Synthesis method of [2-(4-aminophenyl)-1-hydroxy-1-phosphinoethyl] phosphonic acid
By using trifluoroacetic acid and propionic acid as solvents and catalysts, controlling the reaction temperature and pH value, and simplifying the purification steps, the problems of condition sensitivity, cumbersome purification, and large amount of wastewater in the synthesis of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid in the prior art have been solved, achieving efficient, environmentally friendly, high-purity, and high-yield synthesis.
Patent Information
- Application Number
- CN202511194475.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-25
- Publication Date
- 2025-11-18
AI Technical Summary
The existing synthesis process of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid has problems such as condition sensitivity, complicated purification, low yield, and large amount of wastewater generation, making it difficult to achieve large-scale application.
Trifluoroacetic acid was used as the solvent acid, propionic acid as the additive acid and catalyst, and the reaction temperature and pH were controlled. The pH of the environment was balanced by buffering solvent, the reaction temperature was reduced, side reactions were reduced, room temperature hydrolysis was used and purification steps were simplified, and the amount of water used for post-treatment was reduced.
It has achieved the synthesis of high purity (above 99%) and high yield (≥55%), reduced production costs and environmental impact, and improved the stability of scale-up production.
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Figure CN120965752A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing a compound. Background Technology
[0002] [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid (hereinafter referred to as "aminoaryl bisphosphonic acid") is a class of functional compounds with significant application value. The synergistic effect of the amino group and bisphosphonic acid group in its molecular structure gives it an important role in pharmaceutical intermediates (such as alendronate sodium analogs for osteoporosis), inkjet printing pigment modifiers, and metal chelating agents. With the functionalization of inkjet printing pigments (such as phosphorus-treated pigment modification in the EP / US patent) and the accelerated development of targeted drugs, the market demand for high-purity aminoaryl bisphosphonic acid has surged. However, existing processes struggle to achieve optimal yield. In summary, a universally applicable continuous production solution is still lacking. Therefore, developing a simple, high-yield, and easily scalable method for synthesizing aminoaryl bisphosphonic acid has become a pressing technical challenge in this field.
[0003] Existing synthetic processes suffer from bottlenecks such as condition sensitivity, cumbersome purification, low yield, and high wastewater generation, which severely restrict their large-scale application. For example, the current mainstream synthetic method is based on the phosphorous acid-carboxylic acid-phosphorus trichloride (PCl3) condensation system, which is reacted in a strong protic solvent (such as methanesulfonic acid). Taking WO2012090477A1 (Dai Nippon Printing), US20180265727A1 (Seiko Epson), and US20160075880A1 (Cabot) as examples, their core steps can be summarized as follows: Condensation reaction: 4-aminophenylacetic acid and phosphorous acid are dissolved in methanesulfonic acid, heated to 65℃ to dissolve, and then PCl3 is slowly added dropwise (molar ratio of about 1:2.1), and the temperature is controlled at 40℃~70℃ for 12h~24h; Quenching and hydrolysis: The reaction solution is poured into an ice-water mixture and heated to 90℃~95℃ to promote hydrolysis; Purification: The pH is adjusted to 4~5 (NaOH solution), cooled to crystallize, filtered, washed and dried. Although this route has been repeatedly verified by multiple patents (e.g., yields are generally 25%~30%), it has inherent drawbacks. For example, it is sensitive to conditions: it requires an inert atmosphere (nitrogen replacement), and fluctuations in temperature or pH can easily lead to an increase in byproducts (such as phosphorylation or pyrophosphate); purification is cumbersome: it requires heating hydrolysis and low-temperature crystallization (5°C ice bath), resulting in poor stability in scale-up production, leading to most production processes being pilot-scale experiments, with the amount of 4-aminophenylacetic acid used being around 30g; yield bottleneck: the steric hindrance and electronic effects of the aminoaryl base cause low condensation efficiency, with the highest yield in the literature being less than 30% (GR Kieczykowski. J. Org. Chem. 1995, 60, 8310-8312); and it generates a lot of wastewater: the amount of methanesulfonic acid and phosphorous acid used in the experiment is large, and the amount of water required for post-treatment is also large. Summary of the Invention
[0004] This invention aims to solve the problems of existing methods for preparing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid, such as sensitive conditions, cumbersome purification, low yield, and large amount of wastewater generation, and thus provides a method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid.
[0005] A method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid, which is carried out according to the following steps:
[0006] I. System reaction:
[0007] Trifluoroacetic acid and propionic acid were added to 4-aminophenylacetic acid, and the mixture was heated to dissolve the 4-aminophenylacetic acid. Then, phosphorus trichloride was slowly added dropwise to the reaction system. After the addition was completed, the reaction was carried out at a temperature of 60℃~65℃ and a stirring speed of 450r / min~500r / min for 12h~16h to obtain a brown transparent solution.
[0008] II. Post-processing:
[0009] The brown transparent solution was cooled to room temperature, then water was added and hydrolyzed at room temperature for 3-5 hours. The pH was then adjusted with sodium hydroxide solution, and a white solid precipitated. Finally, the solution was allowed to stand, washed, and dried in sequence to complete the synthesis of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid.
[0010] The beneficial effects of this invention are:
[0011] 1. This invention uses trifluoroacetic acid as the solvent acid, which has a strong proton-donating ability, and propionic acid as the additive acid, which acts as a buffer solvent and catalyst. By balancing the pH of the environment and lowering the reaction temperature, possible side reactions in the reaction are reduced. The purity is above 99% and the yield is ≥55%.
[0012] 2. The reaction temperature of this invention is relatively low, and the pH can be well controlled by using propionic acid as a buffer solvent. Nitrogen purging is not required, and the conditions are relatively mild and not harsh.
[0013] 3. This invention uses a small amount of acid in the reaction, requires less water for post-treatment, and is environmentally friendly;
[0014] 4. The hydrolysis of this invention does not require heating and can be carried out at room temperature. There is no need for ice bath crystallization when adjusting the pH, and the purification steps are simple.
[0015] 5. This invention has good stability in large-scale production, and the amount of raw material 4-aminophenylacetic acid can be increased to more than 100g.
[0016] This invention relates to a method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid. Attached Figure Description
[0017] Figure 1 The NMR spectrum of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 1;
[0018] Figure 2 The high-resolution mass spectra of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 1 are shown.
[0019] Figure 3 The liquid chromatogram is of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 1. Detailed Implementation
[0020] Specific Implementation Method 1: This embodiment describes a method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid, which is carried out according to the following steps:
[0021] I. System reaction:
[0022] Trifluoroacetic acid and propionic acid were added to 4-aminophenylacetic acid, and the mixture was heated to dissolve the 4-aminophenylacetic acid. Then, phosphorus trichloride was slowly added dropwise to the reaction system. After the addition was completed, the reaction was carried out at a temperature of 60℃~65℃ and a stirring speed of 450r / min~500r / min for 12h~16h to obtain a brown transparent solution.
[0023] II. Post-processing:
[0024] The brown transparent solution was cooled to room temperature, then water was added and hydrolyzed at room temperature for 3-5 hours. The pH was then adjusted with sodium hydroxide solution, and a white solid precipitated. Finally, the solution was allowed to stand, washed, and dried in sequence to complete the synthesis of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid.
[0025] The 4-aminophenylacetic acid described in step one of this specific embodiment has the following structural formula;
[0026] ;
[0027] The specific synthetic route of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid in this embodiment is as follows:
[0028] .
[0029] The beneficial effects of this embodiment are:
[0030] 1. In this embodiment, trifluoroacetic acid is used as the solvent acid, which has a strong proton-donating ability. Propionic acid is used as the additive acid, which acts as a buffer solvent and catalyst. By balancing the pH of the environment and lowering the reaction temperature, possible side reactions in the reaction are reduced. The purity is above 99% and the yield is ≥55%.
[0031] 2. This embodiment has a low reaction temperature, and the pH can be well controlled by using propionic acid as a buffer solvent. It does not require nitrogen purging, and the conditions are relatively mild and not harsh.
[0032] 3. This embodiment uses a small amount of acid in the reaction and requires less water for post-treatment, making it environmentally friendly;
[0033] 4. In this embodiment, hydrolysis does not require heating and can be carried out at room temperature. No ice bath is required when adjusting the pH for crystallization, and the purification steps are simple.
[0034] 5. This embodiment has good stability in large-scale production, and the amount of raw material 4-aminophenylacetic acid can be increased to more than 100g.
[0035] Specific Implementation Method Two: This implementation method differs from Specific Implementation Method One in that the molar ratio of 4-aminophenylacetic acid to trifluoroacetic acid in step one is 1 mol:(200~300) mL. Everything else is the same as in Specific Implementation Method One.
[0036] Specific Implementation Method Three: This implementation method differs from Specific Implementation Method One or Two in that the molar ratio of 4-aminophenylacetic acid to propionic acid in step one is 1:(0.75~2). Everything else is the same as in Specific Implementation Method One or Two.
[0037] Specific Implementation Method Four: This implementation method differs from Specific Implementation Methods One to Three in that the molar ratio of 4-aminophenylacetic acid to phosphorus trichloride in step one is 1:(2~3). Everything else is the same as in Specific Implementation Methods One to Three.
[0038] Specific Implementation Method Five: This implementation method differs from Specific Implementation Methods One to Four in that: in step one, the temperature is raised to 55℃~65℃ to dissolve 4-aminophenylacetic acid. Everything else is the same as in Specific Implementation Methods One to Four.
[0039] Specific Implementation Method Six: This implementation method differs from Specific Implementation Methods One to Five in that: in step one, phosphorus trichloride is slowly added dropwise to the reaction system using a constant pressure dropping funnel at a temperature of 60℃~65℃ and a dropping time of 0.5h~2h. Everything else is the same as in Specific Implementation Methods One to Five.
[0040] Specific Implementation Method Seven: This implementation method differs from Specific Implementation Methods One to Six in that hydrogen chloride gas is generated during the reaction in step one, and the hydrogen chloride gas is passed into the sodium hydroxide aqueous solution. Everything else is the same as in Specific Implementation Methods One to Six.
[0041] Specific Implementation Method Eight: This implementation method differs from Specific Implementation Methods One to Seven in that water is added at a rate of 2 mL / min to 10 mL / min in step two. Everything else is the same as in Specific Implementation Methods One to Seven.
[0042] Specific Implementation Method Nine: This implementation method differs from Specific Implementation Methods One to Eight in that the volume ratio of the brown transparent solution to water in step two is 1:(0.5~2). Everything else is the same as in Specific Implementation Methods One to Eight.
[0043] Specific Implementation Method Ten: This implementation method differs from Specific Implementation Methods One to Nine in that: in step two, sodium hydroxide solution is added at a rate of 2 mL / min to 10 mL / min under a water bath at room temperature to adjust the pH to 4 to 5, precipitating a white solid. The solid is then allowed to stand at room temperature, the upper yellow liquid is removed, and the white solid is washed with water. This process of standing, removing the upper liquid, and washing is repeated multiple times. The solid product is then collected by suction filtration and finally vacuum dried overnight. Everything else is the same as in Specific Implementation Methods One to Nine.
[0044] The beneficial effects of the present invention are verified using the following embodiments:
[0045] Example 1:
[0046] A method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid, which is carried out according to the following steps:
[0047] I. System reaction:
[0048] Trifluoroacetic acid and propionic acid were added to 50g of 4-aminophenylacetic acid, and the mixture was heated to 60℃~65℃ to dissolve the 4-aminophenylacetic acid. Then, using a constant pressure dropping funnel, phosphorus trichloride was slowly added dropwise to the reaction system at 60℃~65℃ for 30min. After the addition was completed, the reaction was carried out for 16h at 60℃~65℃ and a stirring speed of 500r / min to obtain a brown transparent solution.
[0049] The molar ratio of 4-aminophenylacetic acid to trifluoroacetic acid is 1 mol: 300 mL; the molar ratio of 4-aminophenylacetic acid to propionic acid is 1:0.75; and the molar ratio of 4-aminophenylacetic acid to phosphorus trichloride is 1:2.
[0050] II. Post-processing:
[0051] The brown transparent solution was cooled to room temperature, and then water was added at a rate of 3-4 mL / min. Hydrolysis was carried out at room temperature for 4 hours. Then, sodium hydroxide solution was added at a rate of 3-4 mL / min under a water bath at room temperature to adjust the pH to 4.1, and a white solid precipitated. The solid was allowed to stand at room temperature, and the upper yellow liquid was removed. The white solid was then washed with water. The process of standing, removing the upper liquid, and washing was repeated three times. The solid product was then collected by filtration and finally dried under vacuum overnight to obtain the white solid product, which is [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid (yield: 58 g, yield: 55%, purity: 99.34%).
[0052] The volume ratio of the brown transparent solution to water is 2:1.
[0053] In step one, a 1000mL three-necked flask is used for the reaction. The three-necked flask is equipped with a condenser (with a gas outlet at the top), a thermometer, and a 125mL constant-pressure dropping funnel (with a gas inlet at the top).
[0054] Hydrogen chloride gas is generated during the reaction in step one. It flows out through the gas outlet and is introduced into a solvent bottle containing sodium hydroxide solution through a PTFE tube.
[0055] The structural formula of the [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of this embodiment is:
[0056] .
[0057] Figure 1 The image shows the NMR spectrum of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 1; as can be seen from the image, 1 ¹H NMR (D₂O) δ 7.47 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 3.26 (t, J = 12.0 Hz, 2H). This confirms the correct structure, indicating it is the target product.
[0058] Figure 2 The image shows the high-resolution mass spectra of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 1. As can be seen from the image, the peak at m / z=296 is the anion fragment ion peak, which is consistent with the theoretical mass-to-charge ratio of the anion in the structure, proving that the structure is correct and is the target product.
[0059] Figure 3The figure shows the liquid chromatogram of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 1. As can be seen from the figure, the purity of the prepared [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid is 99.34%, and the byproduct is pyrophosphate.
[0060] Example 2: This example differs from Example 1 in that the amount of 4-aminophenylacetic acid used in step 1 is 100g. Everything else is the same as in Example 1.
[0061] The [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid prepared in step two of Example 2 was confirmed to have the correct structure by NMR and liquid chromatography, and was the target product. The yield was 123g, the yield rate was 58%, and the purity was 99.14%.
Claims
1. A method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid, characterized in that... It is done in the following steps: I. System reaction: Trifluoroacetic acid and propionic acid were added to 4-aminophenylacetic acid, and the mixture was heated to dissolve the 4-aminophenylacetic acid. Then, phosphorus trichloride was slowly added dropwise to the reaction system. After the addition was completed, the reaction was carried out at a temperature of 60℃~65℃ and a stirring speed of 450r / min~500r / min for 12h~16h to obtain a brown transparent solution. II. Post-processing: The brown transparent solution was cooled to room temperature, then water was added and hydrolyzed at room temperature for 3-5 hours. The pH was then adjusted with sodium hydroxide solution, and a white solid precipitated. Finally, the solution was allowed to stand, washed, and dried in sequence to complete the synthesis of [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid.
2. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... The molar ratio of 4-aminophenylacetic acid to trifluoroacetic acid in step one is 1 mol: (200~300) mL.
3. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... The molar ratio of 4-aminophenylacetic acid to propionic acid in step one is 1:(0.75~2).
4. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... The molar ratio of 4-aminophenylacetic acid to phosphorus trichloride mentioned in step one is 1:(2~3).
5. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... In step one, the temperature is raised to 55℃~65℃ to dissolve 4-aminophenylacetic acid.
6. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... In step one, phosphorus trichloride is slowly added to the reaction system using a constant pressure dropping funnel at a temperature of 60℃~65℃ and a dropping time of 0.5h~2h.
7. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... Hydrogen chloride gas is generated during the reaction in step one, and the hydrogen chloride gas is passed into the sodium hydroxide aqueous solution.
8. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... In step two, add water at a rate of 2 mL / min to 10 mL / min.
9. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... The volume ratio of the brown transparent solution to water in step two is 1:(0.5~2).
10. The method for synthesizing [2-(4-aminophenyl)-1-hydroxy-1-phosphonoethyl]phosphonic acid according to claim 1, characterized in that... In step two, sodium hydroxide solution is added at a rate of 2 mL / min to 10 mL / min in a water bath at room temperature to adjust the pH to 4 to 5, precipitating a white solid. The solid is then allowed to stand at room temperature to remove the upper yellow liquid. The white solid is then washed with water, and the process of standing, removing the upper liquid, and washing is repeated multiple times. The solid product is then collected by filtration and finally dried under vacuum overnight.
Citation Information
Patent Citations
Modified Colorants and Inkjet Ink Compositions Comprising Modified Colorants
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Aqueous ink jet ink composition, ink jet recording method, and ink jet recording apparatus
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