Preparation method of 8-(2-hydroxybenzamido) sodium caprylate

Abstract

The invention relates to the technical field of medicines, and provides a preparation method of sodium 8-(2-hydroxybenzamido) octanoate, aiming at the problems of complicated synthesis steps and low product purity of the sodium 8-(2-hydroxybenzamido) octanoate. The reaction route is as follows: the compound II is 8-amino caprylic acid salt, and X in the formula is HCl, 1 / 2 H2SO4 or 1 / 3 H3PO4; the compound III is salicylate, and in the formula, R is methyl or ethyl; the compound I is 8-(2-hydroxybenzamido) sodium caprylate. The method is a one-step synthesis method, the route is short, the used raw materials are cheap and easy to obtain, the cost is low, and the method has important industrial application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing sodium 8-(2-hydroxybenzamido)octanoate. Background Technology

[0002] Sodium 8-(2-hydroxybenzamido)octanoate (CAS: 203787-91-1) is a small-molecule fatty acid derivative that promotes drug absorption in gastrointestinal epithelial cells, effectively addressing absorption barriers in orally administered peptide drugs. Sodium 8-(2-hydroxybenzamido)octanoate was initially selected by Emisphere from numerous penetration enhancers as a highly efficient molecule; its molecular formula is C1. 15 H 20 NNaO4, with a molecular weight of 301 Da and pKa = 5.0, has the following structural formula:

[0003] Based on safety data from multiple preclinical and clinical studies, sodium 8-(2-hydroxybenzamido)octanoate has been designated as a generally recognized as safe (GRAS) additive according to the U.S. Food and Drug Administration's regulations on food and food additives. Currently, the successful preparation of semaglutide tablets relies on its co-formulation with sodium 8-(2-hydroxybenzamido)octanoate. As oral peptides are gradually becoming the future trend in peptide drug development, sodium 8-(2-hydroxybenzamido)octanoate, as a penetration enhancer with both excellent efficacy and safety, has enormous application potential.

[0004] To date, the main synthetic methods for sodium 8-(2-hydroxybenzamido)octanoate reported in the literature are as follows: (1) Patent US5650386 describes the preparation of sodium 8-(2-hydroxybenzamido)octanoate by reacting 8-aminooctanoic acid and O-acetyl salicyl chloride; The limitations of this method are: the raw material O-acetyl salicyl chloride is highly reactive and difficult to preserve; there are many reaction byproducts; and the finished product has a high impurity content.

[0005] (2) Patent US20220332688 uses salicylamide as the starting material, reacts with ethyl chloroformate to generate carbapenem, and then reacts with 8-bromooctanoate. The product is hydrolyzed by acid and alkali to generate sodium 8-(2-hydroxybenzamide)octanoate. This method involves a long route, and the reactant ethyl chloroformate is a highly toxic substance, posing significant harm to the environment and human health.

[0006] Therefore, it is necessary to develop a simple synthetic route for sodium 8-(2-hydroxybenzamido)octanoate that is suitable for large-scale industrial production. Summary of the Invention

[0007] To overcome the problems of cumbersome synthesis steps and low product purity in the synthesis of sodium 8-(2-hydroxybenzamido)octanoate, this invention provides a method for preparing sodium 8-(2-hydroxybenzamido)octanoate. 8-aminooctanoate and salicylate react under the action of an alkoxide. After purification of the reaction solution, high-purity sodium 8-(2-hydroxybenzamido)octanoate can be obtained. This method is a one-step synthesis, with a short route, inexpensive and readily available raw materials, and low cost, making it of significant industrial application value.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, the reaction route is as follows: Compound II is 8-aminooctanoate, where X is HCl, 1 / 2H2SO4 or 1 / 3H3PO4; Compound III is salicylate, where R is methyl or ethyl; Compound I is sodium 8-(2-hydroxybenzamido)octanoate. The synthesis steps are as follows: Step a. Compound II 8-aminooctanoate and compound III salicylate react in the presence of an alkoxide to give a solution containing I-Crude; Step b. In a solution containing I-Crude, acid is added sequentially, followed by crystallization, then alkali is added, and crystallization is repeated to obtain compound I 8-(2-hydroxybenzamido)octanoate sodium.

[0009] Preferably, step a is carried out in an inert atmosphere.

[0010] Preferably, the molar ratio of 8-aminooctanoate to salicylate is 1:(1.1-1.5).

[0011] Preferably, the alkoxide is sodium methoxide or sodium ethoxide, and the reaction solvent is an alcohol solvent. More preferably, the alcohol solvent is methanol or ethanol.

[0012] Preferably, the molar ratio of 8-aminooctanoate to alkoxide is 1:(3-5).

[0013] As a preferred method, the 8-aminooctanoate and salicylate are mixed as follows: first, 8-aminooctanoate is added to a solvent and heated to dissolve, and then salicylate is added.

[0014] Preferably, the reaction temperature in step a is 40-80℃.

[0015] Preferably, the reaction time for step a is 16-24 hours.

[0016] Preferably, step b is as follows: add acid to a solution containing I-Crude, cool down to crystallize for the first time, and take the solid; disperse the solid in an alcohol solvent, add an alkaline solution, heat to 20-55℃ and react for 1-3 hours, cool down to crystallize for the second time, and obtain sodium 8-(2-hydroxybenzamido)octanoate.

[0017] Preferably, the acid is HCl, H2SO4 or H3PO4, and the base is an aqueous solution of NaOH, Na2CO3 or NaHCO3.

[0018] Preferably, the pH is adjusted to 3-4 with acid; the molar ratio of 8-aminooctanoate to base is 1:(0.60-0.96).

[0019] Preferably, the alcohol solvent is ethanol or isopropanol.

[0020] Therefore, the beneficial effects of the present invention are as follows: (1) The method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate from 8-aminooctanoate requires only one step of reaction, and sodium 8-(2-hydroxybenzamido)octanoate can be obtained after purification.

[0021] (2) The method for synthesizing sodium 8-(2-hydroxybenzamide)octanoate from 8-aminooctanoate has a high reaction yield of over 81%, and the process is simple and more suitable for industrial scale-up production.

[0022] (3) The method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate from 8-aminooctanoate uses only alcohol and water as reaction solvents, and the reaction solvents are green and environmentally friendly.

[0023] (4) This invention uses 8-aminooctanoate and salicylate directly as raw materials. In the prior art, 8-aminooctanoic acid and salicylate are reacted. However, the preparation of 8-aminooctanoic acid involves pH adjustment and purification and desalting processes, which can lead to product loss, low yield, and increased raw material costs. Therefore, using 8-aminooctanoate as a raw material can reduce costs. Attached Figure Description

[0024] Figure 1 It is the sodium 8-(2-hydroxybenzamido)octanoate prepared in Example 1. 1 H NMR spectrum.

[0025] Figure 2 This is the ESI-MS spectrum of sodium 8-(2-hydroxybenzamido)octanoate prepared in Example 1. Detailed Implementation

[0026] The technical solution of the present invention will be further described below through specific embodiments.

[0027] In this invention, unless otherwise specified, the raw materials and equipment used are commercially available or commonly used in the art. The methods in the embodiments, unless otherwise specified, are conventional methods in the art. Unless otherwise specified, all parts are parts by weight, temperatures are expressed in °C or at ambient temperature, and pressures are at or near atmospheric pressure. Various variations and combinations of reaction conditions (e.g., component concentrations, required solvents, solvent mixtures, temperature, pressure, and other reaction ranges) and conditions that can be used to optimize the purity and yield of the product obtained by the method exist, and only reasonable routine experiments are needed to optimize such method conditions.

[0028] Example A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, the reaction route is as follows: Compound II is 8-aminooctanoate, where X is HCl, 1 / 2H2SO4 or 1 / 3H3PO4; Compound III is salicylate, where R is methyl or ethyl; and Compound I is sodium 8-(2-hydroxybenzamido)octanoate.

[0029] The steps for synthesizing sodium 8-(2-hydroxybenzamido)octanoate from 8-aminooctanoate are as follows: Step 1: The reaction of compound II 8-aminooctanoate and compound III salicylate in the presence of an alkoxide to obtain a solution containing I-Crude is specifically carried out as follows: Under a nitrogen atmosphere, an alcohol solvent and an alkoxide are mixed and added to a reaction flask, followed by the addition of compound II 8-aminooctanoate. The mixture is heated until compound II 8-aminooctanoate is completely dissolved, and then compound III salicylate is added. The temperature is raised to 40-80℃ and maintained for 16-24 hours. HPLC detection indicates the end of the reaction, yielding a solution containing I-Crude. The alkoxide is either sodium methoxide or sodium ethoxide, and the alcohol solvent is either methanol or ethanol. The molar ratio of compound II 8-aminooctanoate, the alkoxide, and compound III salicylate is 1:(3-5):(1.1-1.5).

[0030] As a preferred method, the preparation of 8-aminooctanoate is as follows: 9-amino-9-oxononanoic acid and a chlorinating reagent are mixed and reacted at 25-50℃ for 1-3 hours. Crystals are then precipitated by cooling, and the filtrate is collected. The filtrate is added to a sodium alkoxide solution, heated, and reacted for 1-3 hours. The pH of the reaction solution is adjusted to 5-7, and crystals are precipitated by cooling. The filtrate is then collected and concentrated. The filtrate is then refluxed with acid for 12-20 hours, concentrated under reduced pressure, and the concentrate is pulped with acetonitrile, filtered, and the filter cake is dried under reduced pressure to obtain 8-aminooctanoate. The reaction formula is as follows: The above preparation method is characterized by simple process and mild conditions, and the obtained 8-aminooctanoate can be directly used for the synthesis of sodium 8-(2-hydroxybenzamido)octanoate.

[0031] Step 2: In a solution containing I-Crude, acid is added sequentially, followed by crystallization, then alkali is added, and crystallization occurs again to obtain compound 8-(2-hydroxybenzamido)octanoate sodium. Specifically, after cooling the solution containing I-Crude obtained in Step 1 to 20-30℃, acid is added dropwise to adjust the pH to 3-4, resulting in a mixture. Under a nitrogen atmosphere, the mixture is further cooled to 0-10℃ to induce crystallization. The mixture is then filtered, and the filter cake is washed with water. The filter cake is transferred to a reaction flask, and an alcohol solvent is added. The mixture is stirred and heated to 20-55℃. After the solution becomes clear, an alkali solution is added, and the reaction is continued at 20-55℃ for 1-3 hours. Then, the temperature is slowly lowered to 0-10℃ to induce crystallization. The mixture is filtered, and the filter cake is washed with isopropanol and dried to obtain the product 8-(2-hydroxybenzamido)octanoate sodium.

[0032] The acid is hydrochloric acid (HCl), sulfuric acid (H₂SO₄), or phosphoric acid (H₃PO₄); the alcohol solvent is ethanol or isopropanol; and the alkaline solution is an aqueous solution of sodium hydroxide (NaOH), sodium carbonate (Na₂CO₃), or sodium bicarbonate (NaHCO₃). The molar ratio of 8-aminooctanoate to the base is 1:(0.60-0.96).

[0033] Example 1 A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0034] The preparation method of 8-aminooctanoic acid salt is as follows: 100g of 9-amino-9-oxononanoic acid is dissolved in methanol, 45.0g of TCCA is added, the reaction is carried out at 40℃ for 3h, the temperature is lowered to crystallize, the mixture is filtered, and the filtrate is collected; the filtrate is added dropwise to 150mL of 4M sodium methoxide-methanol solution, the reaction is carried out at 50℃ for 3h, the pH is adjusted to 6, the temperature is lowered to 10℃ to crystallize, the mixture is filtered, and the filtrate is collected and concentrated to obtain a concentrate; 6M HCl aqueous solution is added to the concentrate, the reaction is refluxed for 12h, the concentration is carried out under reduced pressure, acetonitrile is used for distillation, the resulting concentrate is slurried with acetonitrile, filtered, and the filter cake is dried under reduced pressure to obtain 8-aminooctanoic acid salt with a purity of over 99%. (All 8-aminooctanoic acid salts mentioned below are prepared by this method. When preparing 8-aminooctanoic acid sulfate and 8-aminooctanoic acid phosphate, simply replace the hydrochloric acid in this method with sulfuric acid and phosphoric acid, respectively. This will not be elaborated further below.) The filter cake was transferred to a reaction flask, 200 mL of isopropanol was added, and the mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, and then the temperature was slowly lowered to 5 °C and kept at that temperature to allow crystallization. The mixture was filtered, the filter cake was washed with isopropanol, and dried to obtain 26.9 g of the product sodium 8-(2-hydroxybenzamido)octanoate.

[0035] The product 8-(2-hydroxybenzamido)octanoic acid sodium salt 1 H NMR spectrum as follows Figure 1 As shown, the ESI-MS spectrum is as follows: Figure 2 As shown, the purity of sodium 8-(2-hydroxybenzamido)octanoate is 99.6%, and the molar yield is 89%.

[0036] Example 2 A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 82 mL of ethanol and 27.2 g (0.4 mol) of sodium ethoxide were mixed and added to a reaction flask, followed by 20.8 g (0.1 mol) of 8-aminooctanoic acid sulfate. The mixture was heated to 50 °C to completely dissolve the 8-aminooctanoic acid sulfate, and then 21.6 g (0.13 mol) of ethyl salicylate was added. The mixture was heated to reflux with ethanol and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 20 °C, and 5% (w / w) dilute sulfuric acid was added dropwise to adjust the pH to 4, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 0 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0037] The filter cake was transferred to a reaction flask, and 200 mL of ethanol was added. The mixture was stirred and heated to 30 °C. After the solution became clear, a saturated aqueous solution of NaHCO3 (containing 8.0 g of NaHCO3) was added. The reaction was continued at 30 °C for 1 h, and then slowly cooled to 0 °C to allow crystallization. The crystals were filtered, and the filter cake was washed with ethanol and dried to obtain 25.3 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 99.8%, and the molar yield was 84%.

[0038] Example 3 A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 75 mL of methanol and 18.9 g (0.35 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 20.8 g (0.108 mol) of 8-aminooctanoic acid phosphate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoic acid phosphate, and then 19.0 g (0.125 mol) of methyl salicylate was added. The mixture was heated to reflux with methanol and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 30 °C, and 5% (w / w) dilute phosphoric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 0 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0039] The filter cake was transferred to a reaction flask, and 200 mL of ethanol was added. The mixture was stirred and heated to 20 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 20 °C for 2 h, then slowly cooled to 0 °C and kept at this temperature to allow crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 24.4 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 99.5%, and the molar yield was 81%.

[0040] Example 4 A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 82 mL of ethanol and 27.2 g (0.4 mol) of sodium ethoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 50 °C to completely dissolve the 8-aminooctanoate, and then 21.6 g (0.13 mol) of ethyl salicylate was added. The mixture was heated to 70 °C and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 20 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 10 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0041] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 55 °C. After the solution became clear, a saturated aqueous solution of NaHCO3 (containing 8.0 g of NaHCO3) was added. The reaction was continued at 55 °C for 1 h, and then the temperature was slowly lowered to 10 °C for crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 26.3 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 99.6%, and the molar yield was 87%.

[0042] Example 5 A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 50 mL of methanol and 16.2 g (0.3 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 50 °C and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 20 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 4, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0043] The filter cake was transferred to a reaction flask, and 200 mL of ethanol was added. The mixture was stirred and heated to 30 °C. After the solution became clear, a saturated aqueous solution of NaHCO3 (containing 8.0 g of NaHCO3) was added. The reaction was continued at 30 °C for 1 h, and then the temperature was slowly lowered to 5 °C for crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 25.0 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 99.2%, and the molar yield was 83%.

[0044] Example 6 The difference from Example 1 is that the molar ratio of 8-aminooctanoate to salicylate is 1:1. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate, and then 15.2 g (0.1 mol) of methyl salicylate was added. The mixture was heated to 60 °C and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0045] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 98.1%, and the molar yield was 71%.

[0046] Example 7 The difference from Example 1 is that the molar ratio of 8-aminooctanoate to salicylate is 1:1.8. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 27.4 g (0.18 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0047] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 94.2%, and the molar yield was 76%.

[0048] Example 8 The difference from Example 1 is that the molar ratio of 8-aminooctanoate to alkoxide is 1:2. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 10.8 g (0.2 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0049] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 95.5%, and the molar yield was 65%.

[0050] Example 9 The difference from Example 1 is that the molar ratio of 8-aminooctanoate to alkoxide is 1:7. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 37.8 g (0.7 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and maintained at this temperature for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0051] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 89.6%, and the molar yield was 68%.

[0052] Example 10 The difference from Example 1 is that the molar ratio of 8-aminooctanoate to base is 1:1.2. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0053] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (0.12 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 hour, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 93.6%, and the molar yield was 88%.

[0054] Example 11 The difference from Example 1 is that acid is added to the solution containing I-Crude, followed by a first cooling and crystallization to collect the solid; the solid is then dispersed in methanol solvent, and an alkaline solution is added. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0055] The filter cake was transferred to a reaction flask, and 200 mL of methanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 99.4%, and the molar yield was 73%.

[0056] Comparative Example Comparative Example 1 The difference from Example 1 is that the molar ratio of 8-aminooctanoate to base is 1:0.5. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0057] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (0.05 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 hour, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 94.2%, and the molar yield was 47%.

[0058] Comparative Example 2 The difference from Example 1 is that the solvent for the reaction of 8-aminooctanoate and methyl salicylate is acetonitrile. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of acetonitrile and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0059] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 76.5%, and the molar yield was 35%.

[0060] Comparative Example 3 The difference from Example 1 is that compound III is propyl salicylate. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 22.5 g (0.125 mol) of propyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0061] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium hydroxide (3.8 g, 0.095 mol NaOH + 9 mL water) was added. The reaction was continued at 50 °C for 1 h, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The mixture was filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 65.3%, and the molar yield was 56%.

[0062] Comparative Example 4 The difference from Example 1 is that the base used is sodium tert-butoxide. Specifically: A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, comprising the following steps: Under a nitrogen atmosphere, 65 mL of methanol and 21.6 g (0.4 mol) of sodium methoxide were mixed and added to a reaction flask, followed by 19.5 g (0.1 mol) of 8-aminooctanoate. The mixture was heated to 40 °C to completely dissolve the 8-aminooctanoate. Then, 19.0 g (0.125 mol) of methyl salicylate was added, and the mixture was heated to 60 °C and reacted for 20 h. After the reaction was completed by HPLC, the temperature was lowered to 25 °C, and 1 M dilute hydrochloric acid was added dropwise to adjust the pH to 3, yielding a mixture. Under a nitrogen atmosphere, the mixture was cooled to 5 °C, stirred overnight, filtered, and the filter cake was washed with water.

[0063] The filter cake was transferred to a reaction flask, and 200 mL of isopropanol was added. The mixture was stirred and heated to 50 °C. After the solution became clear, an aqueous solution of sodium tert-butoxide (0.09 mol sodium tert-butoxide + 9 mL water) was added. The reaction was continued at 50 °C for 1 hour, then slowly cooled to 5 °C and kept at that temperature to allow crystallization. The crystals were filtered, and the filter cake was washed with isopropanol and dried to obtain 26.9 g of sodium 8-(2-hydroxybenzamido)octanoate. The purity of sodium 8-(2-hydroxybenzamido)octanoate was 56.8%, and the molar yield was 28%.

[0064] Performance testing The product yields and purities obtained from each embodiment and comparative example are shown in the table below. Yield % purity% Example 1 89 99.6 Example 2 84 99.8 Example 3 81 99.5 Example 4 87 99.6 Example 5 83 99.2 Example 6 71 98.1 Example 7 76 94.2 Example 8 65 95.5 Example 9 68 89.6 Example 10 88 93.6 Example 11 73 99.4 Comparative Example 1 47 89.6 Comparative Example 2 35 76.5 Comparative Example 3 56 65.3 Comparative Example 4 28 56.8

[0065] As can be seen from the table above, the sodium 8-(2-hydroxybenzamido)octanoate prepared in the various embodiments of the present invention has high purity and high yield.

[0066] Compared to Example 1: In Example 6, only 1.0 eq. of methyl salicylate was used, but salicylic acid byproducts were generated during the reaction, leading to incomplete conversion of 8-aminooctanoic acid and a slight decrease in purity and yield. In Example 7, a larger amount of methyl salicylate was used, resulting in more residual methyl salicylate and salicylic acid byproducts in the reaction, which could not be completely removed in subsequent operations, leading to a decrease in purity and yield. In Example 8, a smaller amount of NaOMe was used, resulting in incomplete reaction and a decrease in purity and yield. In Example 9, a larger amount of NaOMe was used, resulting in more salicylic acid byproducts, which could not be completely removed in subsequent operations, leading to a decrease in purity and yield. In Example 10, a larger amount of NaOH was used, resulting in inorganic salt residues during post-processing, leading to a decrease in purity. It is evident that these reaction parameters, within their optimal range, can achieve higher purity and yield.

[0067] Compared to Example 1: In Comparative Example 1, the amount of NaOH used was less, resulting in incomplete salt formation of sodium 8-(2-hydroxybenzamido)octanoate and a significant decrease in yield. Comparative Example 2 used MeCN as the solvent, where NaOMe was difficult to fully protonate, leading to incomplete reaction and a significant decrease in yield and purity. Comparative Example 3 used propyl salicylate as the raw material, which had low reactivity, resulting in a significant decrease in yield and purity. In Example 11, methanol had relatively good solubility for the product, leading to a low product yield. In Comparative Example 4, sodium tert-butoxide was highly basic, causing amide hydrolysis during salt formation, mainly producing 8-aminooctanoic acid and salicylic acid, resulting in a significant decrease in yield and purity. It is evident that the choice of reagents has a significant impact on the reaction effect of this invention; only the reagents preferred in this invention can yield high-purity and high-yield sodium 8-(2-hydroxybenzamido)octanoate.

[0068] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing sodium 8-(2-hydroxybenzamido)octanoate, characterized in that, The reaction route is as follows: Compound II is 8-aminooctanoate, where X is HCl, 1 / 2H2SO4 or 1 / 3H3PO4; Compound III is salicylate, where R is methyl or ethyl; Compound I is sodium 8-(2-hydroxybenzamido)octanoate. The synthesis steps are as follows: Step a. Compound II 8-aminooctanoate and compound III salicylate react in the presence of an alkoxide to give a solution containing I-Crude; Step b. In a solution containing I-Crude, acid is added sequentially, followed by crystallization, then alkali is added, and crystallization is repeated to obtain compound I 8-(2-hydroxybenzamido)octanoate sodium.

2. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that, The molar ratio of 8-aminooctanoate to salicylate is 1:(1.1-1.5).

3. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that, The alkoxide is either sodium methoxide or sodium ethoxide, and the reaction solvent is an alcohol solvent.

4. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, 2, or 3, characterized in that, The molar ratio of 8-aminooctanoate to alkoxide is 1:(3-5).

5. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that, The reaction temperature in step a is 40-80℃.

6. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1 or 5, characterized in that, The reaction time for step a is 16-24 hours.

7. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1, characterized in that, The specific steps of step b are as follows: add acid to the solution containing I-Crude, cool down to crystallize for the first time, and take the solid; disperse the solid in an alcohol solvent, add an alkaline solution, heat to 20-55℃ and react for 1-3 hours, cool down to crystallize for the second time, and obtain sodium 8-(2-hydroxybenzamido)octanoate.

8. The method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 7, characterized in that, The alcohol solvent is ethanol or isopropanol.

9. A method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1 or 7, characterized in that, The acid is HCl, H2SO4 or H3PO4, and the base is an aqueous solution of NaOH, Na2CO3 or NaHCO3.

10. A method for preparing sodium 8-(2-hydroxybenzamido)octanoate according to claim 1 or 7, characterized in that, Adjust the pH to 3-4 by adding acid; the molar ratio of 8-aminooctanoate to base is 1:(0.60-0.96).

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