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3-bromo-2-methoxypyridine is an important heterocyclic organic compound and a versatile chemical synthetic structural unit. Its molecular structure consists of a pyridine ring and a methoxy group (- OCH ∝) substituted at the 2-position and a bromine atom (- Br) substituted at the 3-position. This special substitution pattern endows this substance with a unique electronic distribution. Its molecular structure consists of a pyridine ring and a methoxy group (- OCH ∝) substituted at the 2-position and a Br atom (- Br) substituted at the 3-position.
Its most important value lies in its widespread application as a key intermediate for efficient synthesis in the fields of pharmaceuticals, pesticides, and materials science: Br atoms can serve as active sites for coupling reactions (such as Suzuki Miyaura, Buchwald Hartwig coupling), promoting the introduction of complex groups such as aromatic and amino groups; And adjacent methoxy groups can not only coordinate to promote metallization reactions, but also deprotect under strong acid conditions and transform into key pyridone structural units. Therefore, this substance is a core raw material for constructing numerous bioactive molecules (such as drug candidate compounds) and functional materials, and its commercial value and synthetic application prospects are very important.
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C.F |
C6H6BrNO |
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E.M |
187 |
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M.W |
188 |
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m/z |
187 (100.0%), 189 (97.3%), 188 (6.5%), 190 (6.3%) |
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E.A |
C, 38.33; H, 3.22; Br, 42.50; N, 7.45; O, 8.51 |
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The chemical formula of this substance is C6H6BrNO, which is an organic molecule containing a pyridine ring. The three-dimensional structure of the molecule can be represented and predicted through molecular models or computational methods.
1. Basic structure:
The basic structure of this compound consists of a six membered pyridine ring, which contains a methoxy group and a Br atom substituted on carbon atoms 2 and 3. The pyridine ring is composed of five carbon atoms and one nitrogen atom, with one hydrogen atom on top of the carbon atom.
2. Spatial orientation:
The molecules of this substance have specific spatial orientations. The nitrogen atom and methoxy group in the plane of the pyridine ring are usually located in the same plane, while the Br atom extends out of the pyridine ring. This arrangement gives molecules a certain degree of spatial chirality.
3. Chiral properties:
Due to the presence of Br atom, there may be chiral isomers of product. Chiral isomers refer to the mirror structure of molecules that cannot overlap through rotation or translation. Chiral isomers can be optically active because they can rotate the vibration direction of plane polarized light. However, the specific chiral properties of this substance require experiments or calculations to determine.
3-Bromo-2-methoxypyridine is a high-value bifunctional pyridine synthetic building block. The 2-methoxy group on the pyridine ring acts as an electron-donating protecting group, which can modulate the electron cloud density of the ring and be removed in later synthetic stages. The Br atom at the 3-position exhibits extremely high reactivity and can participate in a wide range of metal-catalyzed coupling reactions and nucleophilic substitution reactions. This compound delivers outstanding site-selective reactivity with minimal side reactions, and its primary applications fall into four major sectors: pharmaceutical intermediate synthesis, research on organic synthetic methodologies, fine agrochemicals, and functional optoelectronic materials.
(I) Pharmaceutical Intermediates: The Core and Dominant Application Sector
The pharmaceutical industry represents the largest application field for this compound. Thanks to its versatile capacity for site-specific structural modification, it is widely adopted to construct small-molecule backbones for neurological agents, anti-tumor therapeutics, and anti-infective drugs. First, it is deployed in the research and development of Alzheimer's disease treatments as a key precursor for γ-secretase modulators. Aromatic heterocyclic fragments are grafted onto its skeleton via Suzuki coupling reactions to regulate amyloid protein deposition in organisms and mitigate neuronal damage.
Additionally, this substance enables the synthesis of BACE1 inhibitors that block the cleavage pathway of pathogenic proteins, making it an indispensable heterocyclic intermediate for developing candidate anti-dementia medicines.Second, it serves in the synthesis of targeted anti-tumor medicines. Through Negishi and Heck coupling reactions, this compound rapidly assembles polycyclic heteroaromatic frameworks to produce JAK and ERK series kinase inhibitors. The pyridine parent core embedded within medicine molecules improves the water solubility and cellular permeability of small molecules, while the methoxy moiety optimizes metabolic stability in vivo and reduces toxic side effects.
At present, this substance has been utilized in the process development of multiple preclinical anti-tumor medicine candidates.
Third, this substance facilitates the synthesis of anti-tuberculosis medicine derivatives. It modifies the parent core structure of bedaquiline to enhance inhibitory activity against medicine-resistant mycobacterium tuberculosis strains and elevate the oral bioavailability of the pharmaceutical agent.
(II) Research on Organic Synthetic Methodologies: Standard Substrate for Heterocyclic Reactions
In fundamental organic chemistry research, 3-bromo-2-methoxypyridine functions as a standard template substrate for investigating regioselective reactions on pyridine rings. Unlike benzene derivatives, the intrinsically electron-deficient pyridine ring enables systematic exploration of the formation rules for carbon-carbon, carbon-nitrogen, and carbon-oxygen bonds within heterocyclic systems. Researchers leverage the 3-bromo substituent to study metal-halogen exchange reactions and nucleophilic substitution of aryl halides.
Relying on the protection and deprotection properties of the 2-methoxy group, targeted cyclization reactions guided by functional groups are investigated. Moreover, this compound is frequently used as a standard reference material for liquid chromatography and mass spectrometry. This substance supports purity testing of heterocyclic intermediates and validation of chromatographic analytical methods, supplying a benchmark for quality control assays of pyridine derivatives.
(III) Intermediates for Fine Agrochemicals
Within pesticide synthesis, this compound is used to manufacture novel pyridine-based fungicides and insecticides. The pyridine ring possesses inherent favorable biological affinity; after functional group modification, this substance yields pyridine amide fungicides that target fungal respiratory pathways and effectively suppress the proliferation of pathogens causing crop powdery mildew and downy mildew.
Furthermore, amination and cyclization transformations convert this substance into intermediates for new neonicotinoid insecticides, which disrupt neurotransmission in the central nervous systems of pests. Such products feature potent insecticidal activity, low environmental residue, and low propensity to trigger pest resistance, aligning with the developmental demands of eco-friendly agricultural pesticides. Compared with conventional benzene-ring pesticide intermediates, the pyridine scaffold drastically enhances the systemic translocation of pesticide molecules inside plant tissues and boosts field disease and pest control efficacy.
(IV) Synthetic Monomer for Functional Optoelectronic Materials
The utilization of this compound in optoelectronic materials has expanded steadily in recent years, and this substance acts as a synthetic monomer for conjugated pyridine-based organic materials. Linear conjugated molecular chains are constructed via coupling reactions to fabricate luminescent materials for organic light-emitting diodes (OLEDs) and organic photoelectric sensor materials.
The nitrogen atom on the pyridine ring delivers superior electron transport capability. Incorporating this ring into molecular architectures optimizes carrier mobility of materials and elevates device luminous efficiency as well as detection sensitivity. In addition, this substance supports the synthesis of fluorescent probes for metal ions. The coordination interaction between pyridine rings and metal ions achieves specific recognition and fluorescent detection of heavy metal ions in water bodies.
A preparation method for the product, with the following reaction steps:
(1) Preparation of 2-bromo-3-hydroxypyridine: Cool the sodium hydroxide aqueous solution to -10-0 ℃ using an ice salt bath, and drop add liquid bromine within this temperature range; Dissolve 3-hydroxypyridine in an aqueous solution of sodium hydroxide, and then add this solution dropwise to the liquid bromine solution mentioned above, keeping the system temperature at 10-15 ℃; After dripping, stir at room temperature for 2.5 to 3 hours, and then adjust the pH to 7 with acid; The obtained crude product was recrystallized to obtain 2-bromo-3-hydroxypyridine.
(2) Preparation of 2-bromo-3-methoxypyridine: Sodium is added to methanol, oil bath is heated to reflux, system reflux is maintained, and a dmf solution of 2-bromo-3-hydroxypyridine is added to the above system; Stir for 10-15 minutes, remove the majority of methanol by vacuum distillation, add iodomethane to the remaining mixture, stir overnight at room temperature, then vacuum distillation to remove dmf, cool to room temperature, add ether for extraction, layer, and wash twice with saturated salt water, dry, and distill to obtain 2-bromo-3-methoxypyridine.
Furthermore, the mass fraction of sodium hydroxide aqueous solution in step (1) is 40%.
Furthermore, the acid in step (1) is concentrated sulfuric acid.
Furthermore, the recrystallization in step (1) is carried out using an ethanol solution with a volume fraction of 75%.
How to optimize the synthesis steps of this compound to improve yield?
In order to optimize the synthesis steps of 3-bromo-2-methoxypyridine and improve yield, the following are some key strategies based on search results:
Choosing appropriate brominating agents and solvents: Studies have shown that different brominating agents and solvents have a significant impact on the yield of the reaction. For example, using NBS (N-bromosuccinimide) as a brominating agent in dichloromethane (DCM) solvent, the yield is 47.0%; The yield of KBr/KBrO3 in acetonitrile (MeCN) solvent can reach as high as 89.5%. Therefore, choosing KBr/KBrO3 and MeCN as bromination systems may be an effective method to improve yield.
Optimizing solvents: The choice of solvent has a significant impact on the yield in the synthesis of 6-bromo-2-methoxy-3-aminopyridine. When toluene is used as a solvent, the yield reaches 90.1%, which is much higher than other solvents such as tetrahydrofuran (57.0%) and 1,4-dioxane (71.0%). Therefore, prioritizing toluene as a solvent during the synthesis process can significantly improve the yield.
Adjusting the dosage of sodium methoxide: The dosage of sodium methoxide also has a significant impact on the reaction yield. As the dosage of sodium methoxide increases, the yield gradually increases, and when the dosage reaches 10 equivalents, the yield reaches the highest point of 90.1%. Therefore, optimizing the dosage of sodium methoxide is another key factor in improving yield.
Optimization of post-processing steps: Studies have shown that the adopted route does not require column chromatography or recrystallization after bromination reaction, which simplifies the operation steps and improves the yield. Avoiding complex purification steps can reduce product loss and improve overall yield.
The product is a haloalkoxy-substituted pyridine derivative. Its research and development were underpinned by the overall advancement of pyridine heterocyclic chemistry, which can be divided into four phases: theoretical groundwork, initial synthesis, process optimization, and large-scale industrial application.
In 1981, a research team from La Trobe University in Australia pioneered the targeted synthesis and structural identification of this compound. Using 2-methoxypyridine as the starting material, they conducted a low-temperature selective bromination reaction to precisely introduce a Br atom at the 3-position of the pyridine ring.
High-purity the product was isolated for the first time, followed by comprehensive structural characterizations including nuclear magnetic resonance (NMR), melting point measurement, and liquid chromatography. The fundamental physicochemical parameters of the compound were officially published, filling the gap in the synthetic methodology for 2,3-disubstituted pyridine monomers.
Reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with an ultraviolet detector serves as the core quantitative testing method for this product.
For qualitative confirmation, proton nuclear magnetic resonance (¹H NMR) is the preferred technique, which accurately identifies substitution positions via characteristic peaks of pyridine ring hydrogens and methoxy groups. GC-MS and LC-MS are utilized for qualitative analysis of trace impurities, where the structures of by-products are traced through characteristic molecular ion peaks.
Supplementary physical, chemical and impurity testing methods are specified as follows: Karl Fischer titration is used for water content determination; heavy metals and residue on ignition are tested in accordance with general chemical industry limit standards. Thin-layer chromatography (TLC) is deployed for rapid in-process control, using a mixed developing solvent of dichloromethane and petroleum ether with visualization under a 254 nm UV lamp, suitable for rapid screening in production workshops.
Infrared spectroscopy (IR) aids structural identification by matching against standard spectra to recognize characteristic vibrational absorptions of C–Br bonds, methoxy C–O bonds and pyridine rings. The complete testing system integrates qualitative analysis for laboratory research and quantitative detection for industrial mass production, featuring high sensitivity and convenient operation.
FAQ
Why does this substance have two different CAS numbers? Is it the same thing?
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No, they are the difference between anhydrous and hydrated substances. The CAS number for anhydrous substance is 13472-59-8, which is a conventional liquid form; And the CAS number of hydrate is 1881332-55-3, which is a solid form with crystalline water. The molecular weight and physicochemical properties of the two are different, so please pay attention when ordering.
Why is its refractive index a 'invisible quality inspector'?
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Its refractive index (n ² ⁰/D) is about 1.566, which is a very sensitive purity indicator. Experienced synthesizers can quickly determine the quality of distillation products through it - even small impurities can cause changes in refractive index readings, which is more immediate than chromatographic analysis.
How sentimental is this substance when stored? Why is this substance necessary to fill with nitrogen?
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Because it has both moisture sensitive and light sensitive properties. This means that it is easy to change color when exposed to light, and easy to decompose when exposed to moisture. The official recommendation is to store under inert gas protection (such as nitrogen) in a cool and dark place, otherwise the purity will quietly decrease.
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