS 20691-89-8

1-Methyl-4-piperidinemethanol, also known as 4-(hydroxymethyl)-1-methylpiperidine, is an important heterocyclic alcohol with a wide range of applications in the chemical and pharmaceutical industries.

This compound features a piperidine ring substituted with a methyl group at the nitrogen atom and a hydroxymethyl group at the 4-position. The combination of these functional groups offers it unique reactivity and biological activity.

In the chemical industry, it serves as a key intermediate for the synthesis of various derivatives, including pharmaceuticals, agrochemicals, and polymers. Its alcohol group can be readily modified through esterification, etherification, or other chemical reactions to produce a diverse range of compounds.

Furthermore, 1-Methyl-4-piperidinemethanol exhibits potential pharmacological properties, such as anti-inflammatory and neuroprotective activities, making it an attractive target for further drug development research. Due to its unique structure and versatile reactivity, which holds great promise for future applications in the fields of medicine and chemistry.

1. Pharmaceutical Industry

 

Intermediate in Drug Synthesis: Serving as an intermediate in the synthesis of various pharmaceutical compounds. Due to its specific chemical structure, it may be used to create molecules that have therapeutic effects on certain diseases.

Active Pharmaceutical Ingredient (API) or Excipient: Depending on its properties and regulatory approvals, it could potentially be used directly as an active ingredient or as an excipient in pharmaceutical formulations.

 

2. Chemical Industry

 

Solvent and Reagent: It may be used as a solvent or reagent in chemical reactions due to its polar nature and ability to dissolve certain compounds.

Synthesis of Polymers and Surfactants: The hydroxyl and piperidine groups in it can be used to synthesize polymers or surfactants with specific properties, such as improved solubility, stability, or surface activity.

3. Material Science

 

Modifier for Polymers: By incorporating it into polymer matrices, it can modify the physical and chemical properties of the polymers, such as their flexibility, strength, or thermal stability.

Coating Agent: It may be used as a component in coating formulations to improve adhesion, durability, or other coating properties.

 

 

4. Research and Development

 

Starting Material for Research: As a versatile chemical compound, it can serve as a starting material for research into new chemical entities, reactions, or processes.

Probe for Biological Studies: Its unique structure and properties may make it a useful probe for studying biological systems, such as protein-ligand interactions or cell signaling pathways.

Excipients are essential components in pharmaceutical formulations, playing crucial roles in the development, stability, and delivery of active pharmaceutical ingredients (APIs). These inactive substances are meticulously chosen to enhance the performance, safety, and patient acceptability of medications. They can be broadly classified into several categories based on their functionalities.

Diluents, such as lactose, mannitol, and cellulose, are used to bulk up the formulation, allowing for accurate dosing. Binders like gelatin, acacia, and polyvinyl pyrrolidone (PVP) help in the formation of a cohesive mass, ensuring tablets remain intact during manufacturing and handling. Lubricants such as magnesium stearate and talc facilitate the ease of tablet compression and ejection from machinery, reducing friction.

Disintegrants like croscarmellose sodium and starches ensure rapid breakup of tablets or capsules in the gastrointestinal tract, aiding rapid drug release. Coatings, which can be sugar, film-forming polymers, or enteric coatings, serve to mask taste, improve appearance, enhance stability, or ensure drug release at a specific site in the gut.

A coating agent, also commonly referred to as a coating material or paint, is a vital substance utilized across various industries for protective, decorative, and functional purposes. It primarily consists of a resin or binder, pigments, additives, and solvents, each component playing a crucial role in determining the final properties of the coated surface.

The resin or binder serves as the backbone, adhering to the substrate and holding the pigments in place. Pigments provide color and opacity, while additives can enhance durability, flow, and resistance to uv rays, chemicals, or water. Solvents facilitate the application process by thinning the coating to the desired consistency, ensuring even coverage.

Coating agents are applied through methods such as brushing, rolling, dipping, spraying, or electrocoating, tailored to the specific requirements of the substrate and desired finish. They find extensive applications in automotive, aerospace, marine, construction, furniture, and electronic industries, among others.

In automotive manufacturing, they protect against corrosion, enhance aesthetics, and improve fuel efficiency through reflective properties. Aerospace coatings ensure durability and thermal resistance in extreme environments. Marine coatings safeguard against harsh saltwater conditions. Construction coatings provide weatherproofing and insulation.

 

 

 

Innovations in coating agents, such as the development of eco-friendly, water-based, and powder coatings, are driving the industry towards sustainability. These advancements not only minimize environmental impact but also offer enhanced performance and cost-effectiveness. Overall, coating agents are indispensable in modern manufacturing, contributing significantly to product durability, aesthetics, and functionality.

1-Methylpiperidine-4-carboxylic acid ethyl ester (78 g) was dissolved in methanol (1.2 L) at room temperature, then formaldehyde (37%, 90 ml) and acetic acid (42 ml) were added and stirred for 2 hours, the mixture was cooled to 0°C, NaCNBH3 (70 g) was added, the mixture was stirred at 0°C for 20 minutes, and then reacted at room temperature overnight. The mixture was cooled to 0°C and then quenched with 6NNaOH. The mixture was concentrated in vacuo to an aqueous layer, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo to obtain 1-methylpiperidin-4-yl)-methanol.

Synthetic Method Optimization: Efforts will likely be directed towards developing more efficient and eco-friendly synthetic routes for 1-Methyl-4-piperidinemethanol. This includes exploring greener solvents, catalysts, and reducing waste generation during production.

Property Enhancement: Researchers may aim to enhance the physical and chemical properties of it, such as improving its thermal stability, solubility, and resistance to degradation. This could broaden its application scope in various industries.

Biological and Pharmaceutical Applications: Given its structural similarity to certain pharmacological agents, further investigation into the biological activities and potential therapeutic uses may yield promising results. This could lead to the development of new pharmaceuticals or drug candidates.

Material Science Integration: Exploring the use as a component in advanced materials, such as polymers, composites, or coatings, may offer unique properties and performance enhancements.

Environmental and Safety Assessment: Comprehensive environmental and safety assessments will be crucial to ensure that any new applications or production methods for 1-Methyl-4-piperidinemethanol comply with regulatory standards and minimize risks to human health and the environment.

1-Methyl-4-piperidinemethanol (CAS number 20691-89-8) is an important organic synthetic intermediate with the molecular formula C ₇ H ₁ NO, molecular weight 129.2 g/mol, and is a colorless to pale yellow viscous liquid at room temperature. This compound is widely used in drug synthesis, such as as as a key intermediate for antidepressants, antipsychotics, and analgesics. Its purity directly affects the yield and quality of downstream products, so it is necessary to achieve high-purity separation through multi-step chromatographic purification technology.

Typical synthetic pathways

 

The synthesis of 1-Methyl-4-piperidinemethanol usually starts with 1-methylpiperidine-4-carboxylic acid ethyl ester as the precursor, and introduces a hydroxymethyl group through a reduction reaction. For example, under the action of lithium aluminum hydride (LiAlH ₄) or sodium borohydride (NaBH ₄), the ester group is reduced to a hydroxymethyl group, and the reaction equation is as follows:
Reaction formula 1:1- Methylpiperidine-4-carboxylic acid ethyl ester+LiAlH ₄ → 1-Methyll-4-piperidinemethanol+ethanol+alumina byproduct

Sources and Classification of Impurities

 

Organic impurities: unreacted esters (such as ethyl 1-methylpiperidine-4-carboxylate), reducing agent residues (such as LiAlH ₄ hydrolysis product Al (OH) ∝), solvents (such as THF, methanol), and side reaction products (such as 1-methylpiperidine-4-carboxaldehyde).
Inorganic impurities: metal salts (such as LiCl, NaCl), catalyst residues (such as Pd/C, Ni catalysts), and inorganic acids (such as HCl).
Structural analogues: positional isomers such as 1-methylpiperidine-3-methanol and 1-methylpiperidine-2-methanol.

Impurities pose a challenge to purification

 

Small polarity difference: The target product has similar polarity to some impurities (such as positional isomers), making it difficult to separate using conventional chromatography columns.
Poor thermal stability: oxidation or dehydration reactions are prone to occur at high temperatures, requiring low-temperature operation.
Solubility limitation: The solubility is high in common solvents such as ethyl acetate and methanol, and the elution system needs to be optimized.

Post treatment of reaction solution

 

Quenching reaction: Slowly add water or dilute hydrochloric acid to the reaction solution to terminate the reduction reaction and avoid excessive reduction. For example, after the reduction of LiAlH ₄, a mixture of THF/water (1:1) needs to be added dropwise at 0 ℃ to prevent severe heat release.
Solid liquid separation: Removing inorganic salts (such as LiCl) and catalyst residues through filtration or centrifugation. For example, the use of diatomite pad filtration can remove Al (OH) ∨ gel.
Solvent displacement: After concentrating the reaction solution, extract the organic phase with ethyl acetate or dichloromethane, and then wash with saturated saline solution to remove water-soluble impurities.

Purification of crude products

 

Recrystallization: Dissolve the crude product in hot ethanol, slowly cool to room temperature, and precipitate crystals. For example, the solubility of 1-Methyl-4-piperidinemethanol in ethanol significantly decreases with decreasing temperature, which can remove some polar impurities.
Liquid liquid extraction: Separation is achieved by utilizing the difference in distribution coefficients between the target product and impurities in different solvents. For example, extraction with n-hexane/ethyl acetate (v/v=3:1) can remove some non-polar impurities.

Step 1: Positive phase silica gel chromatography

 

Purpose: To remove impurities with significant polarity differences, such as unreacted esters and inorganic salts.
Fixed phase: 200-300 mesh silicone gel, column diameter: column length=1:10.
Mobile phase: gradient elution of petroleum ether/ethyl acetate (v/v=3:1 → 1:1).
Detection method: TLC (thin layer chromatography) monitoring, with Rf value of 0.3-0.5 as the target product.

Key points:
Silica gel needs to be activated (baked at 110 ℃ for 2 hours) to remove moisture and improve separation efficiency.
The elution rate should be controlled at 1-2 mL/min to avoid peak broadening.
Result: The purity of the crude product increased from 60% to 85%, with a recovery rate of 80% -85%.

Step 2: Reversed phase high performance liquid chromatography

 

Objective: To separate isomers with similar polarity (such as 1-methylpiperidine-3-methanol).
Fixed phase: C18 chromatographic column (5 μ m, 250 × 4.6 mm).
Mobile phase: Acetonitrile/water (v/v=60:40) isocratic elution, pH adjusted with 0.1% TFA (trifluoroacetic acid).
Detection method: UV detector (λ=254 nm).

Key points:
The mobile phase needs to be degassed (by ultrasound or nitrogen purging) to avoid bubble interference.
Control the column temperature at 25 ℃ to reduce the impact of temperature on retention time.
Result: The purity increased from 85% to 98%, with a recovery rate of 75% -80%.

Step 3: Preparation type high-performance liquid chromatography

 

Objective: To prepare high-purity target products (≥ 99.5%) on a large scale.
Fixed phase: C18 preparation column (10 μ m, 250 × 21.2 mm).
Mobile phase: acetonitrile/water (v/v=70:30), flow rate 20 mL/min.
Collection method: Peak cutting collection, with a sample injection volume of 50-100 mg per needle.

Key points:
Pre equilibration of the chromatographic column is required (mobile phase rinse for 30 minutes).
The collected liquid needs to be concentrated to dryness to avoid solvent residue.
Result: The purity of a single preparation is ≥ 99.5%, and the recovery rate is 70% -75%.

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