Synthesis process of hydroxyphenyl propionamide benzoic acid

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of hydroxyphenyl propionamide benzoic acid. The synthesis process specifically comprises the following steps: (1) by taking p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials and toluene as a solvent, carrying out condensation reaction under the action of a specific condensing agent DCC to obtain an SN1 intermediate; and (2) hydrolyzing the SN1 intermediate under an alkaline condition to obtain hydroxyphenyl propionamide benzoic acid. The synthesis process provided by the invention is simple in route and short in production period, and compared with a traditional preparation process of hydroxyphenyl propionamide benzoic acid, the yield and the purity of the product are greatly improved, and experimental results show that the highest yield of the product is 86%, and the purity of the product reaches 99.7%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of hydroxyphenylpropionamide benzoic acid. Background Art

[0002] Hydroxyphenylpropionamide benzoic acid, referred to as "dihydroavenine", is one of the main components of oat extract. Most of it exists in the bran and secondary endosperm of the outer layer of the grain. It has anti-allergic, anti-inflammatory, antioxidant, anti-irritation, and erythema improvement effects. It can relieve or improve symptoms such as itching, irritation, and redness of sensitive skin. It is widely used in medicine, cosmetics and other fields.

[0003] Studies have shown that when used as an antiallergic drug, dihydrooatmeal alkaloids have significant advantages over antihistamines, glucocorticoids and other antiallergic drugs. Its inhibition of allergic reactions is a causal treatment with few side effects. It can effectively prevent and treat the development of allergic reactions and has significant antiallergic efficacy. In addition, dihydrooatmeal alkaloids can replace glucocorticoids and be used as an anti-inflammatory and antipruritic agent in various skin cream products to treat contact dermatitis, eczema, athlete's foot and other diseases.

[0004] In the field of cosmetics, dihydrooatmeal alkaloids can relieve skin erythema and private itching, and soothe scalp itching. They are widely used in washing products, after-sun repair products, skin care products and other products.

[0005] However, at present, there are few reports on the synthesis of such products. The mainstream process is to first protect the hydroxyl group in the raw material p-hydroxyphenylpropionic acid or p-hydroxyphenylpropionic aldehyde, and then condense it with methyl anthranilate to prepare amide, and finally deprotect it by adding acid or base to prepare the final product. Patents such as CN106511110A, CN109553550A, CN112939803A, and CN118459358A all use this process. However, the synthesis method is relatively complicated, and the total yield is low, about 60%, and the intermediates obtained in the reaction process have poor controllability.

[0006] In addition, patent CN118290291A provides a process in which aniline and sodium nitrite are used as starting materials to prepare oxime acid compounds, p-hydroxyphenylpropionyl chloride is added to react to prepare an intermediate, and the final product is prepared by hydrolysis. However, the selectivity of the oxime acid compounds involved in this process is not high and the reaction stability is relatively poor. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides a synthesis process of hydroxyphenylpropionamide benzoic acid.

[0008] The present invention provides a synthesis process of hydroxyphenylpropionamide benzoic acid, comprising the following steps:

[0009] (1) Preparation of SN1 intermediate: p-hydroxyphenylpropionic acid and methyl anthranilate are used as raw materials, the raw materials are first dissolved in an organic solvent, and a condensation reaction is carried out under the action of a condensation agent to prepare the SN1 intermediate; the reaction mechanism is shown in the following formula:

[0010]

[0011] (2) Preparation of hydroxyphenylpropionamide benzoic acid: First, the SN1 intermediate obtained in (1) is hydrolyzed under alkaline conditions, and then the pH is adjusted to 3-5, and filtered to obtain hydroxyphenylpropionamide benzoic acid; the reaction mechanism is shown in the following formula:

[0012]

[0013] In the above steps, preferably, the organic solvent in (1) is selected from at least one of benzene, toluene, xylene, pyridine, dichloromethane, methanol and ethanol; and the condensing agent is selected from at least one of N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI).

[0014] More preferably, the organic solvent in (1) is selected from at least one of benzene, toluene, xylene and pyridine; and the condensing agent is selected from at least one of N,N'-dicyclohexylcarbodiimide and N,N'-diisopropylcarbodiimide.

[0015] Preferably, the molar ratio of p-hydroxyphenylpropionic acid to methyl anthranilate in (1) is 1:1-1.5, the mass of the organic solvent is 2-3 times the mass of p-hydroxyphenylpropionic acid, and the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid is 1-1.2:1.

[0016] Preferably, the reaction conditions of the condensation reaction described in (1) are: reaction temperature is 90-120° C., and reaction time is 2-4 h.

[0017] Preferably, the conditions of the hydrolysis reaction described in (2) are: reaction temperature is 40-50° C., and reaction time is 2-3 h.

[0018] Preferably, the alkaline conditions described in (2) are specifically: adding a NaOH solution with a mass fraction of 20% to 40% to the SN1 intermediate obtained in (1), and the molar ratio of NaOH to p-hydroxyphenylpropionic acid is 1.1 to 1.5:1.

[0019] Furthermore, the present invention provides a synthesis process of hydroxyphenylpropionamide benzoic acid, which specifically comprises the following steps:

[0020] (1) Preparation of SN1 intermediate: using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, first dissolving the raw materials in an organic solvent, toluene, and carrying out a condensation reaction at 90 to 120° C. under the action of a condensation agent, N,N′-dicyclohexylcarboximide, for 2 to 4 hours to obtain an SN1 intermediate;

[0021] The molar ratio of p-hydroxyphenylpropionic acid to methyl anthranilate is 1:1-1.5, the mass of the organic solvent is 2-3 times the mass of p-hydroxyphenylpropionic acid, and the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid is 1-1.2:1;

[0022] (2) Preparation of hydroxyphenylpropionamide benzoic acid: First, add a 20% to 40% NaOH solution with a molar ratio of NaOH to p-hydroxyphenylpropionic acid of 1.1 to 1.5:1 to the SN1 intermediate obtained in (1), hydrolyze under alkaline conditions, adjust the pH to 3 to 5, and filter to obtain hydroxyphenylpropionamide benzoic acid.

[0023] The beneficial effects of the present invention are:

[0024] (1) The present invention uses p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, uses toluene as solvent, performs condensation under the action of a specific condensing agent, and then performs alkaline hydrolysis to obtain the product hydroxyphenylpropionamide benzoic acid. The entire preparation process is simple, the production cycle is short, the content of by-products in each step of the reaction is low, and it is more suitable for industrial production;

[0025] (2) The process provided by the present invention does not require additional protection of the hydroxyl functional group. By reasonably adjusting the parameters of each step of the synthesis process, the yield and purity of the obtained product are significantly improved compared with the traditional method. The experimental results show that when hydroxyphenylpropionamide benzoic acid is prepared by the process of the present invention, the total yield of the product is above 80% and the purity is above 99.0%;

[0026] (3) The entire synthesis process of the present invention does not involve high pressure and high temperature. The catalysts, solvents, etc. used in the process are all conventional reagents, which are highly safe and operable, and the reaction can be carried out in a conventional reactor. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a high performance liquid chromatogram of the target product after purification by the process of Example 1 of the present invention;

[0028] Figure 2 This is a high performance liquid chromatogram of the target product after purification by the process of Comparative Example 2 of the present invention;

[0029] Figure 3 This is a high performance liquid chromatogram of the target product after purification by the process of Comparative Example 5 of the present invention;

[0030] Figure 4 This is a high performance liquid chromatogram of the target product after purification by the process of comparative example 10 of the present invention. DETAILED DESCRIPTION

[0031] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in conjunction with specific implementation methods.

[0032] Example 1

[0033] A synthesis process of hydroxyphenylpropionamide benzoic acid comprises the following steps:

[0034] (1) Add 0.1 mol (16.6 g) of p-hydroxyphenylpropionic acid, 0.1 mol of anthranilate, and 50 g of toluene to a 500 mL three-necked flask, stir and heat to 90° C., wait until all the materials are dissolved and the solution is colorless and transparent, then slowly dropwise add 0.1 mol (20.6 g) of N,N'-dicyclohexylcarboximide, react for 4 h, and when the p-hydroxyphenylpropionic acid content is ≤1.0% by liquid phase detection, stop the reaction, add 50 g of water, stir for 0.5 h, stand and separate, cool and filter to obtain SN1 intermediate, the intermediate content is above 95%;

[0035] (2) The SN1 intermediate obtained in (1) was added to a 500 mL three-necked flask, 100 g of water was added, the mixture was stirred and heated to 50° C., 20 g of a 30% sodium hydroxide solution was added dropwise, and after the addition was completed, the mixture was reacted for 2 h, cooled to room temperature, hydrochloric acid was added dropwise to adjust the pH to 3-5, and filtered to obtain an off-white solid product, hydroxyphenylpropionamide benzoic acid.

[0036] The obtained target product was tested by high performance liquid chromatography. The high performance liquid chromatography of the target product is shown in the attached Figure 1 As shown, the specific parameters of each peak in the figure are shown in Table 1 below.

[0037] Table 1 Parameters of each peak in the HPLC

[0038] Peak Retention time area high area(%) 1 1.606 1777 157 0.009 2 2.210 2574 813 0.013 3 2.687 19798506 3926777 99.769 4 3.476 21049 1205 0.106 5 4.271 20398 894 0.103 total / 19844305 3939846 100.000

[0039] The test results showed that the yield of the target product was 85% and the purity was 99.7%.

[0040] Example 2

[0041] The difference from Example 1 is that the reaction time in (1) is reduced to 2 h, and the other process conditions are exactly the same as those in Example 1. After testing, the yield of the target product is 80% and the purity is 99.4%.

[0042] Example 3

[0043] The only difference from Example 1 is that the temperature of the condensation reaction in (1) is 120°C.

[0044] After testing, the yield of the target product was 83% and the product purity was 99.6%.

[0045] Example 4

[0046] The only difference from Example 1 is that the molar ratio of the condensing agent DCC to p-hydroxyphenylpropionic acid in (1) is adjusted to 1.2:1. After testing, the yield of the target product is 81% and the purity is 99.5%.

[0047] Example 5

[0048] The only difference from Example 1 is that the amount of sodium hydroxide added in (2) is adjusted to 14.6 g. After testing, the yield of the obtained target product is 86% and the purity is 99.6%.

[0049] Example 6

[0050] The only difference from Example 1 is that the hydrolysis reaction time in (2) is increased to 3 h. After testing, the yield of the target product obtained is 84% ​​and the purity of the product is 99.5%.

[0051] Comparative Example 1

[0052] The same synthesis process as in Example 1 was used, with the only difference being that the condensation reaction time in (1) was 5 h. After testing, the yield of the target product was 79% and the purity was 99.3%.

[0053] Comparative Example 2

[0054] The same synthesis process as in Example 1 was used, with the only difference being that the condensation reaction time in (1) was 1 h. The results of the detection of the obtained target product by high performance liquid chromatography are shown in the attached figure. Figure 2 The parameters of each peak in the HPLC are shown in Table 2 below.

[0055] Table 2 Parameters of each peak in the HPLC

[0056] Peak Retention time area high area(%) 1 2.417 10333 1046 0.085 2 2.754 12008578 2225853 98.390 3 2.984 186225 31728 1.526 total / 12205136 2258627 100.000

[0057] The above test results show that the yield of the target product is 62% and the purity is 98.3%.

[0058] Comparative Example 3

[0059] The same synthesis process as in Example 1 was used, with the only difference being that the reaction temperature in (1) was 130° C. The yield of the target product obtained was 75% and the purity of the product was 99.1%.

[0060] Comparative Example 4

[0061] The same synthesis process as in Example 1 was used, with the only difference being that the reaction temperature of the condensation reaction in (1) was 80° C. After testing, the yield of the target product was 72% and the purity of the product was 98.0%.

[0062] Comparative Example 5

[0063] The same synthesis process as in Example 1 was used, with the only difference being that the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid in (1) was 0.9:1. The results of the detection of the obtained target product by high performance liquid chromatography are shown in the attached figure. Figure 3 The parameters of each peak in the HPLC are shown in Table 3 below.

[0064] Table 3 Parameters of each peak in the HPLC

[0065] Peak Retention time area high area(%) 1 1.527 15999 2517 0.178 2 2.288 33483 5473 0.372 3 2.720 7690407 1426450 85.499 4 2.934 1254795 230513 13.950 total / 8994685 1664953 100.000

[0066] The above test results show that the yield of the target product obtained by the process of this comparative example is 60%, and the product purity is 85.4%.

[0067] Comparative Example 6

[0068] The same synthesis process as in Example 1 was used, with the only difference being that the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid in (1) was 1.3:1. After testing, the yield of the target product was 77% and the purity of the product was 99.5%.

[0069] Comparative Example 7

[0070] The same synthesis process as in Example 1 was used, with the only difference being that in (2), the molar ratio of sodium hydroxide to p-hydroxyphenylpropionic acid was 1:1. After testing, the yield of the target product was 71% and the purity of the product was 97.9%.

[0071] Comparative Example 8

[0072] The same synthesis process as in Example 1 was used, with the only difference being that in (2), the reaction time was shortened to 1 h. After testing, the yield of the target product was 56% and the purity of the product was 96.6%.

[0073] Comparative Example 9

[0074] The synthesis method is the same as that of Example 1, except that in (2), the reaction time is increased to 4 h. After testing, the yield of the target product obtained is 75%, and the purity of the product is 97.4%.

[0075] Comparative Example 10

[0076] Hydroxyphenylpropionamide benzoic acid is prepared according to the traditional method, that is, firstly, p-hydroxyphenylpropionic acid is used as a raw material to prepare p-hydroxyphenylpropionyl chloride, then reacted with methyl anthranilate, and finally hydrolyzed to obtain hydroxyphenylpropionamide benzoic acid. The specific synthesis method is as follows:

[0077] Step 1: Add 0.1 mol (16.6 g) of p-hydroxyphenylpropionic acid and 60 mL of dimethylacetamide to a three-necked flask, control the temperature below 10°C, then add 0.1 mol (15.1 g) of methyl anthranilate, stir to dissolve; add 0.15 mol of chlorination reagent (thionyl chloride) dropwise, continue the reaction for about 12 hours, and after the reaction is completed, add the reaction solution dropwise into water, filter, and wash the filter cake with a small amount of water until it is neutral to obtain an intermediate;

[0078] Step 2: Take the intermediate obtained in step 1 above, add 60g of water, add 30% sodium hydroxide solution by mass until all the solids are dissolved, heat to 45°C, keep warm for 1h, cool and add hydrochloric acid dropwise to adjust the pH to 3-5, filter and obtain the target product.

[0079] The results of the high performance liquid chromatography (HPLC) test on the obtained target product are shown in the attached figure. Figure 4 The parameters of each peak in the HPLC are shown in Table 4 below.

[0080] Table 4 Parameters of each peak in the HPLC

[0081] Peak Retention time area high area(%) 1 2.417 10353 1056 0.085 2 2.754 12124545 2225853 99.434 3 2.984 58699 14289 0.481 total / 12193597 2241198 100.000

[0082] The above test results show that the yield of the obtained target product is 65% and the purity is 99.4%.

[0083] In order to more clearly compare the effects of various process parameters on the yield and purity of the target product in the present invention, the yield and purity of the target product obtained in Examples 1-6 and Comparative Examples 1-10 of the present invention are tabulated again, as shown in Table 5 below.

[0084] Table 5 Yield and purity of target products under different process conditions

[0085]

[0086]

[0087] It can be seen from the results in Table 5 that the target product can be successfully prepared by the process of the present invention under certain conditions. However, only under the process conditions and parameters of Example 1, the total yield and purity of the prepared hydroxyphenylpropionamide benzoic acid are the highest, especially the yield of the product is as high as 85%, which is 20 percentage points higher than the total yield of 65% prepared by the traditional method in Comparative Example 10.

[0088] In addition, the experimental results of the embodiments and comparative examples of the present invention show that in the process of preparing hydroxyphenylpropionamide benzoic acid, the solvent used, the molar ratio between the raw materials, and the temperature and time control of the reaction process will have a great influence on the yield of the product.

[0089] The reaction temperature was adjusted in Example 3, Comparative Example 3 and Comparative Example 4, wherein the reaction temperatures in the condensation reaction stage in Example 3 and Comparative Example 3 were higher than those in Example 1, 120° C. and 130° C., respectively. The product yields of the two groups of experiments were lower than those in Example 1, and the change in Example 3 was not significant. However, the product yield in Comparative Example 3 was only 75%, which may be because at a higher reaction temperature, the condensation agent and the solvent would volatilize severely, resulting in a decrease in reaction efficiency; the reaction temperature in the condensation reaction stage in Comparative Example 4 was slightly lower than that in Example 1, and the product yield was only 72%, which was also much lower than that in Example 1, and when the temperature was lower, the reaction time would be extended, resulting in a decrease in the overall reaction efficiency.

[0090] In Example 4, Comparative Example 5 and Comparative Example 6, the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid was adjusted on the basis of Example 1. In Example 1, the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid was 1:1, and in Example 4, the molar ratio of the two was 1.2:1. In Comparative Example 5 and Comparative Example 6, the molar ratio of the two was 0.9:1 and 1.3:1, respectively. The results showed that the yields of the target products in Comparative Example 5 and Comparative Example 6 were 60% and 77%, respectively, which were significantly lower than those in Example 1 or Example 4. The possible reason is that when the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid is too low, exceeding 1.2:1, the types and contents of by-products in the reaction process increase, and when the molar ratio is less than 1:1, the raw materials react incompletely.

[0091] Compared with Example 1, Example 5 and Comparative Example 7 respectively adjusted the amount of alkali added during hydrolysis. The results showed that when the molar ratio of alkali to p-hydroxyphenylpropionic acid in Example 5 was 1.1:1, the yield of the product did not change significantly compared with Example 1. It can be seen that both of them can achieve complete hydrolysis of the intermediate product within the ratio range of 1.1 to 1.5:1; however, when the molar ratio is further reduced, such as 1:1 in Comparative Example 7, the product yield may be significantly lower than that of Example 1 or 5 due to insufficient hydrolysis of the intermediate product. Therefore, the yield of the product in Comparative Example 7 is only 71%.

[0092] In addition, in Example 2, Example 6 and Comparative Examples 8-9, the reaction time of each process was adjusted on the basis of Example 1. The results showed that in (1), when the reaction time was less than 2 hours, there might be residual raw materials; when the reaction time was greater than 4 hours, it might lead to an increase in side reactions, thereby reducing the yield of the intermediate product and affecting the yield of the target product; in (2), when the reaction time was less than 2 hours, the residual raw materials were large; when the reaction time was greater than 3 hours, the product color would deepen and the amide group would decompose, resulting in a decrease in the content of the target product.

[0093] In summary, by adopting the synthesis process of the present invention, the target product with higher yield and purity can be obtained only within the range defined by the process parameters of the present invention.

Claims

1. A synthesis process of hydroxyphenylpropionamide benzoic acid, characterized in that, The following steps are involved: (1) Preparation of SN1 intermediate: using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, first dissolving the raw materials in an organic solvent, and carrying out a condensation reaction under the action of a condensation agent to prepare the SN1 intermediate; (2) Preparation of hydroxyphenylpropionamide benzoic acid: First, the SN1 intermediate obtained in (1) is hydrolyzed under alkaline conditions, and then the pH is adjusted to 3-5, and filtered to obtain hydroxyphenylpropionamide benzoic acid.

2. A synthesis process for hydroxyphenylpropionamide benzoic acid as claimed in claim 1, characterized in that: The organic solvent described in (1) is at least one selected from benzene, toluene, xylene, pyridine, dichloromethane, methanol, and ethanol; the condensing agent is at least one selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

3. A synthesis process for hydroxyphenylpropionamide benzoic acid as claimed in claim 1, characterized in that: The molar ratio of p-hydroxyphenylpropionic acid to methyl anthranilate in (1) is 1:1-1.5, the mass of the organic solvent is 2-3 times the mass of p-hydroxyphenylpropionic acid, and the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid is 1-1.2:

1.

4. A synthesis process for hydroxyphenylpropionamide benzoic acid as claimed in claim 1, characterized in that: The reaction conditions of the condensation reaction described in (1) are: reaction temperature of 90-120°C and reaction time of 2-4 h.

5. A synthesis process for hydroxyphenylpropionamide benzoic acid as claimed in claim 1, characterized in that: The conditions of the hydrolysis reaction described in (2) are: reaction temperature of 40-50°C and reaction time of 2-3 h.

6. A synthesis process for hydroxyphenylpropionamide benzoic acid as claimed in claim 1, characterized in that: The alkaline conditions described in (2) are specifically: adding a NaOH solution with a mass fraction of 20% to 40% to the SN1 intermediate obtained in (1), and the molar ratio of NaOH to p-hydroxyphenylpropionic acid is 1.1 to 1.5:

1.

7. A synthesis process for hydroxyphenylpropionamide benzoic acid as claimed in claim 1, characterized in that: The following steps are involved: (1) Preparation of SN1 intermediate: Using p-hydroxyphenylpropionic acid and methyl anthranilate as raw materials, the raw materials are first dissolved in an organic solvent, toluene, and a condensation reaction is carried out at 90-120°C under the action of a condensation agent, N,N'-dicyclohexylcarboximide, for 2-4 h to obtain an SN1 intermediate; The molar ratio of p-hydroxyphenylpropionic acid to methyl anthranilate is 1:1-1.5, the mass of the organic solvent is 2-3 times the mass of p-hydroxyphenylpropionic acid, and the molar ratio of the condensing agent to p-hydroxyphenylpropionic acid is 1-1.2:1; (2) Preparation of hydroxyphenylpropionamide benzoic acid: First, add a 20% to 40% NaOH solution with a molar ratio of NaOH to p-hydroxyphenylpropionic acid of 1.1 to 1.5:1 to the SN1 intermediate obtained in (1), hydrolyze under alkaline conditions, adjust the pH to 3 to 5, and filter to obtain hydroxyphenylpropionamide benzoic acid.

Images