Synthesis method of 3-(4-methylpyridine-3-yl) propionic acid
By using a simple synthetic route with amide solvents and palladium on carbon catalyst, the problems of high-temperature corrosion, complex operation and high cost in the synthesis of 3-(4-methylpyridin-3-yl)propionic acid in the prior art have been solved, and the production of high-yield and high-quality products has been achieved.
Patent Information
- Application Number
- CN202511365282.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-23
- Publication Date
- 2026-01-02
AI Technical Summary
Existing methods for synthesizing 3-(4-methylpyridin-3-yl)propionic acid suffer from problems such as high reaction temperature, highly corrosive equipment, long reaction steps, high reagent costs, complex operation, high risk, significant environmental pollution, and low overall yield.
Using amide solvents and palladium on carbon catalysts, the reaction temperature and time were optimized through mild reaction conditions and a simple synthetic route. The reaction was carried out using widely available raw materials, including the reaction of 4-methyl-3-bromopyridine, benzyl acrylate and triethylamine. The target product was then obtained by palladium on carbon hydrogenation.
It achieves high product yield and quality, mild reaction conditions, simple operation, reduced equipment corrosion and environmental pollution, and is suitable for large-scale production.
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Figure CN121248482A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid, belonging to the field of pharmaceutical chemical organic synthesis technology. Background Technology
[0002] As early as the 1980s, scientists began studying the symbiotic behavior of fish induced by chemicals secreted by sea anemones, investigating two host-guest pairs: *Radianthus kuekenthali* (sea anemone) – *Anemonefish* (sea anemonefish) and *Stoichatis kenti* – *A. ocellaris*. A novel pyridinium compound, *Amphikuemin*, was discovered that induces the characteristic attracted swimming (towards a chemical stimulus) of *A. perideraion*, and has been isolated from *R. kuekenthali*. (Science, 1986, vol. 234, # 4776, p. 585-587) In 1900, Japanese scientists extracted 48 micrograms of amphikuemin from 15 kilograms of sea anemone homogenate, finally confirming the structure of amphikuemin.
[0003]
[0004] (Heterocycles, 1990, vol. 30, # 1, p. 247 - 251) The 3-(4-methylpyridin-3-yl)propionic acid referred to in this invention is a small molecule compound of the pyridine heterocyclic class, with CAS code 129483-51-8, and has the following structure:
[0005] Its physical properties are that of a white solid.
[0006] Further in-depth research on Amphikuemin was not feasible through biological isolation alone. Therefore, chemical synthesis was used to obtain large quantities of 3-(4-methylpyridin-3-yl)propionic acid, which became an important key intermediate.
[0007] The methods reported in the literature for the synthesis of 3-(4-methylpyridin-3-yl)propionic acid are as follows: Heterocycles, 1990, vol. 30, # 1, p. 247 - 251
[0008]
[0009] The synthetic route has the following drawbacks: high reaction temperature, high corrosiveness to equipment, long reaction steps, and lack of reliability for subsequent research and scale-up.
[0010] Meanwhile, the literature also proposes another synthesis method:
[0011]
[0012] This synthetic route also has the following shortcomings: the cost of the reaction reagents is too high, the oxidation operation has a high risk factor, the reaction steps are still very complicated, and it is not conducive to scale-up to obtain intermediates. Further research is needed.
[0013] The raw materials used in this type of synthetic route are not easy to obtain, the synthetic operation is relatively complex, and the highly toxic phosphorus oxychloride and the dangerous reagent potassium permanganate are used as reaction reagents, making the treatment of waste difficult and causing great environmental pollution. In addition, the reaction routes are very long, requiring 6-7 steps, with low overall yield, and cannot meet the requirements of rapid synthesis, processing and purification.
[0014] The inventors concluded that further research on Amphikuemin aims to obtain a reliable product, 3-(4-methylpyridin-3-yl)propionic acid, in a stable and convenient manner. Therefore, the inventors designed a new reaction route:
[0015] However, this approach also encountered problems during implementation. In the final step of hydrolyzing the ester group, the resulting product did not show correct NMR results.
[0016] Therefore, finding a new method to synthesize 3-(4-methylpyridin-3-yl)propionic acid is of great significance. Summary of the Invention
[0017] To address the problems in the prior art, this invention provides a method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid. This method has mild reaction conditions, widely available raw materials, high product yield, and good product quality.
[0018] The structural formula of the 3-(4-methylpyridin-3-yl)propionic acid synthesized in this invention is shown in Formula I, with CAS code 129483-51-8.
[0019] (I) The synthetic reaction route involved in this invention is shown in Formula II: (II) To achieve the above technical objectives, the technical solution of the present invention is as follows: A method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid, comprising the following steps: (1) Add amide solvent to the reaction flask, add raw material A, namely 4-methyl-3-bromopyridine, benzyl acrylate, triethylamine, and catalyst, and heat the reaction under nitrogen protection. Then, purify the product by column chromatography to obtain double bond intermediate product B. (2) Add the double bond intermediate product B obtained in step (1) to the reaction flask, and then add palladium on carbon, alcohol or ether or lipid solvent. After hydrogenation at room temperature, the product C, namely 3-(4-methylpyridin-3-yl)propionic acid, can be obtained.
[0020] Preferably, the molar ratio of 4-methyl-3-bromopyridine, benzyl acrylate and triethylamine in step (1) is 1:(2-5):(2-5).
[0021] Preferably, the reaction temperature in step (1) is 90-120°C and the reaction time is 6-10h.
[0022] Preferably, the amide solvent in step (1) is N,N-dimethylformamide.
[0023] Preferably, the amount of N,N-dimethylformamide used is 6V to 12V. Preferably, the catalyst in step (1) is palladium acetate.
[0024] Preferably, the amount of catalyst is 1% to 10% of the raw material mass.
[0025] Preferably, the alcohol, ether, or lipid solvent is methanol, ethanol, tetrahydrofuran, or ethyl acetate.
[0026] Preferably, the amount of palladium on carbon is 1% to 10% of the mass of the double bond intermediate product.
[0027] As can be seen from the above description, the present invention has the following advantages: 1. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid in this invention uses widely available and inexpensive raw materials, with mild reaction conditions that avoid high-temperature reactions, reduce corrosion to equipment, and have simple reaction steps. In addition, the synthetic route is short, the operation is simple, and the post-processing is efficient. 2. In the synthesis process, the present invention optimizes and controls the reaction temperature, reaction time, and feed ratio of raw materials to reduce the generation of by-products. Attached Figure Description
[0028] Figure 1 The NMR spectrum of the structure of 3-(4-methylpyridin-3-yl)propionic acid obtained in Example 3 is shown. Detailed Implementation
[0029] The features of the present invention will be further illustrated below through examples, but the claims of the present invention are not limited in any way.
[0030] Example 1: (1) In a 1L single-necked flask, N,N-dimethylformamide (20ml), 4-methyl-3-bromopyridine (2g, 11.63mmol, 1eq), benzyl acrylate (3.8g, 23.25mmol, 2eq), triethylamine (2.3g, 23.25mol, 2eq), and palladium acetate catalyst were added. The mixture was heated to 100℃ and reacted for 8 hours under nitrogen protection. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed twice with ethyl acetate, and the filtrate was added to water. The mixture was separated, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride, dried, concentrated to dryness, and purified by column chromatography to obtain product B (2.5g), with a yield of 86.2% and a purity of 95%. (2) Add the obtained product B (2.5g), palladium on carbon (10%) 0.1g, and methanol 25ml to a 100mL single-necked flask. React at room temperature for one day. After the reaction is complete, filter through a diatomaceous earth liner. Concentrate the filtrate to dryness and slurry to obtain white solid C, namely 3-(4-methylpyridin-3-yl)propionic acid (1g), with a yield of 62.5% and a purity of 95%.
[0031] Example 2: (1) In a 1L single-necked flask, N,N-dimethylformamide (250ml), 4-methyl-3-bromopyridine (25g, 0.145mol, 1eq), benzyl acrylate (47.14g, 0.29mol, 2eq), triethylamine (29.35g, 0.29mol, 2eq), and palladium acetate catalyst were added. The mixture was heated to 100℃ and reacted for 8 hours under nitrogen protection. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed twice with ethyl acetate, and the filtrate was added to water. The mixture was separated, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride, dried, concentrated to dryness, and purified by column chromatography to obtain product B (35g), with a yield of 97.2% and a purity of 96%. (2) Add the obtained product B (35g), palladium on carbon (10%) 0.5g, and methanol 1L to a 3L single-necked flask. React at room temperature for one day. After the reaction is complete, filter through diatomaceous earth, concentrate the filtrate to dryness, and slurry to obtain white solid C, namely 3-(4-methylpyridin-3-yl)propionic acid (16g), with a yield of 72.7% and a purity of 95%.
[0032] Example 3: (1) In a 1L single-necked flask, N,N-dimethylformamide (1L), 4-methyl-3-bromopyridine (98g, 0.57mol, 1eq), benzyl acrylate (185g, 1.14mol, 2eq), triethylamine (115g, 1.14mol, 2eq), and palladium acetate catalyst were added. The mixture was heated to 100℃ and reacted for 8 hours under nitrogen protection. The reaction was checked by TLC to confirm the complete reaction of the raw materials. The mixture was filtered through diatomaceous earth, washed twice with ethyl acetate, and the filtrate was added to water. The mixture was separated and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried, concentrated to dryness, and purified by column chromatography to obtain product B (140g), with a yield of 97.2% and a purity of 97%. (2) Add B (100g), palladium on carbon (10%) 5g and methanol 1L to a 3L single-necked flask. React at room temperature for one day. After the reaction is complete, filter through diatomaceous earth, concentrate the filtrate to dryness, and slurry to obtain white solid C, namely 3-(4-methylpyridin-3-yl)propionic acid (50g), with a yield of 76.92% and a purity of 97%.
[0033] The obtained product, 3-(4-methylpyridin-3-yl)propionic acid, was characterized by its structure and NMR data: 1 H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.31 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 7.15 (d, J =4.9 Hz, 1H), 2.83 (t, J = 7.7 Hz, 2H), 2.52 (t, J = 5.3 Hz, 2H), 2.29 (s, 3H); NMR spectrum as follows Figure 1 .
[0034] It is understood that the above detailed description of the present invention is for illustrative purposes only and is not intended to limit the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that modifications or equivalent substitutions can still be made to the present invention to achieve the same technical effects; as long as the usage requirements are met, they are all within the protection scope of the present invention.
Claims
1. A method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid, characterized in that, The steps are as follows: (1) Add amide solvent to the reaction flask, add raw materials 4-methyl-3-bromopyridine, benzyl acrylate, triethylamine and catalyst, heat the reaction under nitrogen protection, and then purify by column chromatography to obtain double bond intermediate product; (2) Add the double bond intermediate product obtained in step (1) to the reaction flask, and then add palladium on carbon, alcohol or ether or lipid solvent. After hydrogenation at room temperature, the product is purified to obtain 3-(4-methylpyridin-3-yl)propionic acid.
2. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 1, characterized in that, The molar ratio of 4-methyl-3-bromopyridine, benzyl acrylate and triethylamine in step (1) is 1:(2-5):(2-5).
3. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 1 or 2, characterized in that, The reaction temperature in step (1) is 90-120℃ and the reaction time is 6-10h.
4. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 1, characterized in that, The amide solvent mentioned in step (1) is N,N-dimethylformamide.
5. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 4, characterized in that, The amount of N,N-dimethylformamide used is 6V to 12V.
6. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 1, characterized in that, The catalyst mentioned in step (1) is palladium acetate.
7. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 6, characterized in that, The amount of catalyst is 1% to 10% of the raw material mass.
8. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 1, characterized in that, The alcohol, ether, or lipid solvent is methanol, ethanol, tetrahydrofuran, or ethyl acetate.
9. The method for synthesizing 3-(4-methylpyridin-3-yl)propionic acid as described in claim 1, characterized in that, The amount of palladium on carbon is 1% to 10% of the mass of the double bond intermediate product.