A pharmaceutical excipient, sodium stearate, and its preparation method

Abstract

This application discloses a pharmaceutical excipient, sodium stearate fumarate impurity, and its preparation method, relating to the field of pharmaceutical excipient synthesis technology. A method for preparing a pharmaceutical excipient, sodium stearate fumarate impurity, includes the following steps: Step 1: Mixing octadecyl alcohol and fumarate chloride in a first solvent to carry out a condensation reaction; Step 2: Performing a first filtration, a first crystallization, and a second filtration on the condensation reaction product to obtain a crude product; Step 3: Dissolving the crude product obtained in Step 2 in a second solvent for purification, thereby obtaining the final product. The pharmaceutical excipient, sodium stearate fumarate impurity, is prepared according to the aforementioned method. Its structural formula is [not specified in the original text]. The method provided by this invention is simple, uses readily available raw materials, and yields a product with high purity and high yield. Its structure is confirmed by H-NMR and IR.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical excipient synthesis technology, and more specifically, to a pharmaceutical excipient, sodium stearate fumarate impurity, and its preparation method. Background Technology

[0002] Sodium stearyl fumarate, CAS number: [4070-80-8], molecular formula: C22H39NaO4, molecular weight: 390.54. Structural formula:

[0003]

[0004] Sodium stearate (C 22 H 39 Sodium stearate (NaO4) is an important excipient widely used in pharmaceuticals and food. During its metabolism in animals, most of sodium stearate is absorbed and hydrolyzed to produce stearyl alcohol and fumaric acid. The former is further oxidized to stearic acid. Both stearyl alcohol and stearic acid are major components of natural foods, while the latter is a normal component of human tissues. A small portion is directly and rapidly metabolized and is non-toxic and non-irritating. Structurally, sodium stearate consists of a hydrophobic stearyl alcohol and a hydrophilic sodium fumarate linked by an ester bond, giving it hydrophilic properties. In the pharmaceutical field, sodium stearate is added to drug formulations as a lubricant for tablets and capsules, and it can also form a protective film in effervescent tablets. This addresses the problems associated with stearate lubricants and can improve drug disintegration and promote drug dissolution. In the food industry, the FDA permits sodium stearate to be added directly to foods intended for human consumption as a regulator and stabilizer, such as various baked goods, flour-based thickening products, dried potatoes, and processed grains, at a rate of 0.2% to 1.0% of the food weight.

[0005] In existing technologies, stearyl alcohol and maleic anhydride are commonly used as raw materials to prepare stearic sodium fumarate. However, during large-scale industrial production, due to the numerous steps and long reaction times, the target product may be contaminated with specific process impurities, primarily the polymeric impurity dioctadecyl fumarate. Although the current editions of the Chinese Pharmacopoeia, the United States Pharmacopoeia, the European Pharmacopoeia, and other pharmacopoeias do not explicitly require the detection of dioctadecyl fumarate impurities for pharmaceutical excipients such as stearic sodium fumarate, this impurity is a common occurrence in stearic sodium fumarate products. It must be controlled during the application for production of pharmaceutical excipient stearic sodium fumarate and during industrial production. It is an essential impurity compound for qualitative and quantitative detection and control of impurities during production and testing. Furthermore, dioctadecyl fumarate is currently not commercially available and cannot be purchased. Therefore, in-house synthesis not only reduces costs but also allows for the preparation of impurities that are not commercially available.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The purpose of this invention is to provide a pharmaceutical excipient, sodium stearate, and its preparation method, in order to solve the above-mentioned problems.

[0008] A method for preparing an impurity of sodium stearate, a pharmaceutical excipient, includes the following steps:

[0009] Step 1: Cetyl alcohol and fumarate chloride are mixed in the first solvent to carry out a condensation reaction;

[0010] Step 2: The condensation reaction product is subjected to one filtration, one crystallization, and a second filtration to obtain the crude product;

[0011] Step 3: Dissolve the crude product obtained in Step 2 in a second solvent for purification, and the product is obtained.

[0012] Preferably, step 1 satisfies one or more of the following conditions:

[0013] a. The mixing process includes: first dissolving the octadecyl alcohol in the first solvent, then controlling the temperature and adding fumarate chloride dropwise;

[0014] b. The first solvent includes one or more of acetone, toluene, tetrahydrofuran, dichloromethane, chloroform, and ethyl acetate;

[0015] c. The condensation reaction is carried out at a temperature of 0–80°C for 1–5 hours.

[0016] d. The mass ratio of the first solvent to the octadecyl alcohol is 2 to 9:1.

[0017] Optionally, the temperature of the condensation reaction can be any value between 0, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, and 80°C, and the time can be any value between 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, and 5h; the mass ratio of the first solvent to the octadecyl alcohol can be any value between 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, and 9:1.

[0018] More preferably, step 1 also satisfies one or more of the following conditions:

[0019] e. The target temperature for temperature control is 0–80°C;

[0020] f. The dripping time is 0.5–2.5 h;

[0021] g. The condensation reaction is carried out at a temperature of 10–50°C for 2.5–4 hours.

[0022] h. The mass ratio of the first solvent to the octadecyl alcohol is 3.5 to 7:1.

[0023] Optionally, the target temperature for temperature control can be any value between 0, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, and 80°C.

[0024] The dripping time can be any value between 0.5h, 1h, 1.5h, 2h, and 2.5h;

[0025] Preferably, the temperature of the first crystallization is 0–30°C, and the time is 0.5–2 hours;

[0026] More preferably, the temperature of the first crystallization is 5 to 20°C, and the time is 1 to 1.5 hours.

[0027] Optionally, the temperature of the first crystallization can be any value between 0, 10°C, 15°C, 20°C, 25°C and 30°C, and the time can be any value between 0.5, 1h, 1.5h and 2h.

[0028] Preferably, step 3 satisfies one or more of the following conditions:

[0029] i. The dissolution temperature is 40–70°C;

[0030] j. The second solvent is a moderately polar organic solvent;

[0031] k. The mass ratio of the second solvent to the crude product is 2 to 10:1;

[0032] l. The refining steps include: placing the crude product in a second solvent, heating to dissolve it, cooling it down, and then sequentially passing it through a second crystallization process, filtration, washing, and drying.

[0033] Optionally, the dissolution temperature is any value between 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, and 70°C.

[0034] Optionally, the mass ratio of the second solvent to the crude product can be any value between 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1.

[0035] More preferably, the preparation method further satisfies one or more of the following conditions:

[0036] m. The target temperature for temperature control is 10–50°C;

[0037] n. The dripping time is 1 to 2 hours;

[0038] o. The first solvent is dichloromethane and / or toluene;

[0039] p. The dissolution temperature is 50–60°C;

[0040] q. The second solvent includes one or more of acetone, toluene, dichloromethane, and ethyl acetate;

[0041] More preferably, the second solvent is ethyl acetate and / or toluene;

[0042] r. The mass ratio of the second solvent to the crude product is 3 to 8:1;

[0043] s. The second crystallization temperature is 10–30°C, and the time is 0.5–3 hours;

[0044] More preferably, the temperature for the second crystallization is 15–25°C, and the time is 1–2 hours;

[0045] The drying process is vacuum drying, with a temperature of 40–55°C and a time of 6–10 hours.

[0046] Optionally, the temperature of the second crystallization can be any value between 10, 15°C, 20°C, 25°C and 30°C, and the time can be any value between 0.5, 1h, 1.5h, 2h, 2.5h and 3h.

[0047] Optionally, the drying temperature can be any value between 40°C, 45°C, 50°C and 55°C, and the time can be any value between 6h, 7h, 8h, 9h and 10h.

[0048] Preferably, the mixing further includes: first dissolving the octadecyl alcohol in the first solvent, then adding an acid-binding agent, and then controlling the temperature and adding fumarate chloride dropwise.

[0049] More preferably, the molar ratio of octadecyl alcohol, fumarate chloride, and acid-binding agent is 2.0:0.8-1.5:1.6-3.0;

[0050] More preferably, the molar ratio of octadecyl alcohol, fumarate chloride and acid-binding agent is 2.0:1.0-1.3:2.0-2.5.

[0051] Preferably, the acid-binding agent includes one or more of pyridine, triethylamine, DIPEA, DMAP, potassium carbonate, sodium carbonate, and ammonium carbonate;

[0052] More preferably, the acid-binding agent is triethylamine and / or sodium carbonate.

[0053] This invention also provides a pharmaceutical excipient, sodium stearate fumarate impurity, dioctadecyl fumarate, with the following structural formula: The product was prepared using the method described above.

[0054] The reactions that occur in the preparation method of this invention are as follows:

[0055]

[0056] By providing alkaline conditions for the condensation reaction of octadecyl alcohol and fumarate chloride with an acid-binding agent, a one-step method was adopted to promote the reaction under relatively milder conditions, thereby obtaining the target product with higher purity and higher yield.

[0057] This invention synthesizes dioctadecyl fumarate, an impurity in sodium stearate, using a novel method. This method can be directly used for qualitative and quantitative detection and control of impurities during production and testing, which is highly beneficial for the control of impurities in sodium stearate. It also helps to optimize the sodium stearate process, reduce impurity content, and improve the pharmaceutical safety of sodium stearate.

[0058] According to the technical content disclosed in this invention, the following beneficial effects are achieved:

[0059] This invention provides a one-step synthesis of dioctadecyl fumarate, an impurity in the pharmaceutical excipient sodium stearate fumarate. The reaction conditions are mild, and the product can be purified using ordinary recrystallization methods without the need for chromatographic purification. The purity of the obtained product is not less than 99%, and the yield is high, generally reaching around 90%. Furthermore, the operation is simple, and the raw materials are inexpensive and readily available, making it suitable for widespread use.

[0060] Other features and advantages of the invention will become clear from the following detailed description of exemplary embodiments of the invention with reference to the accompanying drawings. Attached Figure Description

[0061] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments of the invention and, together with their description, serve to explain the principles of the invention.

[0062] Figure 1 The GC spectrum of the product obtained in Example 1;

[0063] Figure 2 The H-NMR spectrum of the product obtained in Example 1;

[0064] Figure 3 The image shows the IR spectrum of the product obtained in Example 1. Detailed Implementation

[0065] Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that, unless otherwise specifically stated, the relative arrangement, numerical expressions, and values ​​of the components and steps set forth in these embodiments do not limit the scope of the invention.

[0066] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use.

[0067] Techniques, methods, and equipment known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques, methods, and equipment should be considered part of the specification.

[0068] In all the examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0069] It should be noted that similar labels and letters in the following figures indicate similar items; therefore, once an item is defined in one figure, it does not need to be discussed further in subsequent figures.

[0070] It should be noted that the "octadecyl alcohol" in this invention has the English name: Stearyl Alcohol, the chemical name: 1-octadecyl alcohol, the CAS number: 112-92-5, other names: stearyl alcohol, and the molecular formula: C 18 H 38 O, with a molecular weight of 270.50, is a white flaky or granular solid, insoluble in water, with a melting point of 57–60°C.

[0071] The "fumaryl chloride" in this invention has the English name: Fumaryl chloride, the chemical name: trans-butenedioic acid chloride, the CAS number: 627-63-4, other names: trans-butenedioic acid dichloride, the molecular formula: C4H2Cl2O2, and the molecular weight: 152.96; it is a corrosive colorless liquid that reacts with water.

[0072] All raw materials and reagents used in this invention are commercially available.

[0073] The following embodiments illustrate the technical solutions provided in this application.

[0074] Example 1

[0075] This embodiment provides a method for preparing impurities in the pharmaceutical excipient sodium stearate, specifically including the following steps:

[0076] S1: In a reaction flask, add 20g of octadecyl alcohol, 70ml of dichloromethane, and 8.2g of triethylamine, and start stirring until the octadecyl alcohol is completely dissolved;

[0077] S2: The solution obtained in S1 is kept at a temperature of 20℃, and 32g of dichloromethane solution containing 5.7g of fumarate chloride is added dropwise over a period of 1 hour.

[0078] S3: After S2 has been added dropwise with fumarate chloride, keep the reaction at the temperature for 3 hours. After the reaction is complete, filter the solution, cool the filtrate to 10°C, keep it at the temperature and stir for 1.5 hours, filter the solution, and obtain about 21.9g of crude dioctadecyl fumarate.

[0079] S4: In another reaction flask, add crude dioctadecyl fumarate obtained in S3 and 80 ml of ethyl acetate. Start stirring and heat to 55°C to dissolve. Then cool down to crystallize. Cool to 20°C and keep stirring to crystallize for 1 h. Filter and wash the filter cake once with 10 ml of ethyl acetate. Collect the filter cake and dry it under reduced pressure at 40°C for 8 h.

[0080] The product, 19.8 g of dioctadecyl fumarate, was obtained, with a calculated yield of 86.5% and a GC purity of 99.28%.

[0081] The GC spectrum of the product obtained in this embodiment is as follows: Figure 1 As shown, its H-NMR spectrum is as follows Figure 2 As shown, the IR spectrum is as follows Figure 3 As shown.

[0082] Depend on Figure 1-3 It can be seen that the present invention successfully prepared dioctadecyl fumarate, an impurity of sodium stearate fumarate used as a pharmaceutical excipient, with high purity, and its structure was confirmed by GC chromatogram, H-NMR and IR.

[0083] Example 2

[0084] This embodiment provides a method for preparing impurities in the pharmaceutical excipient sodium stearate, specifically including the following steps:

[0085] S1: In a reaction flask, add 20g of octadecyl alcohol, 100ml of toluene, and 8.3g of triethylamine, and start stirring until the octadecyl alcohol is completely dissolved;

[0086] S2: The solution obtained in S1 is kept at 40℃ and 23g of toluene solution containing 6g of fumarate chloride is added dropwise over 1 hour.

[0087] S3: After S2 has been added dropwise with fumarate chloride, keep the reaction at the temperature for 2.5 hours. After the reaction is complete, filter the solution, cool the filtrate to 15°C, keep it at the temperature and stir for 1 hour, filter the solution, and obtain about 22.8 g of crude dioctadecyl fumarate.

[0088] S4: In another reaction flask, add crude dioctadecyl fumarate obtained in S3 and 130 ml of ethyl acetate, start stirring, heat to 60°C to dissolve, then cool to crystallize, cool to 25°C, keep warm and stir to crystallize for 1.5 h, filter, wash the filter cake once with 10 ml of ethyl acetate, collect the filter cake, and dry under reduced pressure at 45°C for 8 h.

[0089] 20.8 g of the product, bis(octadecyl) fumarate, was obtained, with a calculated yield of 90.6% and a GC purity of 99.17%.

[0090] Example 3

[0091] This embodiment provides a method for preparing impurities in the pharmaceutical excipient sodium stearate, specifically including the following steps:

[0092] S1: In a reaction flask, add 50g of octadecyl alcohol, 200ml of dichloromethane, and 21.5g of triethylamine, and start stirring until the octadecyl alcohol is completely dissolved.

[0093] S2: Keep the temperature of the solution obtained in S1 at 20℃ and add 15.5g of fumarate chloride dropwise over 1 hour;

[0094] S3: After S2 has been added dropwise with fumarate chloride, keep the reaction at the temperature for 3 hours. After the reaction is complete, filter the solution, cool the filtrate to 5°C, keep it at the temperature and stir for 1.5 hours, filter the solution, and obtain about 55.3g of crude dioctadecyl fumarate.

[0095] S4: In another reaction flask, add crude dioctadecyl fumarate obtained in S3 and 200 ml of ethyl acetate. Start stirring and heat to 50°C to dissolve. Then cool down to crystallize. Cool to 20°C and keep stirring to crystallize for 2 hours. Filter and wash the filter cake once with 30 ml of ethyl acetate. Collect the filter cake and dry it under reduced pressure at 40°C for 8 hours.

[0096] 52.5 g of the product, dicoctadecyl fumarate, was obtained, with a calculated yield of 91.5% and a GC purity of 99.21%.

[0097] Example 4

[0098] This embodiment provides a method for preparing impurities in the pharmaceutical excipient sodium stearate, specifically including the following steps:

[0099] S1: In a reaction flask, add 40g of octadecyl alcohol, 100ml of toluene, and 16.4g of triethylamine, and start stirring until the octadecyl alcohol is completely dissolved;

[0100] S2: The solution obtained in S1 is kept at a temperature of 45℃, and 11.3g of fumarate chloride is added dropwise over a period of 1 hour.

[0101] S3: After S2 has been added dropwise with fumarate chloride, keep the reaction at the temperature for 2.5 hours. After the reaction is complete, filter the solution, cool the filtrate to 18°C, keep it at the temperature and stir for 1 hour, filter the solution, and obtain about 45.2 g of crude dioctadecyl fumarate.

[0102] S4: In another reaction flask, add crude dioctadecyl fumarate obtained in S3 and 220 ml of ethyl acetate. Start stirring and heat to 55°C to dissolve. Then cool down to crystallize. Cool to 22°C and keep stirring to crystallize for 1 h. Filter and wash the filter cake once with 20 ml of ethyl acetate. Collect the filter cake and dry it under reduced pressure at 40°C for 8 h.

[0103] The product, 42.3 g of dioctadecyl fumarate, was obtained, with a calculated yield of 92.1% and a GC purity of 99.10%.

[0104] Example 5

[0105] This embodiment provides a method for preparing impurities in the pharmaceutical excipient sodium stearate, specifically including the following steps:

[0106] S1: In a reaction flask, add 20g of octadecyl alcohol, 120ml of dichloromethane, and 4.7g of sodium carbonate, and start stirring until the octadecyl alcohol is completely dissolved.

[0107] S2: The solution obtained in S1 is kept at a temperature of 20℃, and 32g of dichloromethane solution containing 5.7g of fumarate chloride is added dropwise over a period of 1 hour.

[0108] S3: After S2 has been added dropwise with fumarate chloride, keep the reaction at the temperature for 3 hours. After the reaction is complete, filter the solution and wash the filtrate twice with drinking water, 40 ml each time. Let the solution stand to separate into layers to obtain the organic phase. Concentrate the organic phase under reduced pressure at 45°C to dryness to obtain approximately 22.7 g of crude dioctadecyl fumarate.

[0109] S4: In another reaction flask, add crude dioctadecyl fumarate obtained in S3 and 100 ml of ethyl acetate, start stirring, heat to 60°C to dissolve, then cool to crystallize, lower to 20°C, keep warm and stir to crystallize for 1 h, filter, wash the filter cake once with 10 ml of ethyl acetate, collect the filter cake, and dry under reduced pressure at 40°C for 8 h.

[0110] 20.3 g of the product, dicoctadecyl fumarate, was obtained, with a calculated yield of 88.5% and a GC purity of 99.12%.

[0111] Example 6

[0112] The difference from Example 1 is that the 80 ml of ethyl acetate used in step S4 is replaced with 100 ml of toluene.

[0113] The product, 20.3 g of dioctadecyl fumarate, was obtained, with a calculated yield of 88.4% and a GC purity of 99.08%.

[0114] Example 7

[0115] The difference from Example 2 is that the ethyl acetate used in step S4 is replaced with toluene.

[0116] 21.0 g of the product, bis(octadecyl) fumarate, was obtained, with a calculated yield of 91.5% and a GC purity of 99.05%.

[0117] Example 8

[0118] The difference from Example 5 is that the ethyl acetate used in step S4 is replaced with toluene.

[0119] 20.9 g of the product, bis(octadecyl) fumarate, was obtained, with a calculated yield of 91% and a GC purity of 99.01%.

[0120] As can be seen from the embodiments of the present invention, the pharmaceutical excipient sodium stearate impurity dioctadecyl fumarate prepared by the preparation method provided by the present invention has stable reaction and good reproducibility. Within the preferred parameter range of the present invention, the product yield is high and the purity is high, which has excellent potential for industrial application.

[0121] Comparative Example 1

[0122] The difference between this comparative example and Example 1 is that in step S1, the amount of triethylamine is reduced to 3.7g, which illustrates the effect of reducing the amount of triethylamine on the reaction.

[0123] Finally, 18.8 g of dioctadecyl fumarate was obtained, with a calculated yield of 81.9% and a GC purity of 97.68%.

[0124] Comparative experiments show that reducing the amount of triethylamine decreases both the product yield and purity.

[0125] Comparative Example 2

[0126] The difference between this comparative example and Example 1 is that in step S2, the amount of fumarate chloride used is reduced to 2.8g, which illustrates the effect of reducing the amount of fumarate chloride on the reaction.

[0127] Finally, 10.3 g of dioctadecyl fumarate was obtained, with a calculated yield of 44.9% and a GC purity of 98.38%.

[0128] Comparative experiments show that reducing the amount of fumarate chloride significantly reduces the product yield and purity.

[0129] Comparative Example 3

[0130] The difference between this comparative example and Example 2 is that in step S2, the solution obtained in S1 is heated to 100°C, illustrating the effect of changing the reaction temperature on the reaction.

[0131] Finally, 16.2 g of dioctadecyl fumarate was obtained, with a calculated yield of 78.5% and a GC purity of 97.58%.

[0132] Comparative experiments show that increasing the reaction temperature reduces both product yield and purity.

[0133] Comparative Example 4

[0134] The difference between this comparative example and Example 1 is that in step S1, the amount of triethylamine, an acid-binding agent, was replaced by an equimolar amount of sodium hydroxide, which is 3.3g. This illustrates the effect of changing the type of acid-binding agent on the reaction.

[0135] Finally, 17.9 g of dioctadecyl fumarate was obtained, with a calculated yield of 77.98% and a GC purity of 97.08%.

[0136] Comparative experiments show that changing the type of acid binder reduces both product yield and purity.

[0137] While specific embodiments of the invention have been described in detail by way of examples, those skilled in the art should understand that the examples are for illustrative purposes only and not intended to limit the scope of the invention. Those skilled in the art should understand that modifications can be made to the above embodiments without departing from the scope and spirit of the invention. The scope of the invention is defined by the appended claims.

Claims

1. A method for preparing an impurity in sodium stearate, a pharmaceutical excipient, characterized in that, Includes the following steps: Step 1: A condensation reaction is carried out by mixing octadecyl alcohol and fumarate chloride in a first solvent; the mixing includes: first dissolving octadecyl alcohol in the first solvent, then adding an acid-binding agent, and then adding fumarate chloride dropwise while controlling the temperature; the first solvent includes one or more of acetone, toluene, tetrahydrofuran, dichloromethane, chloroform, and ethyl acetate; the temperature of the condensation reaction is 0~80℃, and the time is 1~5h; the mass ratio of the first solvent to the octadecyl alcohol is 2~9:1; the target temperature for temperature control is 0~80℃; the dropwise addition time is 0.5~2.5h; the acid-binding agent includes one or more of pyridine, triethylamine, DIPEA, DMAP, potassium carbonate, sodium carbonate, and ammonium carbonate; the molar ratio of octadecyl alcohol, fumarate chloride, and acid-binding agent is 2.0:0.8~1.5:1.6~3.0; Step 2: The condensation reaction product is subjected to a first filtration, a first crystallization, and a second filtration to obtain a crude product; the temperature of the first crystallization is 0~30℃ and the time is 0.5~2h; Step 3: The crude product obtained in Step 2 is dissolved in a second solvent for purification, thereby obtaining the final product. The purification steps include: placing the crude product in the second solvent, heating to dissolve, cooling, and then sequentially undergoing a second crystallization, filtration, washing, and drying. The dissolution temperature is 40~70℃. The second solvent includes one or more of acetone, toluene, dichloromethane, and ethyl acetate. The mass ratio of the second solvent to the crude product is 2~10:

1. The second crystallization temperature is 10~30℃, and the time is 0.5~3h.

2. The preparation method according to claim 1, characterized in that, Step 1 also satisfies one or more of the following conditions: g. The condensation reaction is carried out at a temperature of 10~50℃ for 2.5~4h; h. The mass ratio of the first solvent to the octadecyl alcohol is 3.5 to 7:

1.

3. The preparation method according to claim 1, characterized in that, The temperature for the first crystallization is 5~20℃, and the time is 1~1.5h.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The preparation method also satisfies one or more of the following conditions: m. The target temperature for temperature control is 10~50℃; n. The dripping time is 1~2 hours; o. The first solvent is dichloromethane and / or toluene; p. The dissolution temperature is 50~60℃; q. The second solvent is ethyl acetate and / or toluene; r. The mass ratio of the second solvent to the crude product is 3 to 8:1; s. The second crystallization temperature is 15~25℃, and the time is 1~2h; The drying process is vacuum drying, with a temperature of 40~55℃ and a time of 6~10h.

5. The preparation method according to claim 1, characterized in that, The molar ratio of octadecyl alcohol, fumarate chloride and tannin-binding agent is 2.0:1.0~1.3:2.0~2.

5.

6. The preparation method according to claim 1, characterized in that, The acid-binding agent is triethylamine and / or sodium carbonate.

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