Synthetic method of hydroxyphenyl propionamide benzoic acid

Abstract

The embodiment of the invention discloses a synthetic method of hydroxyphenyl propionamide benzoic acid, which comprises the following steps: generating an ester ammonia exchange intermediate from methyl 3-(3, 5-di-tert-butyl-4-hydroxyphenyl) propionate and methyl anthranilate under the action of a first catalyst; and carrying out alkali dissolution and acid precipitation on the ester ammonia exchange intermediate under the action of a second catalyst to generate hydroxyphenyl propionamide benzoic acid.

Description

Technical Field

[0001] This specification relates to the field of chemical technology, and in particular to a method for synthesizing hydroxyphenylpropionamide benzoic acid. Background Technology

[0002] Hydroxyphenyl propionamide benzoic acid, also known as oat alkaloid, Deminshu, Nashumin, and dihydrooat alkaloid D, is a commonly used soothing, anti-allergic, and skin-protecting ingredient in cosmetics. It has the advantages of low risk and high safety, and is suitable for sensitive skin and daily skin care.

[0003] In existing technologies, the traditional method for synthesizing hydroxyphenylpropionamide benzoic acid using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials relies on highly toxic acylation reagents to drive the reaction process. Although these acylation reagents can promote the chemical reaction, their strong corrosiveness corrodes the metal surfaces of the equipment, thus shortening its normal service life. With technological advancements, a synthetic route using p-hydroxyphenylpropionaldehyde and methyl anthranilate as raw materials has emerged. This route requires the use of oxidizing reagents in the early stages of the reaction to oxidize the aldehyde group to a carboxyl group before proceeding to the critical acylation condensation step. The entire reaction process is lengthy and complex, involving numerous intermediate steps and precise control of operating conditions, resulting in low production efficiency and difficulty in meeting the requirements for large-scale, high-quality products.

[0004] Based on this, this application provides a method for synthesizing hydroxyphenylpropionamide benzoic acid. Summary of the Invention

[0005] To solve the above-mentioned technical problems, the embodiments in this specification are implemented as follows: This specification provides a method for synthesizing hydroxyphenylpropionamide benzoic acid, addressing the following problem: In the prior art, traditional methods for synthesizing hydroxyphenylpropionamide benzoic acid using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials rely on highly toxic acylation reagents to drive the reaction process. Although these acylation reagents can promote the chemical reaction, their strong corrosiveness corrodes the metal surfaces of equipment, thus shortening the normal service life of the equipment. With technological advancements, a synthetic route using p-hydroxyphenylpropionaldehyde and methyl anthranilate as raw materials has emerged. This route requires the use of oxidizing reagents in the early stages of the reaction to oxidize the aldehyde group to a carboxyl group before proceeding to the crucial acylation condensation step. The entire reaction process is lengthy and complex, involving numerous intermediate steps and precise control of operating conditions, resulting in low production efficiency and difficulty in meeting the requirements for large-scale, high-quality products.

[0006] This specification provides a method for synthesizing hydroxyphenylpropionamide benzoic acid, the method being as follows: Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and methyl anthranilate react in the presence of a first catalyst to form an ester-ammonia exchange intermediate. The ester-ammonia exchange intermediate is dissolved in alkali and precipitated by acid under the action of a second catalyst to generate hydroxyphenylpropionamide benzoic acid.

[0007] Further, the methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and methyl anthranilate, under the action of the first catalyst, generate an ester-amine exchange intermediate, specifically comprising: The methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, the methyl anthranilate, and the first catalyst are dissolved in an organic solvent, and the mixture is catalyzed by the first catalyst at 40-60°C. The mixture undergoes ester hydrolysis and amidation reactions to generate an ester-ammonia exchange intermediate. The molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, methyl anthranilate, and the first catalyst is 1:1.0-1.5:0.1-0.3, and the optimal molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, methyl anthranilate, and the first catalyst is 1:1.05:0.12.

[0008] Furthermore, the first catalyst is at least one of concentrated sulfuric acid, trifluoroacetic acid, phosphotungstic acid, p-toluenesulfonic acid, and acidic ion exchange resin.

[0009] Further, the organic solvent is at least one selected from toluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0010] Furthermore, the transesterification intermediate, under the action of a second catalyst, undergoes alkali dissolution and acid precipitation to generate hydroxyphenylpropionamide benzoic acid, specifically comprising: The ester-ammonia exchange intermediate, under the action of a second catalyst, undergoes a detert-butyl reaction to generate a solution containing methyl hydroxyphenylpropionamide benzoate; The solution containing methyl hydroxyphenylpropionamide benzoate generates a corresponding salt solution under the action of an alkaline solution, and the pH of the salt solution is adjusted to precipitate methyl hydroxyphenylpropionamide benzoate.

[0011] Furthermore, the transesterification intermediate, under the action of a second catalyst, generates a solution containing methyl hydroxyphenylpropionamide benzoate, specifically comprising: The ester-ammonia exchange intermediate, under the catalysis of the second catalyst at 80-100°C, undergoes a detert-butyl reaction to generate the solution containing methyl hydroxyphenylpropionamide benzoate; The molar ratio of the ester-ammonia exchange intermediate to the second catalyst is 1:1.0-3.0, and the optimal molar ratio of the ester-ammonia exchange intermediate to the second catalyst is 1:2.1.

[0012] Furthermore, the second catalyst is a detert-butyl catalyst, and the second catalyst is at least one of aluminum trichloride, ferric trichloride, perchloric acid, and ZSM-5 molecular sieve.

[0013] Furthermore, the solution containing methyl hydroxyphenylpropionamide benzoate, under the action of an alkaline solution, generates a corresponding salt solution, and the pH of the salt solution is adjusted to precipitate methyl hydroxyphenylpropionamide benzoate, specifically including: After quenching to terminate the reaction, the lower organic phase solution is treated with an alkaline solution to generate the corresponding salt solution. The corresponding salt solution is separated to obtain an aqueous solution. The pH value of the aqueous solution is adjusted to a preset pH range using an acidic solution. After filtration and drying, hydroxyphenylpropionamide benzoic acid is obtained.

[0014] Furthermore, the alkaline solution is any one of NaOH, KOH, and LiOH; The reaction temperature for alkaline treatment of the lower organic phase solution is 35-55℃, with the optimal reaction temperature being 45℃.

[0015] Furthermore, the acidic solution is any one of hydrochloric acid, sulfuric acid, and phosphoric acid; The preset pH range is pH 2-4, and the optimal pH within the preset pH range is 3. The at least one technical solution described above in the embodiments of this specification can achieve the following effective effects: compared with traditional methods, this method for synthesizing hydroxyphenylpropionamide benzoic acid is more convenient to operate, eliminating the need for intermediate filtration and purification operations, and the method does not require the use of acylation reagents and strong oxidizing reagents, effectively improving the efficiency of industrial production and increasing the purity of hydroxyphenylpropionamide benzoic acid. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments or prior art of this specification, the drawings used in the description of the embodiments or prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in this specification. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 A schematic diagram of the synthesis reaction of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this application; Figure 2The 1H NMR spectrum of the ester-ammonia exchange intermediate provided in Example 1 of this application; Figure 3 The 1H NMR spectrum of hydroxyphenylpropionamide benzoic acid provided in Example 1 of this application; Figure 4 This is a high-performance liquid chromatogram of the transesterification intermediate provided in Example 1 of this application; Figure 5 This is a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid provided in Example 1 of this application; Figure 6 This is a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid provided in Example 2 of this application; Figure 7 This is a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid provided in Example 3 of this application; Figure 8 This is a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid provided in Example 4 of this application; Figure 9 The high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid provided in Comparative Example 1 of this application is shown. Detailed Implementation

[0018] To enable those skilled in the art to better understand the technical solutions in this specification, the technical solutions in the embodiments of this specification will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this specification, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this application.

[0019] This specification provides a method for synthesizing hydroxyphenylpropionamide benzoic acid, the method being as follows: Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and methyl anthranilate react in the presence of a first catalyst to form an ester-ammonia exchange intermediate. The ester-ammonia exchange intermediate is dissolved in alkali and precipitated by acid under the action of a second catalyst to generate hydroxyphenylpropionamide benzoic acid.

[0020] The reaction equation is as follows: Figure 1 As shown.

[0021] In this reaction equation, It is methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. It is methyl anthranilate; It is an ester-amine exchange intermediate, which is N-(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)o-aminobenzoate methyl ester. For hydroxyphenylpropionamide benzoic acid, Cat1 represents the first catalyst, Cat2 represents the second catalyst, Toluene represents the organic solvent, Base represents the alkaline solution, and H represents the alkali solution. + It indicates an acid solution.

[0022] In the embodiments of this application, methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and methyl anthranilate, under the action of a first catalyst, generate an ester-amine exchange intermediate, specifically including: The methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, the methyl anthranilate, and the first catalyst are dissolved in an organic solvent, and the mixture is catalyzed by the first catalyst at 40-60°C, undergoing ester hydrolysis and amidation reactions to generate the ester-ammonia exchange intermediate. The molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, methyl anthranilate, and the first catalyst is 1:1.0-1.5:0.1-0.3, and the optimal molar ratio of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, methyl anthranilate, and the first catalyst is 1:1.05:0.12.

[0023] In the embodiments of this specification, the first catalyst is at least one of concentrated sulfuric acid, trifluoroacetic acid, phosphotungstic acid, p-toluenesulfonic acid, and acidic ion exchange resin.

[0024] In the embodiments of this application, the organic solvent is at least one selected from toluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0025] In this embodiment, the transesterification intermediate is reacted with a second catalyst to generate hydroxyphenylpropionamide benzoic acid via alkali dissolution and acid precipitation, specifically including: The ester-ammonia exchange intermediate, under the action of a second catalyst, undergoes a detert-butyl reaction to generate a solution containing methyl hydroxyphenylpropionamide benzoate; The solution containing methyl hydroxyphenylpropionamide benzoate generates a corresponding salt solution under the action of an alkaline solution, and the pH of the salt solution is adjusted to precipitate methyl hydroxyphenylpropionamide benzoate.

[0026] In this embodiment, the transesterification intermediate, under the action of a second catalyst, generates a solution containing methyl hydroxyphenylpropionamide benzoate, specifically including: The ester-ammonia exchange intermediate is subjected to a detert-butyl reaction by the second catalyst at 80-100°C to generate the solution containing methyl hydroxyphenylpropionamide benzoate. The molar ratio of the ester-ammonia exchange intermediate to the second catalyst is 1:1.0-3.0, and the optimal molar ratio of the ester-ammonia exchange intermediate to the second catalyst is 1:2.1.

[0027] In the embodiments of this specification, the second catalyst is a detert-butyl catalyst, and the second catalyst is at least one of aluminum trichloride, ferric trichloride, perchloric acid, and ZSM-5 molecular sieve.

[0028] In the embodiments of this specification, the solution containing methyl hydroxyphenylpropionamide benzoate generates a corresponding salt solution under the action of an alkaline solution, and the pH of the salt solution is adjusted to precipitate methyl hydroxyphenylpropionamide benzoate, specifically including: After quenching to terminate the reaction, the lower organic phase solution is treated with an alkaline solution to generate the corresponding salt solution. The corresponding salt solution is separated to obtain an aqueous solution. The pH value of the aqueous solution is adjusted to a preset pH range using an acidic solution. After filtration and drying, hydroxyphenylpropionamide benzoic acid is obtained.

[0029] In this embodiment, the alkaline solution is any one of NaOH, KOH, and LiOH; The reaction temperature for alkaline treatment of the lower organic phase solution is 35-55℃, with the optimal reaction temperature being 45℃.

[0030] In the embodiments described in this specification, the acidic solution is any one of hydrochloric acid, sulfuric acid, and phosphoric acid; The preset pH range is pH 2-4, and the optimal pH within the preset pH range is 3.

[0031] To understand the synthesis method of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this specification, the specific synthesis process is described below.

[0032] Step S101: Dissolve the raw materials.

[0033] Take appropriate amounts of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, methyl anthranilate, and the first catalyst; Weigh out methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate, methyl anthranilate, and the first catalyst, and add them sequentially to a clean, dry three-necked flask equipped with a stirrer and thermometer. Then add an appropriate amount of organic solvent to ensure that the solutes are fully dissolved in the solvent. To accelerate the dissolution process, turn on the stirrer and set the stirring speed to 800-1000 rpm (adjust according to the actual situation) to make the reactants uniformly dispersed in the organic solvent to form a homogeneous and stable reaction solution.

[0034] Step S102: Initial heating reaction.

[0035] After the raw materials have completely dissolved, place the three-necked flask on a temperature-controlled heating device, which can be an oil bath or a heated magnetic stirrer. The temperature of the reaction solution is slowly increased to 40°C at a heating rate of 5°C / min, and the stirring device is turned on. The stirring speed can be maintained at 800-1000 rpm to ensure that the reaction solution is in a good mixed state.

[0036] At this temperature, the reaction should continue for 2 hours. During the reaction, closely observe the reaction phenomena, such as color changes in the solution, the presence of bubbles, or the formation of precipitates, and record them in detail. Simultaneously, use gas chromatography, liquid chromatography, or other suitable analytical methods to periodically (e.g., every 30 minutes) to monitor the reaction progress and ensure that the reaction proceeds to the desired stage. If the reaction does not reach the expected result, the reaction time can be appropriately extended depending on the situation, but should not exceed 6 hours. The observation and judgment of the reaction process will utilize existing techniques and will not be elaborated upon here.

[0037] Step S103: Secondary heating and detert-butylation reaction.

[0038] After the reaction in step S102 is completed, the temperature of the reaction solution is slowly raised to 80°C at a heating rate of 5°C / min, and the second catalyst is added. To promote the detert-butylation reaction, the temperature of the reaction solution is further slowly raised to 100°C at a heating rate of 5°C / min, and the reaction is continuously stirred for 2-10 hours, depending on the amount of reactants. During the reaction, the amount of reaction products generated, the amount of reactants consumed, and the changes in the properties of the solution are monitored. The reaction is terminated when the remaining amount of the ester-amine exchange intermediate is less than 1%.

[0039] Step S104: Quenching reaction and alkaline dissolution treatment. After the reaction in step S103 is completed, immediately stop heating and move the reaction apparatus to an ice-water bath. Slowly add 10-15 times the volume of ice water to the reaction solution to quench the reaction. Stir continuously during the addition of ice water to prevent local overheating or overcooling.

[0040] After the reaction is quenched, transfer the reaction solution to a separatory funnel and let it stand for 0.5-1 hour to allow the organic and aqueous phases to separate completely. Once the separation is clear, carefully separate the lower organic phase and slowly add it dropwise to a pre-prepared alkaline solution. During the dropwise addition, strictly control the reaction temperature within the range of 35-55℃ and maintain stirring at a speed of 300-500 rpm to ensure full contact between the organic phase and the alkaline solution.

[0041] Step S105: Adjust pH and separate and purify the product.

[0042] After the alkaline dissolution reaction is complete, transfer the reaction solution back to the separatory funnel and let it stand for 0.5-1 hour to allow the aqueous and organic phases to separate completely. Separate the lower aqueous phase and place it in a clean container. Prepare the acid needed to adjust the pH. One or more of hydrochloric acid, sulfuric acid, and phosphoric acid can be used. While stirring, slowly add the acid dropwise to the aqueous phase, monitoring the pH value of the solution using a precision pH meter until it reaches the range of 2-4. As the pH value decreases, a white solid will gradually precipitate in the solution. Once the pH value stabilizes within the range of 2-4, stop adding the acid.

[0043] Finally, the solution containing the white solid is filtered using a Buchner funnel and filter paper or other suitable filtration equipment. During filtration, the filter cake is washed several times with an appropriate amount of distilled water until the filtrate is neutral to remove impurity ions and residual acid.

[0044] Finally, the filtered white solid product was placed in a drying oven for drying to obtain hydroxyphenylpropionamide benzoic acid with a purity greater than 99%.

[0045] To further understand the synthesis method of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this specification, different embodiments will be described below.

[0046] Example 1: A method for synthesizing hydroxyphenylpropionamide benzoic acid Under nitrogen protection, toluene (146.2 ml, 5.0 vols) was added to a 500 ml four-necked flask. Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (29.24 g, 100 mmol), methyl anthranilate (16.63 g, 110 mmol), and p-toluenesulfonic acid (3.44 g, 20 mmol) were added with stirring. The mixture was heated to 50 °C and reacted at this temperature for 5 h. After the reaction was complete, the temperature was raised to 80 °C, and aluminum trichloride (20 g, 150 mmol) was added in portions. The mixture was then reacted at this temperature for 8 h. After the reaction was complete, the temperature was lowered to below 10 °C, and ice water (146.2 g, 5.0 wt%) was slowly added to the reaction mixture while stirring for 0.5 h. After quenching the reaction, the mixture was allowed to stand and separated. A 15% NaOH solution (80 g, 300 mmol) was slowly added dropwise to the organic phase, and the temperature was raised to 40 °C. The reaction was carried out at this temperature for 2 h. After the reaction was completed, the mixture was allowed to stand and separated. Concentrated hydrochloric acid (43.86 g, 444 mmol) was slowly added dropwise to the aqueous phase. After the addition was complete, a white solid precipitated. The solid was filtered, washed with water until neutral, and dried to give 22.43 g of hydroxyphenylpropionamide benzoic acid, with a yield of 78.62% and an HPLC accuracy of ≥98%.

[0047] To further verify the synthetic effect of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this application, this application further provides the 1H NMR spectrum and HPLC chromatogram of the ester-amine exchange intermediate of Example 1, as well as the 1H NMR spectrum and HPLC chromatogram of the final product hydroxyphenylpropionamide benzoic acid, as detailed below. Figures 2-5 As shown. From Figure 2 The NMR results of the intermediate show that the structure of the ester-amine exchange intermediate is correct. Figure 3 The NMR results show that the structure of hydroxyphenylpropionamide benzoic acid is correct. Figure 4 The injection volume was 1.0 μl, from... Figure 4 The results show that the retention time of the main peak corresponding to the ester-ammonia exchange intermediate is 4.89 minutes, and the peak area is 99.53%. This means the purity of the ester-ammonia exchange intermediate is 99.53%. Figure 5 The injection volume was 1.0 μl, from... Figure 5 As can be seen, the retention time of the main peak corresponding to the final product hydroxyphenylpropionamide benzoic acid is 2.840 minutes, and the area of ​​the main peak is 98.73%.

[0048] Example 2: A method for synthesizing hydroxyphenylpropionamide benzoic acid Under nitrogen protection, toluene (146.2 ml, 5.0 vols) was added to a 500 ml four-necked flask. Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (29.24 g, 100 mmol), methyl anthranilate (16.63 g, 110 mmol), and trifluoroacetic acid (2.28 g, 20 mmol) were added with stirring. The mixture was heated to 50 °C and reacted at this temperature for 5 h. After the reaction was complete, the temperature was raised to 90 °C, and aluminum trichloride (20 g, 150 mmol) was added in portions. The mixture was then reacted at this temperature for 8 h. After the reaction was complete, the temperature was lowered to below 10 °C, and ice water (146.2 g, 5.0 wt%) was slowly added to the reaction mixture while stirring for 0.5 h. After quenching the reaction, the mixture was allowed to stand and separated. 15% NaOH solution (80 g, 300 mmol) was slowly added dropwise to the organic phase, and the mixture was heated to 40 °C and reacted at this temperature for 2 h. After the reaction was complete, the mixture was allowed to stand and separated. Concentrated hydrochloric acid (43.86 g, 444 mmol) was slowly added dropwise to the aqueous phase. After the addition was complete, a white solid precipitated. The solid was filtered, washed with water until neutral, and dried to obtain 20.57 g of hydroxyphenylpropionamide benzoic acid, with a yield of 72.11% and an HPLC accuracy of ≥98%.

[0049] To further verify the synthesis effect of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this application, this application further provides a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid from Example 2, as shown in the figure below. Figure 6 As shown. In Figure 6 The injection volume was 1.0 μl, from... Figure 6As can be seen from the data, the retention time of the main peak corresponding to hydroxyphenylpropionamide benzoic acid is 2.817 minutes, and the area of ​​the main peak is 98.55%. That is to say, the purity of hydroxyphenylpropionamide benzoic acid is 98.55%.

[0050] Example 3: A method for synthesizing hydroxyphenylpropionamide benzoic acid Under nitrogen protection, toluene (146.2 ml, 5.0 vols) was added to a 500 ml four-necked flask. Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (29.24 g, 100 mmol), methyl anthranilate (17.38 g, 115 mmol), and p-toluenesulfonic acid (3.44 g, 20 mmol) were added with stirring. The mixture was heated to 50 °C and reacted at this temperature for 5 h. After the reaction was complete, the temperature was raised to 80 °C, and aluminum trichloride (20 g, 150 mmol) was added in portions. The mixture was then reacted at this temperature for 8 h. After the reaction was complete, the temperature was lowered to below 10 °C, and ice water (146.2 g, 5.0 wt%) was slowly added to the reaction mixture while stirring for 0.5 h. After quenching the reaction, the mixture was allowed to stand and separated. A 15% NaOH solution (80 g, 300 mmol) was slowly added dropwise to the organic phase, and the temperature was raised to 40 °C. The reaction was carried out at this temperature for 2 h. After the reaction was completed, the mixture was allowed to stand and separated. Concentrated hydrochloric acid (43.86 g, 444 mmol) was slowly added dropwise to the aqueous phase. After the addition was complete, a white solid precipitated. The solid was filtered, washed with water until neutral, and dried to give 23.11 g of hydroxyphenylpropionamide benzoic acid, with a yield of 81.01% and HPLC ≥ 99%.

[0051] To further verify the synthesis effect of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this application, this application further provides a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid in Example 3, as shown in the figure below. Figure 7 As shown. In Figure 7 The injection volume was 1.0 μl, from... Figure 7 As can be seen from the data, the retention time of the main peak corresponding to hydroxyphenylpropionamide benzoic acid is 2.825 minutes, and the area of ​​the main peak is 99.48%. That is to say, the purity of hydroxyphenylpropionamide benzoic acid is 99.48%.

[0052] Example 4: A method for synthesizing hydroxyphenylpropionamide benzoic acid Under nitrogen protection, toluene (584.8 ml, 5.0 vols) was added to a 2000 ml four-necked flask. Methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (116.96 g, 400 mmol), methyl anthranilate (69.53 g, 460 mmol), and p-toluenesulfonic acid (13.78 g, 80 mmol) were added with stirring. The mixture was heated to 50 °C and maintained at this temperature for 5 h. After the reaction was complete, the temperature was raised to 100 °C, and aluminum trichloride (106.66 g, 800 mmol) was added in portions. The mixture was maintained at this temperature for 8 h. After the reaction was complete, the temperature was lowered to below 10 °C, and ice water (584.8 g, 5.0 wt%) was slowly added to the reaction mixture while stirring for 0.5 h. After quenching the reaction, the mixture was allowed to stand and separated. A 15% NaOH solution (342.83 g, 800 mmol) was slowly added dropwise to the organic phase, and the temperature was raised to 40 °C. The reaction was carried out at this temperature for 2 h. After the reaction was completed, the mixture was allowed to stand and separated. Concentrated hydrochloric acid (175.44 g, 1778 mmol) was slowly added dropwise to the aqueous phase. After the addition was complete, a white solid precipitated. The solid was filtered, washed with water until neutral, and dried to give 97.52 g of hydroxyphenylpropionamide benzoic acid, with a yield of 85.46% and an HPLC accuracy of ≥99%.

[0053] To further verify the synthesis effect of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this application, this application further provides a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid in Example 4, as shown in the figure below. Figure 8 As shown. In Figure 8 The injection volume was 1.0 μl, from... Figure 8 As can be seen from the data, the retention time of the main peak corresponding to hydroxyphenylpropionamide benzoic acid is 2.834 minutes, and the area of ​​the main peak is 99.29%. That is to say, the purity of hydroxyphenylpropionamide benzoic acid is 99.29%.

[0054] Comparative Example 1: A method for synthesizing hydroxyphenylpropionamide benzoic acid Under nitrogen protection, dichloromethane (300 ml, 3.0 vols), DMF (2.20 g, 30 mmol), and p-hydroxyphenylpropionic acid (100 g, 600 mmol) were added to a 1000 ml four-necked flask. The temperature was lowered to below 0 °C, and SOCl2 (108 g, 900 mmol) was slowly added dropwise while maintaining the temperature below 5 °C. After the addition was complete, the reaction was allowed to proceed at this temperature for 8 hours. After the reaction was complete, reaction solution A was obtained. Under nitrogen protection, dichloromethane (300 g, 3.0 vols), triethylamine (152 g, 1500 mmol), and methyl anthranilate (92.79 g, 610 mmol) were added to a 2000 ml four-necked flask. The temperature was raised to reflux, and reaction solution A was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at this temperature for another 10 hours. After the reaction was complete, the mixture was washed with water, and the organic phase was concentrated to dryness to obtain the intermediate. In a 1000 ml four-necked flask, 515.82 g (1810 mmol) of 14% NaOH was added with stirring. The mixture was heated to 40 °C and stirred until completely dissolved. The solution was then cooled to room temperature, and sulfuric acid was slowly added dropwise to adjust the pH to 2–3, precipitating a solid. The solid was filtered, washed with water until neutral, and dried to obtain 69.69 g of hydroxyphenylpropionamide benzoic acid, with a yield of 61.08% (HPLC ≥ 95%).

[0055] To further verify the synthesis effect of hydroxyphenylpropionamide benzoic acid provided in the embodiments of this application, this application further provides a high-performance liquid chromatogram of hydroxyphenylpropionamide benzoic acid in Comparative Example 1, as shown in the figure below. Figure 9 As shown. In Figure 9 The injection volume was 1.0 μl, from... Figure 6 As can be seen from the data, the retention time of the main peak corresponding to hydroxyphenylpropionamide benzoic acid is 2.832 minutes, and the area of ​​the main peak is 97.71%. That is to say, the purity of hydroxyphenylpropionamide benzoic acid is 97.71%.

[0056] As can be seen from the above examples, this method for synthesizing hydroxyphenylpropionamide benzoic acid is more convenient than traditional methods, eliminating the need for intermediate filtration and purification. Furthermore, this method does not require the use of acylation reagents or strong oxidizing reagents, effectively improving the efficiency of industrial production and increasing the purity of hydroxyphenylpropionamide benzoic acid.

[0057] The various embodiments in this specification are described in a progressive manner. Similar or identical parts between embodiments can be referred to interchangeably. Each embodiment focuses on describing the differences from other embodiments. In particular, the system embodiments are basically similar to the method embodiments, so the description is relatively simple; relevant parts can be referred to the descriptions in the method embodiments.

[0058] The above description is merely an embodiment of this specification and is not intended to limit this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of this application should be included within the scope of the claims of this application.

Claims

1. A method for synthesizing a hydroxyphenylpropionamide benzoic acid, characterized by, The synthesis method is: 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid methyl ester and methyl anthranilate generate an ester-ammonia exchange intermediate under the action of a first catalyst; The ester-ammonia exchange intermediate generates hydroxyphenyl propionamide benzoic acid through alkali dissolution and acid precipitation under the action of a second catalyst.

2. The method of synthesis of claim 1, wherein, The 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid methyl ester and the methyl anthranilate generate an ester-ammonia exchange intermediate under the action of a first catalyst, specifically including: The 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid methyl ester, the methyl anthranilate, and the first catalyst are dissolved in an organic solvent, and the first catalyst is catalyzed at 40-60°C to generate an ester-ammonia exchange intermediate through ester hydrolysis reaction and amidation reaction; The molar ratio of the 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid methyl ester, the methyl anthranilate, and the first catalyst is 1:1.0-1.5:0.1-0.3, and the optimal molar ratio of the 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid methyl ester, the methyl anthranilate, and the first catalyst is 1:1.05:0.

12.

3. The method of synthesis of claim 1, wherein, The first catalyst is at least one of concentrated sulfuric acid, trifluoroacetic acid, phosphotungstic acid, p-toluenesulfonic acid, and acidic ion resin.

4. The method of synthesis of claim 2, wherein, The organic solvent is at least one of toluene, xylene, N,N-dimethylformamide, and N,N-dimethylacetamide.

5. The method of synthesis of claim 1, wherein, The ester-ammonia exchange intermediate generates hydroxyphenyl propionamide benzoic acid through alkali dissolution and acid precipitation under the action of a second catalyst, specifically including: The ester-ammonia exchange intermediate generates a solution containing hydroxyphenyl propionamide benzoic acid methyl ester through de-tert-butyl reaction under the action of a second catalyst; The solution containing hydroxyphenyl propionamide benzoic acid methyl ester generates a corresponding salt solution under the action of an alkali solution, and hydroxyphenyl propionamide benzoic acid is precipitated by adjusting the pH of the salt solution.

6. The method of synthesis of claim 5, wherein, The ester-ammonia exchange intermediate generates a solution containing hydroxyphenyl propionamide benzoic acid methyl ester under the action of a second catalyst, specifically including: The ester-ammonia exchange intermediate generates the solution containing hydroxyphenyl propionamide benzoic acid methyl ester through de-tert-butyl reaction under the action of the second catalyst at 80-100°C; The molar ratio of the ester-ammonia exchange intermediate and the second catalyst is 1:1.0-3.0, and the optimal molar ratio of the ester-ammonia exchange intermediate and the second catalyst is 1:2.

1.

7. The method of synthesis of claim 1, wherein, The second catalyst is a de-tert-butyl catalyst, and the second catalyst is at least one of aluminum chloride, iron trichloride, perchloric acid, and ZSM-5 molecular sieve.

8. The method of synthesis of claim 5, wherein, The solution containing hydroxyphenyl propionamide benzoic acid methyl ester generates a corresponding salt solution under the action of an alkali solution, and hydroxyphenyl propionamide benzoic acid is precipitated by adjusting the pH of the salt solution, specifically including: After the solution containing hydroxyphenyl propionamide benzoic acid methyl ester is quenched to terminate the reaction, the lower organic phase solution is treated with an alkali solution to generate a corresponding salt solution; The water phase solution is obtained by separating the corresponding salt solution, and the pH value of the water phase solution is adjusted to a preset pH range by using an acidic solution, and hydroxyphenylpropionamide benzoic acid is obtained by filtering and drying.

9. The method of synthesis of claim 8, wherein, The alkaline solution is any one of NaOH, KOH and LiOH; The reaction temperature of the lower organic phase solution treated by the alkaline solution is 35-55 DEG C, and the optimum reaction temperature is 45 DEG C.

10. The method of synthesis of claim 8, wherein, The acidic solution is any one of hydrochloric acid, sulfuric acid and phosphoric acid; The preset pH range is pH 2-4, and the optimum pH of the preset pH range is 3.

Images