Method for preparing 5-fluorosalicylaldehyde from p-fluorophenol

Abstract

The invention discloses a method for preparing 5-fluorosalicylaldehyde from p-fluorophenol, and belongs to the technical field of organic synthesis. A mild formylation method is realized by innovatively adopting a catalyst and an active methylene derivative (POCl3 + DMF) as a C1 source. According to the method, p-fluorophenol is taken as a raw material, in the presence of a catalytic amount of titanium tetrachloride, p-fluorophenol, phosphorus oxychloride and N, N-dimethylformamide are subjected to Vilsmeier-Haack reaction in dichloromethane to synthesize p-fluorobenzaldehyde, and then a methanol-water recrystallization process is adopted to replace distillation for purification. Core improvements include: (1) titanium tetrachloride catalyzes Vilsmeier-Haack reaction, and by-products are few; (2) the temperature is controlled by stages, and the operation is easy to control; (3) directly dropwise adding reaction liquid to hydrolyze at 10-25 DEG C; and (4) methanol / water recrystallization purification. According to the method, the defects of a traditional process are overcome, the purity of a crude product reaches 85%-92%, the purity after recrystallization is larger than or equal to 98.5%, the yield is stabilized at 88%-91%, and the method is easy and convenient to operate, low in energy consumption, environmentally friendly and easy to industrialize.

Description

Technical Field

[0001] This invention belongs to the field of organofluorine synthesis technology, specifically relating to a method for preparing 5-fluorosalicylaldehyde from p-fluorophenol. Background Technology

[0002] 5-Fluorosalicylic acid aldehyde is a key intermediate in the pharmaceutical and pesticide fields, and the efficiency and economy of its synthesis process have always been a focus of industry research. Current synthetic methods have significant limitations: the NaOH / chloroform method has extremely low yields, only 20%-25%, which is insufficient for industrial applications; the anhydrous magnesium chloride / formaldehyde / tetrahydrofuran method, while achieving yields of around 85%, requires high anhydrous content, has high TFA recovery costs, cannot be used directly, and faces difficulties in impurity separation; processes using acetonitrile as a solvent have low yields and limited practicality; the TFA / hexamethylenetetramine method has unstable yields and is unsuitable for industrial scale-up. Among existing technologies, the anhydrous magnesium chloride / formaldehyde / tetrahydrofuran method has become mainstream due to its relatively high yield, but it still fails to solve the core problems commonly found in traditional processes, such as yield fluctuations, complex reaction systems, and difficulty in impurity removal. Therefore, developing new synthetic methods to overcome these bottlenecks is of great significance. Summary of the Invention

[0003] The purpose of this invention is to provide a method for preparing 5-fluorosalicylaldehyde from p-fluorophenol. To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing 5-fluorosalicylaldehyde from p-fluorophenol includes the following steps: The specific process is as follows: (1) Wilsmayer-Hacker reaction: p-fluorophenol, phosphorus oxychloride, and DMF are reacted in the presence of a solvent and a catalyst to generate a 5-fluorosalicylaldehyde imine salt intermediate; the catalyst is titanium tetrachloride; the solvent is dichloromethane; (2) Direct hydrolysis: Add the reaction solution from step (1) dropwise to water at 10-25℃ at a rate of 1-2 mL / min, with a volume ratio of reaction solution to water of 1:(3-5), and stir for 1-2 h; (3) Separation and purification: 5-fluorosalicylaldehyde crude product was obtained by extraction, washing and drying, and then purified by recrystallization using a mixed solvent of methanol and water to obtain 5-fluorosalicylaldehyde; The molar ratio of p-fluorophenol, phosphorus oxychloride, DMF and titanium tetrachloride is 1:(1.2~1.3):(2.8~3.2):(0.25~0.35); the volume ratio of methanol to water in the mixed solvent of methanol and water is 1:(2~3).

[0004] Furthermore, the specific process of step (1) is as follows: a) Add p-fluorophenol, partially dried DMF and anhydrous dichloromethane to the reaction flask, and cool to 0-15°C in an ice bath with stirring; b) Dilute phosphorus oxychloride with anhydrous dichloromethane and add it dropwise to the reaction flask at a rate of 1-2 mL / min; c) Add the remaining dry DMF, remove the ice bath, raise the temperature to 15~30℃, dilute titanium tetrachloride with anhydrous dichloromethane and add it in batches, and keep it at the temperature for 40~50min after the addition is complete. d) Increase the temperature to 35~55℃, and if the GC monitoring shows that the conversion rate of p-fluorophenol is <1%, stop the reaction.

[0005] Further, in step a), the amount of dried DMF added is 1 / 2 to 2 / 3 of the total amount of DMF added, and the concentration of p-fluorophenol in anhydrous dichloromethane is 1 to 5 mol / L; in step b), the concentration of phosphorus oxychloride in anhydrous dichloromethane is 1 to 5 mol / L; in step c), the concentration of titanium tetrachloride in anhydrous dichloromethane is 1 to 5 mol / L.

[0006] Furthermore, in step b), when adding diluted phosphorus oxychloride, the system temperature is controlled to be ≤10℃.

[0007] Furthermore, in step c), titanium tetrachloride needs to be diluted with dichloromethane and added in batches, with an interval of 10-15 minutes between each batch, and the system temperature should be controlled to be ≤30℃.

[0008] Furthermore, the molar ratio of p-fluorophenol to titanium tetrachloride is 1:(0.3~0.32).

[0009] Further, the process parameters for recrystallization purification in step (3) using a mixed solvent of methanol and water are as follows: the crude product is added to a mixed solvent of methanol and water, stirred at 60~65℃ until completely dissolved, cooled to 5~10℃ at a rate of 1~2℃ / min, and aged for 2~3h; then vacuum filtered, and the filter cake is washed 1~3 times with ice water below 5℃; finally, it is vacuum dried at 40~45℃ and -0.09~-0.095MPa for 3~4h to obtain 5-fluorosalicylaldehyde with a purity ≥98.5%.

[0010] Furthermore, the pressure during vacuum filtration is -0.08 to -0.09 MPa.

[0011] Furthermore, in step (3), the pH is adjusted to 1-2 with acid during extraction, the layers are separated, and the organic phase is taken; washing is performed 1-3 times with saturated brine; drying is performed with anhydrous magnesium sulfate or anhydrous sodium sulfate.

[0012] This application innovatively uses TiCl4-catalyzed active methylene derivatives (POCl3+DMF) as the C1 source to achieve a milder formylation method. The optimal catalyst was determined through systematic screening. At the same time, low-cost reagents and solvents were used, and the purification process was optimized (such as recrystallization using a methanol-water system). This resulted in a technical solution that can significantly improve the synthesis efficiency of 5-fluorosalicylaldehyde and reduce production costs, providing a better path for its industrial production. Attached Figure Description

[0013] Figure 1 It is the 5-fluorosalicylaldehyde prepared in Example 1. 1 H-NMR spectrum; Figure 2 This is the F-NMR spectrum of 5-fluorosalicylaldehyde obtained in Example 1; Figure 3 This is the HPLC chromatogram of 5-fluorosalicylaldehyde prepared in Example 1. Detailed Implementation

[0014] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0015] Catalyst system screening experiment The performance of three catalysts, AlCl3, TiCl4, and BF3·Et2O, was compared using the controlled variable method. The experimental conditions were: 30 g (1 eq) of p-fluorophenol, 1.2 eq of POCl3, 3 eq of DMF, 120 mL of dichloromethane, reaction temperature of 45℃, and catalyst dosage of 0.3 eq. The results are shown in Table 1.

[0016] Table 1: Conclusion: Titanium tetrachloride is significantly superior to AlCl3 and BF3·Et2O in terms of conversion, selectivity and yield, and is the optimal catalyst. The optimal dosage range is 0.25~0.35 eq (conversion rate <98% when dosage <0.25 eq, by-product increase >2% when dosage >0.35 eq).

[0017] The core advantages of the titanium tetrachloride catalytic system 1. High stability of the active complex: The [Me2N] complex formed by titanium tetrachloride and DMF + =CHCl] TiCl5⁻ complex has a half-life of more than 10 hours (AlCl3 complex has a half-life of 6-7 hours), and can maintain its activity in a wide temperature range of 35-55℃, avoiding side reactions caused by complex decomposition during the reaction process; 2. Excellent selectivity: Titanium tetrachloride has strong activation specificity for the ortho-position of the hydroxyl group on the benzene ring, which can reduce substitution reactions at other sites on the benzene ring; 3. Simple post-processing: The hydrolysis product of titanium tetrachloride can be completely removed by washing with water at pH=1 without the need for additional neutralization steps, providing a high-purity crude product basis for subsequent methanol-water recrystallization purification.

[0018] Process parameter optimization 1. DMF dosage 3 eq: Excess DMF can further stabilize the active titanium tetrachloride complex, while neutralizing the HCl generated in the reaction, avoiding HCl damage to raw materials and products, ensuring that the purity of crude product reaches 88%~92%, meeting the requirements for recrystallization raw materials; 2. Main reaction temperature: 35~55℃; below 35℃, the reaction rate is slow (>6h); above 55℃, [Me2N] + =CHCl]TiCl5⁻ is easily decomposed, increasing byproducts. 35~55℃ is the optimal temperature range for titanium tetrachloride catalysis, which can reduce the interference of byproducts on recrystallization purification. 3. Direct hydrolysis process: Hydrolysis at 10~25℃ can avoid the aggregation of titanium tetrachloride hydrolysis product Ti(OH)4 at high temperature, ensuring that it is completely soluble in water, reducing the pollution to the organic phase, and increasing the purity of crude product to 88%~92%. It can directly enter the recrystallization process without pretreatment. 4. Optimization of methanol-water recrystallization parameters: (1) Solvent ratio: The volume ratio of methanol to water is 1:2 to 1:3. Under this ratio, 5-fluorosalicylaldehyde can be completely dissolved at 60 to 65°C. After cooling, the crystals precipitated have a purity of ≥98.5%. If the methanol ratio is too high (>1:2), the loss will be large, impurities will be difficult to remove, and the yield will be low. If the water ratio is too high (<1:3), the raw materials will not be completely dissolved. (2) Temperature control: Dissolving at 60~65℃ can reduce solvent loss and oxidation of 5-fluorosalicylaldehyde; slowly cooling to 5~10℃ at 1~2℃ / min and aging for 2~3h can form uniform crystals and reduce residual impurities in the mother liquor; vacuum drying at 40~45℃ will not cause product deterioration and will shorten the drying time.

[0019] Based on the above-mentioned optimized parameters, the preferred embodiments of this application are as follows: Example 1 A method for preparing 5-fluorosalicylaldehyde from p-fluorophenol, the process is as follows: (1) Reaction preparation: Add 30g (0.268mol, 1 eq) of p-fluorophenol, 29.75g (0.412mol, 1.5 eq, first batch) of ultra-dry DMF, and 120g (100mL) of anhydrous dichloromethane to a 500mL three-necked flask, and cool to 0~5℃ in an ice bath with stirring.

[0020] (2) POCl3 addition: Dilute 46.8g (0.312mol, 1.2 eq) of phosphorus oxychloride with 90mL of dichloromethane and add it dropwise to the flask at a rate of 1~1.2mL / min, keeping the temperature ≤10℃ and the addition time 60min.

[0021] (3) Addition and activation of titanium tetrachloride: Add the remaining 29.75g of DMF (1.5 eq, second batch), remove the ice bath, and heat to 25℃; dilute 11.8g of titanium tetrachloride (0.067mol, 0.3 eq) with 20mL of dichloromethane, add it in 3 batches (15min interval between each batch), and control the temperature ≤30℃; after the addition is complete, keep warm for 45min to ensure that the active complex is fully formed.

[0022] (4) Main reaction: Heat to 45℃ and react for 4.5h; GC monitoring shows that the residual amount of p-fluorophenol is 1%, then stop the reaction.

[0023] (5) Hydrolysis and separation: The reaction solution was added dropwise to 300 mL of 15℃ water at a rate of 1.5 mL / min and stirred for 1.5 h. The pH was adjusted to 1 with 1N concentrated hydrochloric acid, and the mixture was allowed to stand for separation. The lower organic phase (about 185 mL) was collected, and the aqueous phase was extracted twice with 60 mL of dichloromethane. The organic phases were then combined.

[0024] (6) Preparation of crude product: The organic phase was washed twice with 50 mL of saturated brine, and dried with 15 g of anhydrous magnesium sulfate for 4 h. After filtration, the dichloromethane was recovered by vacuum distillation (38 °C, -0.085 MPa) (recovery rate 83%), and 32.8 g of crude product (purity 90.5%) was obtained.

[0025] (7) Methanol-water recrystallization: 32.8 g of crude product was added to a 500 mL three-necked flask, along with 40 mL of methanol and 80 mL of deionized water (volume ratio 1:2). The mixture was heated to 62 °C with stirring and kept at this temperature for 15 min until the solid was completely dissolved. The temperature was then lowered to 8 °C at a rate of 1.5 °C / min and aged for 2.5 h. Subsequently, the mixture was filtered under reduced pressure (vacuum degree -0.085 MPa), and the filter cake was washed twice with 10 mL of 5 °C deionized water. The filter cake was then placed in a vacuum drying oven and dried at 42 °C and -0.092 MPa for 3.5 h to obtain 29.85 g of pure 5-fluorosalicylaldehyde, with a yield of 91%. The HPLC chromatogram is shown below. Figure 3 As shown, the purity is 98.5%. 1 H-NMR spectrum as follows Figure 1 As shown, HNMR (400M, d-DMSO): 10.69 (s, 1H); 10.25 (d, J=2.8Hz, 1H); 7.42-7.36 (m, 2H); 7.05-7.01 (dd, J=9.2Hz; 3.3Hz). F-NMR spectrum as follows Figure 2 As shown, FNMR (376M, d-DMSO): 124.56.

[0026] Example 2 Except for replacing the catalyst with 8.9 g (0.3 eq) of anhydrous AlCl3, the main reaction temperature with 45 °C, and the reaction time with 6 h, the other steps were the same as in Example 1. Results: The purity of the crude product was 85.2%. After recrystallization from methanol and water (solvent ratio 1:2.5), the pure product yield was 86.3%, the purity was 98.0%, and the total content of by-products was 2.5%, which was significantly lower than that of the titanium tetrachloride catalytic system.

[0027] Example 3 Except for replacing the catalyst with 10.2 g (0.3 eq) of BF3·Et2O solution, the main reaction temperature with 55℃, and the reaction time with 7 h, the other steps were the same as in Example 1. Results: The crude product purity was 81.3%. After recrystallization with methanol-water (solvent ratio 1:3), the pure product yield was 80.1%, the purity was 97.3%, and the total content of by-products was 4.0%, which was the worst performance.

[0028] In conclusion: Catalyst optimality was clearly demonstrated: through systematic screening, titanium tetrachloride was determined to be the optimal catalyst, compared to AlCl3 and BF3. . H2O increases yield by 3% to 10% and reduces byproducts by 1.5% to 3.5%, providing high-purity crude product for subsequent recrystallization and purification, thus reducing purification difficulty; The purification process has significant advantages: methanol-water recrystallization replaces traditional distillation, eliminating the need for complex packed towers and reflux ratio control, reducing operational difficulty and energy consumption by more than 40%; and the purity after recrystallization is ≥98.5%, comparable to the distillation process, meeting the requirements for pharmaceutical-grade intermediates; The process is highly efficient and stable: the reaction time of the titanium tetrachloride catalytic system is shortened to 4-5 hours (AlCl3 requires 6-7 hours), the methanol-water recrystallization process takes only 5-6 hours (distillation requires 8-10 hours), and the total process cycle is shortened by 30%; the yield fluctuation in the pilot-scale test (100L reactor) is ≤1.0%, and it has strong adaptability to industrialization. Low environmental cost: The amount of titanium tetrachloride used is only 0.25~0.35 eq, the amount of titanium-containing wastewater discharged is reduced by 60% compared with the AlCl3 process, and titanium can be recovered through wastewater treatment (to prepare TiO2); methanol can be recovered through mother liquor distillation (recovery rate ≥85%), realizing resource recycling and reducing environmental costs and raw material losses.

Claims

1. A method for preparing 5-fluorosalicylaldehyde from p-fluorophenol, characterized in that, Includes the following steps: The specific process is as follows: (1) Wilsmayer-Hacker reaction: p-fluorophenol, phosphorus oxychloride, and DMF are reacted in the presence of a solvent and a catalyst to generate p-fluorobenzaldehyde imine salt intermediate; the catalyst is titanium tetrachloride; the solvent is dichloromethane; (2) Direct hydrolysis: Add the reaction solution from step (1) dropwise to water at 10-25℃ at a rate of 1-2 mL / min, with a volume ratio of reaction solution to water of 1:(3-5), and stir for 1-2 h; (3) Separation and purification: p-fluorobenzaldehyde crude product was obtained by extraction, washing and drying, and then p-fluorobenzaldehyde was purified by recrystallization using a mixed solvent of methanol and water. The molar ratio of p-fluorophenol, phosphorus oxychloride, DMF and titanium tetrachloride is 1:(1.2~1.3):(2.8~3.2):(0.25~0.35); the volume ratio of methanol to water in the mixed solvent of methanol and water is 1:(2~3).

2. The method according to claim 1, characterized in that, The specific process of step (1) is as follows: a) Add p-fluorophenol, partially dried DMF and anhydrous dichloromethane to the reaction flask, and cool to 0-15°C in an ice bath with stirring; b) Dilute phosphorus oxychloride with anhydrous dichloromethane and add it dropwise to the reaction flask at a rate of 1-2 mL / min; c) Add the remaining dry DMF, remove the ice bath, raise the temperature to 15~30℃, dilute titanium tetrachloride with anhydrous dichloromethane and add it in batches, and keep it at the temperature for 40~50min after the addition is complete. d) Increase the temperature to 35~55℃, and stop the reaction when the GC monitoring shows that the conversion rate of p-fluorophenol is <1%.

3. The method according to claim 2, characterized in that, In step a), the amount of dried DMF added is 1 / 2 to 2 / 3 of the total amount of DMF added, and the concentration of p-fluorophenol in anhydrous dichloromethane is 1 to 5 mol / L; in step b), the concentration of phosphorus oxychloride in anhydrous dichloromethane is 1 to 5 mol / L; in step c), the concentration of titanium tetrachloride in anhydrous dichloromethane is 1 to 5 mol / L.

4. The method according to claim 2, characterized in that, In step c), titanium tetrachloride needs to be diluted with dichloromethane and added in batches, with an interval of 10-15 minutes between each batch, and the system temperature should be controlled to be ≤30℃.

5. The method according to claim 1, characterized in that, The molar ratio of p-fluorophenol to titanium tetrachloride is 1:(0.3~0.32).

6. The method according to claim 1, characterized in that, The process parameters for recrystallization purification in step (3) using a mixed solvent of methanol and water are as follows: Add the crude product to a mixed solvent of methanol and water, stir at 60~65℃ until completely dissolved, cool down to 5~10℃ at a rate of 1~2℃ / min, and keep warm for aging for 2~3h; then filter under reduced pressure, and wash the filter cake with ice water below 5℃; finally, vacuum dry at 40~45℃ and -0.09~-0.095MPa for 3~4h to obtain p-fluorobenzaldehyde with a purity ≥98.5%.

7. The method according to claim 6, characterized in that, The pressure during vacuum filtration is -0.08 to -0.09 MPa.

8. The method according to claim 1, characterized in that, In step (3), the pH is adjusted to 1-2 with acid during extraction, the layers are separated, and the organic phase is taken; washing is done with saturated brine; drying is done with anhydrous magnesium sulfate or anhydrous sodium sulfate.

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