Method for preparing 4-(2-bromopropyl) benzene-1, 2-diol
Through the reaction of eugenol and boron tribromide, combined with extraction and beating purification methods, the problems of high cost and low efficiency in the prior art were solved, and the preparation of 4-(2-bromopropyl)benzene-1,2-diol was achieved with an efficient and low cost.
Patent Information
- Application Number
- CN202510430603.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-07
- Publication Date
- 2025-07-04
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The existing preparation method of 4-(2-bromopropyl)benzene-1,2-diol requires the use of expensive starting materials and cumbersome operations, and the resulting impurities are high, resulting in high cost and low efficiency.
Eugenol was used to react with boron tribromide, and the reaction temperature was controlled from -78°C to 0°C, and the target compound was obtained by simple extraction and beating purification methods, avoiding column chromatography separation.
It reduces raw material costs, simplifies operating steps, improves work efficiency, reduces impurities, and improves product purity and yield.
Smart Images
Figure CN120247659A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the synthesis technical field of the development and application of organic pharmaceutical intermediates and pesticide insecticide intermediates. Specifically, it relates to a practical preparation method of 4-(2-bromopropyl)benzene-1,2-diol. Background Art
[0002] As a kind of compound with a unique structure in the field of organic chemistry, the 4-(2-bromopropyl)benzene-1,2-diol compound occupies a very crucial position in the modern drug synthesis system, especially as an important raw material for synthesizing anticancer drugs, antiviral drugs, and antibacterial drugs. Currently, for the preparation of 4-(2-bromopropyl)benzene-1,2-diol, the following route is adopted:
[0003]
[0004] However, in the above synthesis route, it is necessary to use expensive 4-allylpyrocatechol as the starting material, and there are many impurities generated in the reaction. After the reaction, it is also necessary to remove the impurities by column chromatography separation. The whole manufacturing process has high costs and low efficiency. In addition to the above route, there are usually methods of using 2-bromopropyl Grignard reagent to react with protected pyrocatechol derivatives, and the direct bromination method. However, these methods all require multiple steps and cumbersome operations. Therefore, developing a preparation route with cheap reaction raw materials, high efficiency, simplicity, and high yield has great significance in industrial manufacturing. Summary of the Invention
[0005] The purpose of the present invention is to provide a manufacturing method with easily accessible and economical starting materials for the reaction, reduced generation of side reactions, and simpler post-treatment. Through this method, a mature and feasible synthesis route suitable for process amplification can be provided, so it is especially suitable for industrial manufacturing.
[0006] The present invention has the following composition.
[0007] 1. A preparation method of 4-(2-bromopropyl)benzene-1,2-diol, characterized in that eugenol reacts with boron tribromide to obtain the above compound, which includes the following steps:
[0008] 1) Add eugenol to a solvent and cool it to a temperature range of -78°C to 0°C;
[0009] 2) Add boron tribromide to the solution obtained in step 1), and react at a constant temperature in the range of -78°C to 0°C for 1 to 2 hours to obtain a reaction product;
[0010] 3) Quench the reaction of the solution after the reaction in step 2), and continue to stir at room temperature for 10 to 30 minutes.
[0011] 2. The preparation method according to 1, characterized in that it comprises the following steps:
[0012] 1) Add eugenol to a solvent and cool the temperature to 0 °C;
[0013] 2) Add boron tribromide to the solution obtained in step 1) and react at a constant temperature of 0 °C for 1 hour to obtain a reaction product;
[0014] 3) Quench the reaction of the solution after the reaction in step 2) with ice water and continue to stir at room temperature for 30 minutes.
[0015] 3. The preparation method according to 1, characterized in that
[0016] The molar ratio of the amounts of eugenol and boron tribromide used is 1:2 to 1:3.
[0017] 4. The preparation method according to claim 1, characterized in that
[0018] The solvent in step 1) is dichloromethane.
[0019] 5. The preparation method according to 1, characterized in that
[0020] The dosage ratio of the solvent to eugenol is 10 - 12 mL / g.
[0021] 6. The preparation method according to any one of 1 to 5, characterized in that
[0022] Sample and detect the solution after the reaction in step 2). If the reaction is not complete, return to step 2); if the reaction is complete, perform step 3).
[0023] 7. The preparation method according to 6, characterized in that
[0024] Sampling and detection are carried out by Prep-TLC detection.
[0025] 8. The preparation method according to any one of 1 to 5, characterized in that it further comprises the following step:
[0026] Purify the product obtained in step 3) to obtain a purified product.
[0027] 9. The preparation method according to 8, characterized in that
[0028] In step 3), the product is obtained by extraction, drying, and concentration.
[0029] 10. The preparation method according to 9, characterized in that
[0030] Add the product obtained by concentration in step 3) to a mixed solvent of petroleum ether: ethyl acetate = 10:1 to 5:1, stir for 2 hours, and obtain the purified product after filtration and drying.
[0031] Advantages of the Invention
[0032] Compared with the prior art, the present invention does not require the use of expensive starting materials. Using cheap and easily available eugenol (4-allyl-2-methoxyphenol) as the starting material, the cost is greatly reduced. At the same time, the manufacturing method of the present invention has simple operation steps, less reaction time, greatly improves work efficiency, and the reaction products are clear with few impurities. There is no need to use column chromatography technology, and the product can be purified by simple slurry purification, further saving time and cost. By adopting the preparation method of the present invention, the 4-(2-bromopropyl)benzene-1,2-diol compound can be obtained conveniently and with high yield. Brief Description of the Drawings
[0033] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of 4-(2-bromopropyl)benzene-1,2-diol prepared in Example 1
[0034] Figure 2 is the LC-MS spectrum of 4-(2-bromopropyl)benzene-1,2-diol prepared in Example 1
[0035] Figure 3 is the MS spectrum of 4-(2-bromopropyl)benzene-1,2-diol prepared in Example 1 Detailed Description of the Invention
[0036] The synthetic route of the present invention is as follows:
[0037]
[0038] Boron tribromide is a strong Lewis acid, generally used in demethylation reactions to synthesize phenolic compounds. It is generally known that boron tribromide usually does not affect the ester groups and double bonds in the molecule during demethylation reactions. However, the inventors of the present invention have found through research that 4-(2-bromopropyl)benzene-1,2-diol can be synthesized by reacting boron tribromide with eugenol, thus completing the present invention.
[0039] Based on the above discovery, the present invention provides a method for synthesizing a target compound based on eugenol, comprising the following steps:
[0040] 1) Reaction preparation and cooling: Add an appropriate amount of eugenol to a reaction vessel containing a solvent. Subsequently, place the reaction vessel in an ice bath environment, and through the continuous cooling effect of the ice bath, gradually lower the temperature of the reaction system and stably maintain it in the temperature range of -78°C to 0°C.
[0041] 2) Reactant addition and reaction progress: When the temperature of the reaction system is stable within the range of -78°C to 0°C, boron tribromide is slowly and uniformly added to the reaction system. The molar ratio of eugenol to boron tribromide is preferably 1:2 to 1:3, and the dosage ratio of the solvent to boron tribromide is preferably 10 - 12 mL / g. The purpose of slowly adding boron tribromide is to avoid overly violent reactions and ensure that the reaction proceeds under mild and controllable conditions. After the addition is complete, the reaction system is maintained at a constant temperature and continues to react for 1 to 2 hours to allow the reactants to fully react to form the target compound.
[0042] In the above steps 1) and 2), as the solvent, appropriate solvents can be selected by comprehensively considering factors such as solubility, reaction conditions, safety, and post-treatment convenience. In the present invention, solvents such as dichloromethane, tetrahydrofuran, benzene, n-pentane, carbon tetrachloride, and carbon disulfide, which have good solubility and stability for the reactants, are preferably used, and dichloromethane is most preferably used.
[0043] 3) Quenching the reaction: After the reaction in step 2) is completed, the reaction is quenched, and then stirred at room temperature for 10 to 30 minutes. This quenching reaction can be carried out using low-temperature quenching, water quenching, alcohol quenching, etc. as needed. In low-temperature quenching, the reaction solution is slowly added dropwise to a sufficient amount of ice water, and the low-temperature environment in the ice water can quickly quench the reaction. Alcohol quenching can use alcohols such as methanol and ethanol as needed.
[0044] 4) Reaction detection: Before quenching after the reaction is completed, samples can be taken from the reaction system, and professional detection means can be used to detect the reaction solution to determine whether the reaction in step 2) is complete. Examples of the above professional detection means include Prep-TLC detection, high-performance liquid chromatography, nuclear magnetic resonance spectroscopy, etc., which can be appropriately selected according to needs. In the present invention, Prep-TLC detection is preferably used for sampling detection.
[0045] 5) Phase separation and extraction: After the treatment in step 3) is completed, the mixture is transferred to a separatory funnel for phase separation. Due to the difference in solubility of the reaction product and impurities in the aqueous and organic phases, the product and some impurities are preliminarily separated through liquid separation operation. Then, an organic solvent such as dichloromethane is used to extract the aqueous phase, and the extraction operation is repeated 3 times to fully extract the residual target product in the aqueous phase and improve the product yield. After the extraction is completed, the organic phases obtained each time are combined.
[0046] 6) Drying and concentration: An appropriate amount of anhydrous sodium sulfate is added to the combined organic phase. Anhydrous sodium sulfate has strong water absorption and can combine with water molecules in the organic phase to play a role in drying the organic phase. After standing for a period of time, when the anhydrous sodium sulfate has fully absorbed the water, a rotary evaporation concentration operation is performed on the organic phase to gradually evaporate and remove organic solvents such as dichloromethane, and the substances in the system are continuously concentrated to finally obtain a solid product.
[0047] 7) Purification and Obtaining of the Target Compound: Add a mixed solvent composed of petroleum ether and ethyl acetate in a ratio of 10:1 to 5:1 to the obtained solid product. Start the stirring device and continuously stir for 2 hours to dissolve the impurities in the mixed solvent, and the target compound precipitates in solid form. After the stirring ends, separate the precipitated solid from the mixed solvent through filtration, and then dry the solid obtained by filtration to remove the solvent molecules remaining on the surface. Finally, a white solid is obtained, which is the target compound.
[0048] The product obtained by the manufacturing method of the present invention has few reaction impurities, and the impurities can be dissolved with a small amount of solvent, so that the target compound can be separated from the impurities. In the present invention, the impurities are dissolved by selecting a mixed solvent of petroleum ether and ethyl acetate. Since the target product will not be dissolved, there is no need to use column chromatography technology, and the product can be purified by simple slurry purification, greatly simplifying the manufacturing process.
[0049] The present invention realizes the efficient and precise synthesis of the target compound by selecting a suitable synthetic route and precisely controlling the reaction conditions, including the dosage ratio of reactants, reaction temperature, reaction time, etc. At the same time, through multiple steps such as extraction, drying, and purification, the purity and yield of the product are effectively improved. This method has the advantages of simple operation, mild reaction conditions, and high product quality, providing a new and effective way for the synthesis of eugenol-derived compounds and having good application prospects.
[0050] The following further elaborates on the present invention in detail with specific examples, but the protection scope of the present invention is not limited thereto.
[0051] Example
[0052] Manufacture of 4-(2-bromopropyl)benzene-1,2-diol
[0053] Add eugenol (8.2 g, 50 mmol) and dichloromethane (100 ml) to a reaction flask, cool to 0 °C in an ice bath, slowly dropwise add boron tribromide (25 g, 100 mmol), and after dropping, keep the temperature at 0 °C and react for 1 h. After sampling and detecting that the reaction is complete, drop the reaction solution into ice water to quench it. Continue to stir at room temperature for 30 minutes and then phase-separate. Extract the aqueous phase with DCM 3 times, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate by rotary evaporation. After obtaining an off-white solid, add 50 ml of a mixed solvent of petroleum ether:ethyl acetate = 10:1, stir for 2 hours, filter and dry to obtain 8.38 g of a white solid, and the yield is 72.60%.
[0054] The hydrogen spectrum data of the product are as follows:
[0055] 11H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 6.73 (d, J = 8.1 Hz, 1H), 5.26 (d, J = 35.2 Hz, 2H), 4.32 (dd, J = 13.6, 6.7 Hz, 1H), 3.18 (dd, J = 14.1, 7.0 Hz, 1H), 3.03 (dd, J = 14.1, 7.2 Hz, 1H), 1.76 (d, J = 6.6 Hz, 3H).
[0056] LC-MS 461.0 (2M + H).
[0057] It can be seen from the NMR spectrum that the methyl group on the methoxy group has been removed, and the substitution position of bromine can be determined, and the structure is correct.
[0058] Comparative example
[0059] 4-Allylpyrocatechol (1.5 g, 10 mmol) and hydrobromic acid (40% (acetic acid solvent), 20 ml) were added to a reaction flask, and the reaction was stirred at room temperature in the dark for 1 week. After sampling and detecting that the reaction was complete, acetic acid was removed by rotary evaporation (and ethanol was added to azeotrope to ensure the removal of all acetic acid). After the residue was cooled to 0 °C in an ice bath, anhydrous potassium carbonate (1 - 2 g) was added in batches, and then purified by column chromatography to obtain 1.41 g of a white solid with a yield of 61.05%.
Claims
1. A method for preparing 4-(2-bromopropyl)benzene-1,2-diol, characterized in that, React eugenol with boron tribromide to obtain the above compound, which includes the following steps: 1) Add eugenol to a solvent and cool the temperature to the range of -78°C to 0°C; 2) Add boron tribromide to the solution obtained in step 1), and react at a constant temperature in the reaction temperature range of -78°C to 0°C for 1 to 2 hours to obtain a reaction product; 3) Quench the reaction of the solution after the reaction in step 2), and then continue to stir at room temperature for 10 to 30 minutes.
2. The preparation method according to claim 1, wherein Include the following steps: 1) Add eugenol to a solvent and cool the temperature to 0°C; 2) Add boron tribromide to the solution obtained in step 1), and react at a constant temperature at 0°C for 1 hour to obtain a reaction product; 3) Quench the reaction of the solution after the reaction in step 2) with ice water, and then continue to stir at room temperature for 30 minutes.
3. The preparation method according to claim 1, wherein The molar ratio of the amount of eugenol to boron tribromide is 1:2 to 1:
3.
4. The preparation method according to claim 1, wherein The solvent in step 1) is dichloromethane.
5. The preparation method according to claim 1, wherein The dosage ratio of the solvent to eugenol is 10 - 12 mL / g.
6. The preparation method according to any one of claims 1 to 5, wherein Sample and detect the solution after the reaction in step 2). If the reaction is not complete, return to step 2); if the reaction is complete, perform step 3).
7. The preparation method according to claim 6, wherein Sampling and detection are carried out by Prep-TLC detection.
8. The preparation method according to any one of claims 1 to 5, characterized in that, Further include the following steps: Purify the product obtained in step 3) to obtain a purified product.
9. The preparation method according to claim 8, wherein In step 3), the product is obtained by extraction, drying, and concentration.
10. The preparation method according to claim 9, wherein Add the product obtained by concentration in step 3) to a mixed solvent of petroleum ether:ethyl acetate = 10:1 to 5:1, stir for 2 hours, and filter and dry to obtain a purified product.