A process for the synthesis of 2-fluoro-4-hydroxybenzaldehyde
By exchanging m-fluoroanisole with TEMPMgCl-LiCl solution and using mixed Lewis acid catalysts, the problems of high equipment requirements, expensive reagents, and complex operation in the preparation of 2-fluoro-4-hydroxybenzaldehyde in the prior art have been solved, achieving a synthesis with high selectivity and high yield, which is suitable for industrial production.
Patent Information
- Application Number
- CN202311812641.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-27
- Publication Date
- 2026-02-17
- Estimated Expiration
- 2043-12-27
AI Technical Summary
Existing methods for preparing 2-fluoro-4-hydroxybenzaldehyde require ultra-low temperature equipment, expensive or toxic reagents, complex operations, and are not suitable for large-scale and industrial production.
2-Fluoro-4-methoxybenzaldehyde was generated by Grignard exchange of m-fluoroanisole with TEMPMgCl-LiCl solution, and then deprotected with a mixed Lewis acid catalyst to generate 2-fluoro-4-hydroxybenzaldehyde.
It achieves highly selective and high-yield synthesis, avoids high-temperature and high-pressure reactions, simplifies operation, reduces costs, and is suitable for industrial production.
Smart Images
Figure BDA0004631862960000011 
Figure BDA0004631862960000012 
Figure BDA0004631862960000021
Abstract
Description
Technical Field
[0001] This invention relates to a process for synthesizing 2-fluoro-4-hydroxybenzaldehyde, belonging to the field of pharmaceutical intermediates technology. Background Technology
[0002] 2-Fluoro-4-hydroxybenzaldehyde is mainly used as an intermediate in physiologically active compounds such as pharmaceuticals or pesticides. It is a widely used organic building block compound, and its structure contains fluorine, aldehyde, and phenolic hydroxyl groups, which can be added to or replaced by other functional groups.
[0003] Currently, there are not many reported methods for preparing 2-fluoro-4-hydroxybenzaldehyde in the literature: the usual route is to protect the hydroxyl group of 3-fluorophenol, then add an aldehyde group to butyllithium / DMF, and then deprotect to obtain 2-fluoro-4-hydroxybenzaldehyde.
[0004] (1) 3-Fluorophenol reacts with tert-butyldimethylchlorosilane to protect the hydroxyl group, and then butyllithium is dehydrogenated at ultra-low temperature and reacts with DMF to generate an aldehyde. Subsequently, under acidic conditions, the protection is removed to obtain 2-fluoro-4-hydroxybenzaldehyde.
[0005]
[0006] (2) Bromine is applied to m-fluoroanisole, followed by aldehyde grouping via butyllithium / DMF, and then deprotection is performed to obtain 2-fluoro-4-hydroxybenzaldehyde.
[0007]
[0008] (3) 2,4-Difluorobromobenzene is reacted with methanol via potassium tert-butoxide substitution to form a methoxy group, which is then subjected to butyllithium / DMF to form an aldehyde group, followed by deprotection to obtain 2-fluoro-4-hydroxybenzaldehyde.
[0009]
[0010] (4) 1-Bromo-2-fluoro-4-hydroxybenzene is etherified with sodium hydride and iodomethane, then aldehyde is added to butyllithium / DMF, and then deprotected to obtain 2-fluoro-4-hydroxybenzaldehyde.
[0011]
[0012] All four methods mentioned above require ultra-low temperatures, which places high demands on equipment and is not conducive to large-scale production. In addition, the reagents required for the first, third, and fourth methods are expensive and the operations are cumbersome; the second method requires the use of highly corrosive bromine; the third method has poor selectivity and low yield, making it unsuitable for industrial production; and the fourth method requires the use of iodomethane, a highly toxic substance, which is environmentally unfriendly, difficult to operate, and poses certain dangers and high safety risks. Summary of the Invention
[0013] To overcome the above-mentioned shortcomings, this invention provides an improved process for synthesizing 2-fluoro-4-hydroxybenzaldehyde. Using m-fluoroanisole as a raw material, it is directly converted to 2-fluoro-4-methoxybenzaldehyde via Grignard exchange with TEMP / MgCl-LiCl solution; then, it is deprotected with a mixed Lewis acid to generate 2-fluoro-4-hydroxybenzaldehyde. This method has the advantages of good selectivity, short steps, high yield, and ease of operation, possessing potential technological advantages and suitable for industrial-scale production.
[0014] The process for synthesizing 2-fluoro-4-hydroxybenzaldehyde according to the present invention includes the following steps:
[0015]
[0016] Step A: Add m-fluoroanisole and organic solvent to the reaction vessel, and add TEMPMgCl-LiCl solution dropwise while stirring at -40±5℃. After the addition is complete, keep the temperature at -40±5℃ to react. After the reaction is complete, add the formylation reagent dropwise while keeping the temperature at -40±5℃. After the addition is complete, let the temperature rise naturally to room temperature to react and obtain 2-fluoro-4-methoxybenzaldehyde.
[0017] Step B: Add 2-fluoro-4-methoxybenzaldehyde and organic solvent to the reaction vessel, control the temperature at 20±5℃, and add the mixed Lewis acid catalyst in batches while stirring. After the addition is complete, keep the temperature and react to obtain 2-fluoro-4-hydroxybenzaldehyde.
[0018] Further, in step A, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, and diethoxymethane.
[0019] Further, in step A, the molar ratio of m-fluoroanisole to TEMPMgCl-LiCl is 1:1-2.5.
[0020] Further, in step A, the formylation reagent is selected from N,N-dimethylformamide or N-formylmorpholine.
[0021] Further, in step A, the molar ratio of m-fluoroanisole to the formylation reagent is 1:1-1.5.
[0022] Further, in step B, the organic solvent is selected from anisole, 1,3-dimethoxybenzene, or 1,3,5-trimethoxybenzene.
[0023] Further, in step B, the mixed Lewis acid catalyst is selected from anhydrous aluminum trichloride / boron tribromide or an anhydrous aluminum trichloride / boron trichloride mixture.
[0024] Further, in step B, the molar ratio of 2-fluoro-4-methoxybenzaldehyde to the mixed Lewis acid catalyst is 1:1.5-2.5.
[0025] Beneficial effects of the invention
[0026] 1. The present invention has a short process, good selectivity, short reaction time, and a total yield of over 80%. The raw materials are readily available, no toxic intermediates are generated, the operation is simple, there are no harsh reactions at high temperature and high pressure, and no heavy metal contaminants. The raw materials are readily available and inexpensive. This method has potential technical advantages and is suitable for industrial-scale production.
[0027] 2. The process of this invention avoids the use of dangerous reagents such as iodomethane in other literature methods. It uses TEMP / mgCl-LiCl solution for Grignard exchange to directly and selectively obtain the target substituted aldehyde group. AlCl3 and other mixed Lewis acids are used to shorten the substitution reaction time and reduce the amount of AlCl3. It has good selectivity, mild and continuous reaction conditions, short reaction time, and is easy to operate. The purity of the final product can reach 99.8%. Attached Figure Description
[0028] Figure 1 The image shows the HNMR spectrum of the 2-fluoro-4-hydroxybenzaldehyde product in Example 1. Specific Implementation
[0029] Example 1
[0030] Step A: Add 80g (0.634mol) of m-fluoroanisole and 370mL of tetrahydrofuran to a three-necked reaction flask, turn on mechanical stirring, cool to -40℃, and slowly add 887mL (0.887mol) of 1M TEMP MgCl-LiCl solution at -40±5℃. After the addition is complete, keep the reaction at this temperature for 1 hour. Once the reaction is complete under GC control, control the temperature at -40±5℃ and add 55.61g (0.761mol) of DMF to the reactor. After the addition is complete, allow the temperature to rise naturally to room temperature and react for 1 hour. Take a sample for testing: under GC control, the reaction is complete. The temperature was controlled below 20℃. 10% hydrochloric acid was added dropwise to the reactor to adjust the pH of the aqueous layer to 3-4. 350 mL of ethyl acetate was added to the reactor and stirred for 15 minutes. The mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure to remove the solvent. 295 mL of heptane was added and stirred at 0-5℃ for 30 minutes. After filtration, 82.38 g of 2-fluoro-4-methoxybenzaldehyde was obtained as a white solid with a GC content of 98.5% and a yield of 84.3%.
[0031] Step B: Add 82.38 g (0.534 mol) of 2-fluoro-4-methoxybenzaldehyde and 375 mL of 1,3,5-trimethoxybenzene to a three-necked reaction flask. Start mechanical stirring and control the temperature at 15–20 °C. Add 85.44 g (0.641 mol) of aluminum trichloride and 18.78 g (0.160 mol) of boron trichloride in four batches. The method of adding the four batches is as follows: first, add the solid aluminum trichloride directly, then pass boron trichloride through the flask, repeating this process four times. Other examples follow the same method. After the addition is complete, maintain the temperature and stir for 6 hours. Stop the reaction in the GC process. Quench the reaction dropwise with ice water at 25 ± 5 °C and stir for 0.5 hours. Extract with 540 mL of MTBE, separate into layers, concentrate the organic layer until it stops flowing, add 435 mL of heptane and stir at room temperature for 15 minutes, filter to obtain 71.08 g of 2-fluoro-4-hydroxybenzaldehyde, a yellow-brown solid, GC 99.8%, yield 95%.
[0032] Example 2
[0033] Step A: Add 80g (0.634mol) of m-fluoroanisole and 370mL of tetrahydrofuran to a three-necked reaction flask, turn on mechanical stirring, cool to -40℃, and slowly add 887mL (0.887mol) of 1M TEMP MgCl-LiCl solution at -40±5℃. After the addition is complete, keep the reaction at this temperature for 1 hour, and take a sample for testing. After the GC reaction is complete, control the temperature at -40±5℃ and add 87.61g (0.761mol) of N-formylmorpholine to the reactor. After the addition is complete, allow the temperature to rise naturally to room temperature and react for 1.5 hours. The GC reaction is then complete. Controlling the temperature below 20℃, 10% hydrochloric acid was added dropwise to the reactor to adjust the pH of the aqueous layer to 3-4. 350 mL of ethyl acetate was added to the reactor and stirred for 15 minutes. After standing and separating the layers, the organic layer was concentrated under reduced pressure to remove the solvent. 290 mL of heptane was added and stirred at 0-5℃ for 30 minutes. After filtration, 78.47 g of 2-fluoro-4-methoxybenzaldehyde was obtained as a white solid with a GC content of 98.75% and a yield of 80.3%.
[0034] Step B: 78.47 g (0.509 mol) of 2-fluoro-4-methoxybenzaldehyde and 375 mL of 1,3,5-trimethoxybenzene were added to a three-necked reaction flask. Mechanical stirring was started, and the temperature was controlled at 15℃~20℃. 81.46 g (0.611 mol) of anhydrous aluminum trichloride and 17.89 g (0.153 mol) of boron trichloride were added in four batches. After the addition was complete, the mixture was kept at this temperature and stirred for 6 hours. The GC reaction was stopped at the control temperature. The reaction was quenched dropwise with ice water at 25±5℃ and stirred for 0.5 hours. 300 mL of dichloromethane was added for extraction, and the layers were separated. The organic layer was concentrated until it did not flow. 435 mL of heptane was added, and the mixture was stirred at room temperature for 15 minutes. Filtration yielded 66.32 g of 2-fluoro-4-hydroxybenzaldehyde, a yellow-brown solid, with a GC purity of 99.5% and a yield of 93%.
[0035] Example 3
[0036] Step A: Add 80g (0.634mol) of m-fluoroanisole and 380mL of 2-methyltetrahydrofuran to a three-necked reaction flask, turn on mechanical stirring, cool to -40℃, and slowly add 887mL (0.887mol) of 1M TEMP MgCl-LiCl solution at -40±5℃. After the addition is complete, keep the reaction at this temperature for 1 hour, and take a sample for testing: the reaction is complete under GC control. Control the temperature at -40±5℃, add 55.61g (0.761mol) of DMF to the reactor, and allow it to rise naturally to room temperature for 1 hour after the addition is complete. Take a sample for testing: the reaction is complete under GC control. Controlling the temperature below 20℃, 10% hydrochloric acid was added dropwise to the reactor to adjust the pH of the aqueous layer to 3-4. 330 mL of ethyl acetate was added to the reactor and stirred for 15 minutes. After standing and separating the layers, the organic layer was concentrated under reduced pressure to remove the solvent. 290 mL of heptane was added and stirred at 0-5℃ for 30 minutes. After filtration, 79.35 g of 2-fluoro-4-methoxybenzaldehyde was obtained as a white solid with a GC content of 98% and a yield of 81.2%.
[0037] Step B: 79.35 g (0.515 mol) of 2-fluoro-4-methoxybenzaldehyde and 426 mL of anisole were added to a three-necked reaction flask. Mechanical stirring was started, and the temperature was controlled at 15–20 °C. 82.40 g (0.618 mol) of anhydrous aluminum trichloride and 18.10 g (0.155 mol) of boron trichloride were added in four batches. After the addition was complete, the mixture was kept at this temperature and stirred for 5 hours. The GC reaction was stopped at the control temperature. The reaction was quenched dropwise with ice water at 25 ± 5 °C, and stirred for 0.5 hours. 460 mL of MTBE was added for extraction, and the layers were separated. The organic layer was concentrated until it did not flow. 435 mL of heptane was added, and the mixture was stirred at room temperature for 15 minutes. Filtration yielded 68.11 g of 2-fluoro-4-hydroxybenzaldehyde, a yellow-brown solid, with a GC purity of 99.25% and a yield of 94.4%.
[0038] Example 4
[0039] Step A: Add 80g (0.634mol) of m-fluoroanisole and 370mL of tetrahydrofuran to a three-necked reaction flask, turn on mechanical stirring, cool to -40℃, and slowly add 793mL (0.793mol) of 1M TEMP MgCl-LiCl solution at -40±5℃. After the addition is complete, keep the reaction at this temperature for 1 hour, and take a sample for testing: the reaction is complete under GC control. Control the temperature at -40±5℃, add 55.61g (0.761mol) of DMF to the reactor, and allow it to rise naturally to room temperature for 1 hour. Take a sample for testing: the reaction is complete under GC control. The temperature was controlled below 20℃. 10% hydrochloric acid was added dropwise to the reactor to adjust the pH of the aqueous layer to 3-4. 333 mL of ethyl acetate was added to the reactor and stirred for 15 minutes. The mixture was allowed to stand and separate into layers. The organic layer was concentrated under reduced pressure to remove the solvent. 293 mL of heptane was added and stirred at 0-5℃ for 30 minutes. After filtration, 77.2 g of 2-fluoro-4-methoxybenzaldehyde was obtained as a white solid with a GC content of 98.7% and a yield of 79%.
[0040] Step B: 77.2 g (0.501 mol) of 2-fluoro-4-methoxybenzaldehyde and 375 mL of 1,3,5-trimethoxybenzene were added to a three-necked reaction flask. Mechanical stirring was started, and the temperature was controlled at 15–20 °C. 86.84 g (0.651 mol) of anhydrous aluminum trichloride and 29.35 g (0.251 mol) of boron trichloride were added in four batches. After the addition was complete, the mixture was kept at this temperature and stirred for 5 hours. The GC reaction was stopped at the control temperature. The reaction was quenched dropwise with ice water at 25 ± 5 °C, and stirred for 0.5 hours. 540 mL of methyl tert-butyl ether was added for extraction, and the layers were separated. The organic layer was concentrated until it did not flow. 435 mL of heptane was added, and the mixture was stirred at room temperature for 15 minutes. Filtration yielded 67.06 g of 2-fluoro-4-hydroxybenzaldehyde, a yellow-brown solid, with a GC purity of 99.64% and a yield of 95.53%.
[0041] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.
Claims
1. A process for the synthesis of 2-fluoro-4-hydroxybenzaldehyde, characterized in that, The method comprises the following steps: Step A: m-fluoroanisole and an organic solvent are added into a reaction kettle, temperature is controlled at -40±5 ℃, and a TEMPMgCl-LiCl solution is added dropwise under stirring, after the dropwise addition is completed, the reaction is kept at the temperature, after the reaction is completed, formylating reagent is added dropwise under stirring at -40±5 ℃, the temperature is naturally increased to room temperature after the dropwise addition is completed, and 2-fluoro-4-methoxybenzaldehyde is obtained; Step B: 2-fluoro-4-methoxybenzaldehyde and an organic solvent are added into a reaction kettle, temperature is controlled at 20±5 ℃, mixed Lewis acid catalyst is added in batches under stirring, after the addition is completed, the reaction is kept at the temperature, and 2-fluoro-4-hydroxybenzaldehyde is obtained; the organic solvent is selected from anisole, 1,3-dimethoxybenzene or 1,3,5-trimethoxybenzene; and the mixed Lewis acid catalyst is selected from anhydrous aluminum chloride / boron tribromide or anhydrous aluminum chloride / boron trichloride mixture.
2. The process for synthesis of 2-fluoro-4-hydroxybenzaldehyde as claimed in claim 1, wherein: In step A, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether or diethoxy methane.
3. The process for synthesis of 2-fluoro-4-hydroxybenzaldehyde as claimed in claim 1, wherein: In step A, the molar ratio of m-fluoroanisole to TEMPMgCl-LiCl is 1:1-2.
5.
4. The process for synthesis of 2-fluoro-4-hydroxybenzaldehyde as claimed in claim 1, wherein: In step A, the formylating reagent is selected from N,N-dimethylformamide or N-formylmorpholine.
5. The process for synthesis of 2-fluoro-4-hydroxybenzaldehyde as claimed in claim 1, wherein: In step A, the molar ratio of m-fluoroanisole to formylating reagent is 1:1-1.
5.
6. The process for synthesis of 2-fluoro-4-hydroxybenzaldehyde as claimed in claim 1, wherein: In step B, the molar ratio of 2-fluoro-4-methoxybenzaldehyde to mixed Lewis acid catalyst is 1:1.5-2.5.