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4-Hydroxy-3-methylpyridine is an organic compound with CAS 22280-02-0 and molecular formula C6H7NO. It is a white to light yellow solid, usually appearing slightly yellow. Stable at room temperature, but may decompose at high temperatures. This compound has weak alkalinity and can react with acids to form salts. It can be used to synthesize other types of ionic liquids, such as phosphorus containing ionic liquids, silicon containing ionic liquids, etc. These ionic liquids have special physical and chemical properties and applications, and have broad application prospects in fields such as materials science and catalytic science. The application in the synthesis of alkaloids is very important as it is an important organic compound that can serve as an intermediate for synthesizing various alkaloids. Alkaloids are a class of natural products that exist in plants, animals, and microorganisms, and have a wide range of physiological and pharmacological activities.
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Chemical Formula |
C6H7NO |
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Exact Mass |
109 |
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Molecular Weight |
109 |
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m/z |
109 (100.0%), 110 (6.5%) |
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Elemental Analysis |
C, 66.04; H, 6.47; N, 12.84; O, 14.66 |
4-hydroxy-3-methylpyridine (CAS number: 1121-19-3 or 22280-02-0) is an organic compound with a pyridine ring structure, with the molecular formula C6H7NO and a molecular weight of 109.13. This compound exhibits unique value in the field of alkaloid synthesis, as its hydroxyl and methyl substituents endow it with multiple functions as a synthetic intermediate, ligand, and structural modification unit.
1. Skeleton construction of pyridine alkaloids
It can participate in the construction of the core structure of complex pyridine alkaloids through the oxidation of hydroxyl groups or the transformation of methyl functional groups. For example:
Synthesis of nicotine alkaloids: Using them as raw materials, aldehyde groups are generated through hydroxyl oxidation, and then amino side chains can be introduced through reductive amination reaction, ultimately forming the pyridine ring skeleton of nicotine. This type of reaction has potential applications in the laboratory synthesis of tobacco alkaloids, such as nicotine and neonicotinoids.
Synthesis of pyridine indole alkaloids: Through the substitution reaction of hydroxyl groups with halogenated compounds, indole ring structures can be introduced to form pyridine indole skeletons. This type of structure is commonly found in the synthetic pathway of anti-tumor alkaloids, such as vinblastine.
2. Structural modification of alkaloid precursors
This compound can serve as a modification unit for alkaloid precursors, regulating the biological activity of target molecules through the stereoselective effect of methyl groups or the nucleophilicity of hydroxyl groups. For example:
Matrine alkaloid modification: In the synthesis of matrine, the condensation reaction between hydroxyl groups and the matrine skeleton can introduce methyl substituents to enhance its inhibitory activity on liver fibrosis cells. The experiment showed that the modified matrine derivative reduced the IC ₅₀ value of HSC-T6 cells by 30%.
Functionalization of tropane alkaloids: Using this substance as a ligand, it undergoes a transesterification reaction with the ester groups of tropane alkaloids (such as atropine) to generate M-cholinergic receptor antagonists with higher selectivity.
1. Transition metal catalyzed alkaloid synthesis
The pyridine ring nitrogen atom and hydroxyl oxygen atom can form stable coordination bonds with transition metals such as Pd and Cu, thereby serving as catalysts or ligands to participate in the synthesis of alkaloids. For example:
Suzuki coupling reaction: In the C-C bond construction of pyridine alkaloids, the modified palladium catalyst can increase the coupling reaction yield from 60% to 90%, and the catalyst can be recycled more than 5 times.
Asymmetric catalytic hydrogenation: Using it as a chiral ligand, a catalytic system can be formed with ruthenium complexes to achieve asymmetric hydrogenation of alkaloid precursors (such as alpha aminonitriles), producing products with chiral purity>99%.
2. Redox catalysis in alkaloid synthesis
This compound can also serve as a catalyst or electron transfer medium for redox reactions. For example:
Alkaloid Oxidative Dehydrogenation: Under the 4-hydroxy-3-methylpyridine/Cu (II) catalytic system, the methyl dehydrogenation reaction rate of terpenoid alkaloids (such as aconitine) is doubled, and the selectivity is greater than 95%.
Alkaloid reductive amination: Using this substance as a hydrogen donor, it can be complexed with palladium nanoparticles to achieve efficient reductive amination of ketone alkaloid precursors, resulting in an 85% yield of amino alkaloids (such as quinine).
1. Functionalization reaction of hydroxyl groups
The hydroxyl group of 4-hydroxy-3-picoline can be introduced into different functional groups through esterification, etherification, or sulfonation reactions, thereby regulating the solubility, membrane permeability, or target binding ability of alkaloids. For example:
Esterification modification enhances lipid solubility: converting hydroxyl groups to acetoxy groups can significantly improve the ability of alkaloids (such as reserpine) to pass through the blood-brain barrier, doubling their inhibitory effect on the central nervous system.
Sulfonation modification improves water solubility: By reacting hydroxyl groups with sulfonyl chloride, water-soluble alkaloid derivatives can be generated, which are suitable for injectable development.
2. Stereoscopic effect regulation of methyl
The steric hindrance of methyl substituents can affect the binding mode between alkaloids and targets. For example:
Optimization of anti-tumor alkaloids: In the synthesis of camptothecin alkaloids, the introduction of a methyl substituent of 4-hydroxy-3-picoline can adjust the binding angle between the molecule and DNA topoisomerase I, reducing the IC50 value by 50%.
Enhancement of antibacterial alkaloid activity: Through the steric hindrance effect of methyl groups, the interaction between alkaloids (such as berberine) and bacterial cell membranes can be optimized, reducing their MIC values against drug-resistant strains by three dilutions.
1. Simulation synthesis of natural alkaloids
Can be used as a key intermediate to simulate the synthetic pathway of natural alkaloids. For example:
Simulated synthesis of lycorine alkaloids: Using 4-hydroxy-3-picoline as the raw material, the isoquinoline skeleton of lycorine alkaloids can be constructed through oxidation and cyclization reactions of hydroxyl groups, with a total yield of 40%.
Simulation synthesis of ergometrine: Aldehyde groups are generated through the oxidation of methyl groups, and then the indolo-pyridine structure of ergometrine can be synthesized through Pictet Spengler reaction.
2. Design of alkaloid analogues
This compound can also be used to design alkaloid analogues with new structures. For example:
Anti Alzheimer's disease alkaloid analogues: Using this substance as a template, analogues with acetylcholinesterase inhibitory activity can be generated through the condensation reaction of hydroxyl groups with choline, with an IC ₅₀ value of 0.5 μ M.
Antiviral alkaloid analogues: By introducing fluorine atoms through the halogenation reaction of methyl groups, analogues with inhibitory activity against HIV reverse transcriptase can be generated, with an EC ₅₀ value of 2 μ M.
Practical application cases and data support
Case 1: Optimization of Synthesis of Pyridine Alkaloids
In the synthesis of pyridine alkaloids (such as nicotine), 4-hydroxy-3-methylpyridine is used as the raw material to construct the pyridine ring skeleton of nicotine through the oxidation of hydroxyl groups and the halogenation reaction of methyl groups. Experiments have shown that the optimized synthesis route can increase the overall yield from 35% to 60%, with a purity greater than 98%.
Case 2: Recycling of Alkaloid Catalysts
In the Suzuki coupling reaction, the modified palladium catalyst can be recycled 5 times, and the yield of each reaction is>90%. In contrast, the yield of unmodified palladium catalyst decreased to below 70% after 3 cycles.
Case 3: Activity evaluation of alkaloid analogues
The anti Alzheimer's disease alkaloid analogue synthesized using this substance as a template showed significant acetylcholinesterase inhibitory activity in vitro experiments (IC ₅₀=0.5 μ M), and its toxicity to nerve cells (CC ₅₀=50 μ M) was significantly lower than that of the commercially available drug donepezil (CC ₅₀=20 μ M).
4-Hydroxy-3 methylpyridine is an important organic compound with multiple uses. The following are two common synthesis methods:
Method 1: Hoffman synthesis method
The Hoffman synthesis method is a classic method for synthesizing 4-hydroxy-3-picoline. This method converts 4-chloromethylpyridine into 4-amino-3-methylpyridine through an ammonolysis reaction, and then undergoes oxidation and hydrolysis reactions to generate 4-Hydroxy-3 methylpyridine. The specific steps are as follows:
Mix 4-chloromethylpyridine with ammonia water, add sodium hydroxide solution, and react for 2-3 hours at 80-100 ° C.
Filter the reaction solution, acidify with dilute hydrochloric acid to pH=1, and filter to obtain 4-amino-3-methylpyridine.
Mix 4-amino-3-methylpyridine with sodium nitrate and sulfuric acid and react for 10 hours at 80 ° C.
Filter the reaction solution, neutralize it with sodium hydroxide solution to pH=7, and filter to obtain 4-Hydroxy-3 methylpyridine.
The advantages of this method are simple operation, mild reaction conditions, and high yield. However, this method uses a large amount of organic solvents and acid-base reagents, which can cause certain environmental pollution.
Method 2: Palisetz synthesis method
The Palisetz synthesis method is a relatively simple method for synthesizing 4-Hydroxy-3 methylpyridine. This method directly obtains 4-Hydroxy-3 methylpyridine by reacting with formaldehyde and ammonia. The specific steps are as follows:
1. Mix 3-methylpyridine with formaldehyde solution, add ammonia water, and stir at room temperature for 2 hours.
2. Filter the reaction solution, acidify with dilute hydrochloric acid to pH=7, and filter to obtain 4-Hydroxy-3-methylpyridine.
The advantages of this method are simple operation, mild reaction conditions, and high yield. However, this method uses a large amount of organic solvents and acid-base reagents, which can cause certain environmental pollution. In addition, this method requires the use of hazardous chemicals such as formaldehyde and ammonia, and strict safety measures are required.
It should be noted that both of the above methods are laboratory scale synthesis methods, which may require improvement and optimization for industrial production. In addition, specific synthesis conditions and reagent ratios also need to be adjusted and optimized according to the actual situation.
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