A method for preparing lauric acid raw material

Abstract

This application relates to the technical field of drug synthesis, specifically disclosing a method for preparing lauric acid raw material. The method for preparing lauric acid raw material is as follows: 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, anhydrous pyridine, and aniline are mixed, heated, and reacted to obtain a mixture. The mixture is then distilled under reduced pressure to recover the anhydrous pyridine. An alkaline solution is added to the mixture, mixed, and the pH is adjusted, resulting in the precipitation of a milky yellow solid. Water is added, mixed, filtered, and washed to obtain a slightly yellow solid. Water is added to the slightly yellow solid from step S1, the pH is adjusted, and decolorization is performed. The solid is then filtered, collected, and the pH is adjusted again. After precipitation, the solid is filtered, washed, and dried to obtain lauric acid raw material. The lauric acid raw material of this application has the advantage of improved yield due to the synergistic effect between the steps.

Description

Technical Field

[0001] This application relates to the field of drug synthesis technology, and in particular to a method for preparing a lauric acid active pharmaceutical ingredient. Background Technology

[0002] Guimaric acid, also known as choleretic acid, methyl ether ethanol acrylic acid, hydroxyethoxymethoxycinnamic acid, and 3-methoxy-4-(2-hydroxyethoxy)phenylacrylic acid, is mainly used to treat chronic cholecystitis and cholelithiasis, and can also be used as an adjunct treatment for biliary tract infections. Guimaric acid can promote bile excretion, with a significant and lasting choleretic effect. It can also relax the bile duct opening, including the sphincter, and has a good antispasmodic and analgesic effect. In addition, it can promote the breakdown of cholesterol in the blood into bile acids and their excretion, so it also has a certain effect on lowering blood cholesterol.

[0003] Currently, lauric acid is frequently appearing on the market, and people's demand for lauric acid is increasing. However, the production process of lauric acid requires several reactions, resulting in a low yield of lauric acid. Therefore, how to improve the yield of lauric acid is an urgent problem to be solved. Summary of the Invention

[0004] To improve the yield of lauric acid, this application provides a method for preparing lauric acid raw material.

[0005] In a first aspect, this application provides a method for preparing lauric acid raw material, which adopts the following technical solution:

[0006] A method for preparing lauric acid raw material includes the following steps:

[0007] S1: Mix 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, anhydrous pyridine, and aniline evenly, heat and react for a period of time to obtain a mixture, distill the mixture under reduced pressure to recover the anhydrous pyridine, add an alkaline solution to the mixture, mix evenly, adjust the pH value, precipitate a milky yellow solid, add water and mix evenly, filter, wash, and obtain a slightly yellow solid.

[0008] S2: Add water to the slightly yellow solid in step S1, adjust the pH value, and perform decolorization treatment. Filter, collect the filtrate, adjust the pH value, precipitate the precipitate, filter, wash, and dry to obtain lauric acid raw material.

[0009] Furthermore, a method for preparing lauric acid raw material includes the following steps:

[0010] S1: Mix 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, anhydrous pyridine, and aniline evenly, heat to 50±5℃, and react for 13-15h to obtain a mixture. Reduce the pressure of the mixture to vacuum ≥0.08MPa, distill, and recover anhydrous pyridine to two-thirds of the original amount. Add an alkaline solution to the mixture, mix evenly, adjust the pH value to 2-3 with sulfuric acid solution, and precipitate a milky yellow solid. Add water, mix evenly, filter, and wash with water to a pH value of 6 to obtain a slightly yellow solid.

[0011] S2: Add water to the slightly yellow solid in step S1, adjust the pH to 7-8, and perform decolorization treatment. Filter, collect the filtrate, adjust the pH to 2-3, precipitate the solid, filter, wash with water until the pH is 7, and dry to obtain lauric acid raw material; wherein, the weight ratio of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, anhydrous pyridine, and aniline is 1:(1.1-1.5):(2-4):(0.02-0.06), and the amount of water added to each 1g of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde in step S1 is 2-4mL.

[0012] By adopting the above technical solution, the preparation method of lauric acid raw material of this application can improve the purity and yield of lauric acid through the synergistic effect between each step. The purity of lauric acid is 98-99.6 wt%, and the yield is 85-98 wt%.

[0013] A condensation reaction was carried out using 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, and aniline, with anhydrous pyridine as the solvent. The reaction was carried out under heating, and a milky yellow solid was precipitated by adjusting the pH value. After adding water, filtering, washing, and drying, a slightly yellow solid was obtained. After adding water, adjusting the pH value, decolorizing, and filtration, the pH value of the filtrate was adjusted, and the precipitate was precipitated. After filtration, washing, and drying, lauric acid raw material was finally obtained. The decolorization treatment can remove the color of the slightly yellow solid by adsorbing pigment molecules, reducing the adverse effects of pigments on human health. Moreover, the preparation method is simple, easy to operate, and can improve the yield of lauric acid raw material.

[0014] As a preferred method, the 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is prepared by the following method: sodium hydroxide and vanillin are added to water, then a portion of chloroethanol is added, the mixture is heated, the remaining chloroethanol is added dropwise, the pH value is adjusted, the mixture is heated under reflux to maintain the pH value, cooled, stirred until crystals precipitate, filtered, washed, and dried to obtain 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde.

[0015] Furthermore, the 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is prepared by the following method: sodium hydroxide and vanillin are added to water, then a portion of chloroethanol is added, the mixture is heated to 80-90℃, the remaining chloroethanol is added dropwise over a period of 1.5-2 hours, the pH is adjusted to 9 with sodium hydroxide solution, the mixture is heated under reflux for 6-8 hours while maintaining the pH at 9, the mixture is cooled, stirred until crystals precipitate, filtered, washed with water until neutral, and dried at 40-50℃ for 12-14 hours to obtain 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde;

[0016] The weight ratio of sodium hydroxide, water, and vanillin is (0.2-0.4):(20-30):1, the weight ratio of vanillin and total chloroethanol is 1:(0.4-0.6), the weight ratio of the first batch of chloroethanol to the remaining chloroethanol is 1:1, and the mass fraction of the sodium hydroxide solution is 30%.

[0017] By adopting the above technical solution and preparation method, 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is prepared by etherifying vanillin with chloroethanol, adjusting the pH value, heating under reflux, cooling and crystallizing, and then filtering, washing and drying to obtain 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde. This method has the advantages of simple preparation and can also obtain 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde in good yield. It also facilitates the subsequent preparation of lauric acid raw material.

[0018] As a preferred option, KI catalyst is added before adding chloroethanol, and the weight ratio of chloroethanol to KI is 1:(0.008-0.012).

[0019] By adopting the above technical solution, the KI catalyst can improve the reaction activity, activate chloroethanol and chloroethanol, accelerate the reaction process, greatly shorten the reaction time, and also improve the yield of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, which facilitates the better preparation of lauric acid raw material and thus improves the yield of lauric acid raw material.

[0020] Preferably, the alkaline solution in step S1 is a sodium hydroxide solution.

[0021] Furthermore, the alkaline solution in step S1 is a sodium hydroxide solution, and the mass fraction of the sodium hydroxide solution is 30%.

[0022] By adopting the above technical solution, the sodium hydroxide solution has strong alkalinity, which can improve the alkaline conditions in the reaction process, ensure the reaction proceeds, and facilitate the preparation of lauric acid raw material.

[0023] As a preferred method, sodium hydroxide solution is added first in step S2 to adjust the pH value, and sulfuric acid solution is added second to adjust the pH value.

[0024] Further: In step S2, sodium hydroxide solution is added first to adjust the pH value, and sulfuric acid solution is added second to adjust the pH value, with the mass fraction of sodium hydroxide solution being 30% and the mass fraction of sulfuric acid solution being 33%.

[0025] By adopting the above technical solution, sodium hydroxide solution is a strong alkaline solution and sulfuric acid solution is a strong acid solution. By using strong base and strong acid to adjust the pH value, the required pH value can be reached more quickly, which facilitates the acceleration of the reaction process and improves production efficiency.

[0026] As a preferred option, the specific steps of the decolorization process in step S2 are as follows: water is added to the slightly yellow solid, the pH value is adjusted, then medicinal charcoal is added, the temperature is raised, and the solid is decolorized for a period of time.

[0027] Furthermore, the specific steps of the decolorization process in step S2 are as follows: water is added to the slightly yellow solid, the pH value is adjusted to 7-8 with sodium hydroxide solution, then medicinal charcoal is added, and the temperature is heated to 50-60℃ for decolorization for 20-40 minutes.

[0028] The amount of water added to each 1g of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is 2-4mL, the mass fraction of sodium hydroxide solution is 30%, and the weight ratio of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde to pharmaceutical charcoal is 1:(0.02-0.03).

[0029] By adopting the above technical solution, medicinal charcoal is used for decolorization treatment, and the amount of medicinal charcoal added is limited. Medicinal charcoal itself has a large specific surface area, high activity, well-developed micropores, and strong decolorization power. It can better adsorb pigments and achieve the purpose of decolorization. Moreover, medicinal charcoal will not have any adverse effects on human health.

[0030] As a preferred method: the filtration method in step S1 is centrifugal filtration, the filtration method in step S2 is filter rod filtration, and the filtration method after precipitation is centrifugal filtration.

[0031] By adopting the above technical solutions and using filtration methods such as centrifugal filtration and filter rod filtration, the production process can be accelerated, time can be saved, production efficiency can be improved, and crystal precipitation can be facilitated.

[0032] Preferably, the lauric acid raw material obtained in step S2 is purified. The purification process is specifically carried out by the following method: the lauric acid raw material is placed in an ethanol solution, heated, decolorized, refluxed, filtered, and cooled while stirring until crystals precipitate. After standing for a period of time, it is centrifuged, filtered, and dried to obtain the purified lauric acid raw material.

[0033] Furthermore, the purification process specifically adopts the following method: lauric acid raw material is placed in an ethanol solution, heated to 50-60℃, decolorized, refluxed, filtered, and crystals are precipitated by stirring and cooling. After standing for 10-14 hours, the mixture is centrifuged, filtered, and dried to obtain purified lauric acid raw material.

[0034] The ethanol solution has a mass fraction of 60%, and the amount of ethanol solution added to each 1g of guimetic acid raw material is 10-30mL.

[0035] By adopting the above technical solution, lauric acid raw material is placed in an ethanol solution for recrystallization, and then decolorized to remove pigments, reducing adverse effects on human health. After crystallization, centrifugation and filtration are performed to obtain purified lauric acid raw material, which is more conducive to improving the yield of lauric acid raw material.

[0036] As a preferred option, the specific steps for decolorization are as follows: After the lauric acid raw material is placed in an ethanol solution and heated, pharmaceutical charcoal is added, and the temperature is continued to rise for a period of time to decolorize.

[0037] As a preferred option, the specific steps of the decolorization are as follows: After the lauric acid raw material is placed in an ethanol solution and heated to 50-60°C, pharmaceutical charcoal is added, and the temperature is further raised to 78-80°C for decolorization for 20-40 minutes.

[0038] The weight ratio of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde to pharmaceutical charcoal is 1:(0.036-0.039).

[0039] By adopting the above technical solution, the medicinal charcoal is decolorized again, utilizing its large adsorption capacity to remove pigments and reduce the impact of pigments on human health.

[0040] In summary, this application includes at least one of the following beneficial technical effects:

[0041] 1. In this application, 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, and aniline are used for a condensation reaction. Anhydrous pyridine is used as a solvent. The reaction is carried out under heat. By adjusting the pH value, a milky yellow solid is precipitated. Water is added, the solid is filtered, washed, and dried to obtain a slightly yellow solid. Water is then added again, the pH value is adjusted, the solid is decolorized, filtered, the pH value of the filtrate is adjusted, the precipitate is precipitated, filtered, washed, and dried to finally obtain lauric acid raw material. The decolorization treatment can remove the color of the slightly yellow solid by adsorbing pigment molecules, reducing the adverse effects of pigments on human health. Moreover, this preparation method is simple, easy to operate, and can improve the yield of lauric acid raw material, achieving a purity of 99.6 wt% and a yield of 98 wt%.

[0042] 2. In this application, it is preferred to purify the lauric acid raw material by placing it in an ethanol solution for recrystallization, followed by decolorization to remove pigments and reduce adverse effects on human health. After crystallization, the purified lauric acid raw material is obtained by centrifugation and filtration, which is more conducive to improving the yield of lauric acid raw material. Detailed Implementation

[0043] The following provides a more detailed description of this application in conjunction with specific details.

[0044] raw material

[0045] All raw materials used in this application are common commercially available materials.

[0046] Preparation Example

[0047] Preparation Example 1

[0048] A 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is prepared by the following method:

[0049] 1.2 kg of sodium hydroxide and 4 kg of vanillin were added to 10 kg of water, followed by 1 kg of chloroethanol. The mixture was heated to 85 °C, and the remaining 1 kg of chloroethanol was added dropwise over 1.7 h. The pH was adjusted to 9 with a 30% sodium hydroxide solution, and the mixture was heated under reflux for 7 h while maintaining the pH at 9. The mixture was then cooled and stirred until crystals precipitated. After filtration, the crystals were washed with water until neutral and dried at 45 °C for 13 h to obtain 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde.

[0050] Preparation Example 2

[0051] A method for preparing 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, which differs from Preparation Example 1 in that a KI catalyst is added before the addition of chloroethanol, and the weight of the added KI catalyst is 0.016 kg.

[0052] Preparation Example 3

[0053] A method for preparing 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde differs from Preparation Example 2 in that the amount of KI catalyst added is different; in Preparation Example 3, the amount of KI catalyst added is 0.02 kg.

[0054] Preparation Example 4

[0055] A method for preparing 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde differs from Preparation Example 2 in that the amount of KI catalyst added is different; in Preparation Example 4, the amount of KI catalyst added is 0.024 kg.

[0056] Example

[0057] Example 1

[0058] A method for preparing lauric acid raw material includes the following steps:

[0059] S1: Mix 5 kg of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde (prepared in Example 1), 6.5 kg of malonic acid, 15 kg of anhydrous pyridine, and 0.2 kg of aniline evenly, heat to 45°C, and react for 14 h to obtain a mixture. Reduce the pressure of the mixture to a vacuum of 0.08 MPa, distill, and recover 10 kg of anhydrous pyridine. Add a 30% sodium hydroxide solution to the mixture, mix evenly, adjust the pH to 2 with a 33% sulfuric acid solution, and precipitate a milky yellow solid. Add water, mix evenly, filter, and wash with water until the pH reaches 6 to obtain a slightly yellow solid.

[0060] S2: Add 15L of water to the slightly yellow solid in step S1, adjust the pH to 7 with a 30% sodium hydroxide solution, add 1kg of pharmaceutical charcoal, heat to 55℃, decolorize for 30min, filter with a filter rod, collect the filtrate, adjust the pH to 2 with a 40% sulfuric acid solution, filter after precipitation, wash with water until the pH is 7, and dry to obtain lauric acid raw material.

[0061] Example 2

[0062] A method for preparing lauric acid raw material, which differs from Example 1 in that the source of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is different. The 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde in Example 2 is prepared using Preparation Example 2.

[0063] Example 3

[0064] A method for preparing lauric acid raw material, which differs from Example 1 in that the source of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is different. The 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde in Example 3 was prepared using the method described in Example 3.

[0065] Example 4

[0066] A method for preparing lauric acid raw material, which differs from Example 1 in that the source of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde is different. The 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde in Example 4 was prepared using Preparation Example 4.

[0067] Example 5

[0068] A method for preparing lauric acid raw material, which differs from Example 3 in that the lauric acid raw material is purified by the following method: the lauric acid raw material is placed in a 60% ethanol solution, heated to 55°C, 1.5 kg of pharmaceutical charcoal is added, the temperature is further increased to 80°C, decolorized for 30 min, refluxed, filtered, and crystals are precipitated by stirring and cooling. After standing for 12 h, centrifuged, filtered, and dried, the purified lauric acid raw material is obtained; wherein, the amount of ethanol solution added to each 1 g of lauric acid raw material is 20 mL.

[0069] Comparative Example

[0070] Comparative Example 1

[0071] A method for preparing lauric acid raw material differs from Example 1 in that it is prepared by the following method: vanillin and malonic acid are placed in anhydrous pyridine, piperidine is added, the mixture is heated to 50°C and reacted for 15 hours. The mixture is then distilled under reduced pressure to recover the anhydrous pyridine, and a mixture is obtained. The pH is then adjusted to 9 with a 30% sodium hydroxide solution, chloroethanol is added, and the mixture is heated to 85°C and refluxed for 6 hours while maintaining the pH at 9. The mixture is then cooled, stirred until crystals precipitate, filtered, washed with water until neutral, and dried to obtain lauric acid raw material. The weight ratio of vanillin, malonic acid, anhydrous pyridine, chloroethanol, and piperidine is 1:1.2:3:0.5:0.02.

[0072] Performance testing

[0073] The following performance tests were performed on Examples 1-5 and Comparative Example 1:

[0074] Yield: The yield of lauric acid raw material was determined, and the test results are shown in Table 1.

[0075] Purity: The purity of the obtained lauric acid raw material was determined, and the test results are shown in Table 1.

[0076] Table 1 Test Results

[0077]

[0078]

[0079] As can be seen from Table 1, the preparation method of lauric acid raw material of this application, through the synergistic effect between each step, facilitates the improvement of the purity and yield of lauric acid, wherein the purity of lauric acid is 98-99.6 wt% and the yield is 85-98 wt%.

[0080] Combining Example 1 and Comparative Example 1, it can be seen that the purity of lauric acid in Example 1 is 98 wt% and the yield is 85 wt%, which is better than that in Comparative Example 1. This indicates that the preparation method of Example 1 is more suitable. First, vanillin and chloroethanol are condensed to generate a condensate, and then lauric acid is synthesized using the condensate, malonic acid, anhydrous pyridine, and aniline. This preparation method is better and can better improve the yield and purity of lauric acid.

[0081] Combining Examples 1 and 2, it can be seen that the purity of lauric acid in Example 2 is 98.8 wt%, and the yield is 89 wt%, which is better than that in Example 1. This indicates that adding a catalyst is more suitable in the preparation of 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, which can improve the reaction activity, accelerate the reaction process, improve production efficiency, and also improve the yield.

[0082] As can be seen from Examples 2-4, the purity of lauric acid in Example 3 is 99.2 wt%, and the yield is 93 wt%, which is better than other examples. This indicates that the 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde prepared by Example 3 is more suitable. The addition of the catalyst not only improves the reaction activity and accelerates the reaction process, but also improves the purity and yield.

[0083] The embodiments described above are preferred embodiments of this application and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made in accordance with the structure, shape and principle of this application should be covered within the scope of protection of this application.

Claims

1. A method for preparing lauric acid raw material, characterized in that: Includes the following steps: S1: Mix 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde, malonic acid, anhydrous pyridine, and aniline evenly, heat and react for a period of time to obtain a mixture, distill the mixture under reduced pressure to recover the anhydrous pyridine, add an alkaline solution to the mixture, mix evenly, adjust the pH value, precipitate a milky yellow solid, add water and mix evenly, filter, wash, and obtain a slightly yellow solid. S2: Add water to the slightly yellow solid in step S1, adjust the pH value, and perform decolorization treatment. Filter, collect the filtrate, adjust the pH value, precipitate the precipitate, filter, wash, and dry to obtain lauric acid raw material. The 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde was prepared by the following method: sodium hydroxide and vanillin were added to water, followed by a portion of chloroethanol. The mixture was heated, and the remaining chloroethanol was added dropwise. The pH was adjusted, and the mixture was heated under reflux while maintaining the pH. The mixture was then cooled and stirred until crystals precipitated. The crystals were filtered, washed, and dried to obtain 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde. Before adding chloroethanol, a KI catalyst was added, and the weight ratio of chloroethanol to KI was 1:(0.008-0.012). The specific steps of the decolorization process in step S2 are as follows: water is added to the slightly yellow solid, the pH value is adjusted, then medicinal charcoal is added, the temperature is raised, and the decolorization is carried out for a period of time. The lauric acid raw material obtained in step S2 is purified. The purification process specifically employs the following method: lauric acid raw material is placed in an ethanol solution, heated to a higher temperature, decolorized, refluxed, filtered, and cooled while stirring until crystals precipitate. After standing for a period of time, it is centrifuged, filtered, and dried to obtain purified lauric acid raw material. The specific steps for decolorization are as follows: After the lauric acid raw material is placed in an ethanol solution and heated, pharmaceutical charcoal is added, and the temperature is continued to rise for a period of time for decolorization.

2. The method for preparing lauric acid raw material according to claim 1, characterized in that: The alkaline solution in step S1 is a sodium hydroxide solution.

3. The method for preparing lauric acid raw material according to claim 1, characterized in that: In step S2, sodium hydroxide solution is added first to adjust the pH value, and sulfuric acid solution is added second to adjust the pH value.

4. The method for preparing lauric acid raw material according to claim 1, characterized in that: The filtration method in step S1 is centrifugal filtration, the filtration method in step S2 is filter rod filtration, and the filtration method after precipitation is centrifugal filtration.

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