Process for the preparation of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate and intermediates thereof

Abstract

The application discloses a preparation method of sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate and an intermediate thereof. The intermediate is a compound of formula (I), and the intermediate is obtained by hydrolyzing a compound of formula (II) in a polar solvent in the presence of an acid catalyst and 2,6-di-tert-butyl-p-cresol, wherein R in the compound of formula (II) is a linear or branched alkyl group; and the sodium N-(8-[2-hydroxybenzoyl]-amino) octanoates are prepared by salifying the intermediate. The application can avoid or reduce the generation of colored impurities in the preparation process of the compound of formula (I) by using a small amount of 2,6-di-tert-butyl-4-methylphenol, and white or white-like compound of formula (I) with a purity of more than 99.9% by HPLC is prepared, and the technical prejudice that 2,6-di-tert-butyl-4-methylphenol cannot be used to avoid or reduce the generation of colored impurities in the hydrolysis process of the compound of formula (II) is overcome.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate and its intermediates. Background Technology

[0002] SNAC (Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate), also known as sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, has the following structural formula:

[0003] A synthetic N-acetylated amino acid derivative of amphoteric salicylic acid is currently the most advanced intestinal permeability enhancer (PEs). It can adhere to the gastric mucosa along with peptides, thereby promoting drug permeation and absorption, and is widely used as a delivery agent for oral drug formulations.

[0004] SNAC was originally developed by Emisphere as a highly efficient carrier molecule through screening among numerous penetration enhancers. Several in vivo studies have shown that the exposure of orally administered target molecules is significantly improved when used in combination with SNAC. For example, Eligen (Eligen Vitamin B12 / SNAC, Emisphere, Roseland, NJ, USA), which has been approved for marketing, has demonstrated in human trials that co-administration with SNAC significantly improves oral exposure of vitamin B12. Furthermore, SNAC has successfully facilitated the development and marketing of the first truly oral peptide drug, semaglutide tablets. Co-administration with SNAC can increase the local gastric pH, thereby reducing pepsin degradation, preventing semaglutide degradation, and promoting its absorption, overcoming the limitation of peptide non-absorption.

[0005] Emisphere, the original research company, discovered during the preparation of SNAC compounds that, in most cases, pink or pink-colored impurities are generated during the preparation of the intermediate SNAC free acid (compound of formula (I)) from the hydrolysis intermediate 2,4-dioxo-1,3-benzoxazinyl octanoate. These impurities persist during the subsequent salt formation preparation of SNAC and even after multiple purifications, thus affecting the purity of the final product SNAC. The original research company has conducted extensive research on how to avoid or reduce the generation of colored impurities. For example, US Patent 7544833B2 discloses that trace metals and / or oxygen may be the cause of pink impurities. Boiling the process water before using it for hydrolysis can successfully avoid pink color. Using ethylenediaminetetraacetic acid (EDTA, 0.01 equivalent) can also successfully avoid pink color. Antioxidants such as ascorbic acid (1%), NaHSO3 (1%), and triphenylphosphine (0.1%) can also effectively prevent the formation of pink color. However, the use of 2,6-di-tert-butyl-4-methylphenol (BHT) (1%) is ineffective in reducing the generation of colored impurities. In addition, patent WO2022264166A discloses that hydrolyzing ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate in the presence of sodium hydroxide, water, and a reducing agent can yield a white SNAC free acid solid, wherein the reducing agent is sodium borohydride, sodium sulfite, or zinc powder; US patent US11667614B2 discloses that hydrolyzing ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate in the presence of benzotriazole, hydrazine, sodium borohydride, or a mixture thereof can remove colored impurities and yield pure SNAC free acid.

[0006] The inventors unexpectedly discovered that in the process of preparing intermediate SNAC free acid by hydrolyzing ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate in an acid catalyst and polar solvent system, using 2,6-di-tert-butyl-4-methylphenol as a reducing agent can remove colored impurities and obtain a white SNAC free acid product. Summary of the Invention

[0007] The purpose of this invention is to provide a novel method for avoiding or reducing the generation of colored impurities during the preparation of SNAC free acid from the hydrolysis of ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate, thereby obtaining high-purity N-(8-[2-hydroxybenzoyl]-amino)octanoate sodium. This method overcomes the technical bias that "2,6-di-tert-butyl-4-methylphenol is ineffective in avoiding or reducing the generation of colored impurities during the preparation of SNAC free acid from the hydrolysis of ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate."

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A method for preparing a sodium N-(8-[2-hydroxybenzoyl]amino)octanoate intermediate of formula (I) is obtained by hydrolyzing the compound of formula (II) in a polar solvent in the presence of an acid catalyst and 2,6-di-tert-butyl-p-cresol;

[0010] In compound (II), R is a straight-chain or branched alkyl group.

[0011] The polar solvent is selected from one or more of water, methanol, ethanol, acetonitrile, diethyl ether, acetone, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide, N-methylpyrrolidone, dimethyl sulfoxide, and methyl tert-butyl ether.

[0012] The acid catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid, hydrobromic acid, nitric acid, formic acid, acetic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, citric acid, acidic resin, and acidic molecular sieve.

[0013] Preferably, the acidic resin is selected from one or more of D005 resin, D211 resin, DT-012 resin, A35 resin, A15 resin, A36 resin, NKC-9 resin, and Amberlyst-15H resin.

[0014] The amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.01 to 0.3% of the amount of compound (II), preferably 0.02 to 0.1%, and more preferably 0.02 to 0.05%.

[0015] The pH value of the mixture of acid catalyst and polar solvent is 1 to 5, preferably 3 to 5.

[0016] When R in the compound of formula (II) is ethyl, the amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.01 to 0.1% of the amount of the compound of formula (II), preferably 0.02 to 0.07%, and more preferably 0.03 to 0.05%.

[0017] In the above preparation method, the polar solvent is selected from one or more of water, methanol, ethanol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0018] In the above preparation method, the acid catalyst is hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid.

[0019] This invention also provides a method for preparing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, comprising:

[0020] (a) The compound of formula (I) was prepared using the method described above;

[0021] (b) The obtained compound of formula (I) reacts with a sodium-containing base in a reaction solvent to generate sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate;

[0022]

[0023] The sodium-containing alkali is one or a combination of sodium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate, preferably sodium hydroxide or sodium bicarbonate; the organic solvent is one or a combination of methanol, ethanol, isopropanol, butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, acetonitrile, and acetone, preferably isopropanol.

[0024] Furthermore, the preparation method further includes the following steps: transferring the mixture of compound (I) and sodium-containing alkali after reaction to a crystallization vessel, adjusting the temperature inside the crystallization vessel to 30-40°C, adding N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium hydrate seed crystals for programmed temperature-controlled dynamic crystallization, centrifuging, drying, and obtaining the finished product; the programmed temperature-controlled dynamic crystallization process is specifically as follows: after adding the seed crystals, adjusting the temperature inside the crystallization vessel to 25-35°C and maintaining the temperature with stirring for 1.5-3.5 h, then slowly raising the temperature to 38-45°C and maintaining the temperature with stirring for 20-60 min, then slowly lowering the temperature to 25-35°C, then slowly raising the temperature to 38-45°C and maintaining the temperature with stirring for 20-60 min, then slowly lowering the temperature to 25-35°C, repeating this cycle 2-4 times, and then slowly lowering the temperature inside the crystallization vessel from 25-35°C to 5-15°C and maintaining the temperature with stirring for 4-8 h.

[0025] The temperature-controlled dynamic crystallization process can be heated / cooled at a uniform rate or at a non-uniform rate, with a uniform rate being preferred.

[0026] More preferably, the heating rate is 0.04–0.2 °C / min; and / or, the cooling rate is 0.08–0.6 °C / min.

[0027] The present invention has the following beneficial effects:

[0028] (1) This invention uses an acidic environment and a polar solvent system to hydrolyze compound (II) to prepare intermediate compound (I), which overcomes the technical prejudice that 2,6-di-tert-butyl-4-methylphenol cannot be used to avoid or reduce the generation of colored impurities during the hydrolysis of compound (II).

[0029] (2) The technical solution of the present invention can avoid or reduce the generation of colored impurities in the preparation process of compound (I) by using a very small amount of 2,6-di-tert-butyl-4-methylphenol, and obtain white or off-white compound (I) with HPLC purity greater than 99.9%.

[0030] (3) The present invention uses a novel programmed temperature-controlled dynamic crystallization technology to prepare large-particle-size N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium with a normal distribution curve, which not only broadens the downstream application boundaries of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium, but also endows it with safety and effectiveness when used as a pharmaceutical excipient. Attached Figure Description

[0031] Figure 1 The HPLC chromatogram of compound (I) prepared in Example 2 is shown.

[0032] Figure 2 The HPLC chromatogram of compound (I) prepared in Example 6 is shown.

[0033] Figure 3 The image shows the HPLC chromatogram of the SNAC compound prepared in Example 2.

[0034] Figure 4 The image shows the HPLC chromatogram of the SNAC compound prepared in Example 6.

[0035] Figure 5 The particle size distribution diagram is shown for the SNAC compound prepared in Example 2.

[0036] Figure 6 The particle size distribution diagram is shown for the SNAC compound prepared in Example 6. Detailed Implementation

[0037] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0038] Example 1

[0039] Preparation of intermediate compound (I): Under nitrogen protection, 100 ml of a prepared mixture of N,N-dimethylformamide and hydrochloric acid aqueous solution (pH=2), 6 mg of BHT, and 30 g of ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate (89.99 mmol) were added to a reaction vessel. The mixture was heated to 50–60 °C and stirred for 6–10 h. The solution was concentrated under reduced pressure until no flow was observed to obtain crude compound (I). Acetonitrile was added and recrystallized 1–2 times. The solution was dried under reduced pressure at 65–75 °C for 10–15 h to obtain 23.2 g of off-white SNAC free acid solid, with a molar yield of 92.3% and an HPLC purity of 99.91%.

[0040] Preparation of SNAC: Add 10g of the compound of formula (I) prepared by the above method and 50ml of isopropanol to a reaction vessel. Heat to 40-50℃ and slowly add NaOH aqueous solution (1.45g NaOH dissolved in 6ml water) dropwise while stirring. After the addition is complete, adjust the temperature inside the reaction vessel to 70-80℃ and maintain this temperature with stirring for 1-2 hours. Transfer the reaction solution to a crystallization vessel and slowly lower the temperature inside the crystallization vessel to 30-40℃. Then, mix 10mg of SNAC hydrate seed crystals with a small amount of purified water and add it to the crystallization vessel. Adjust the temperature inside the crystallization vessel to 25-35℃ and maintain this temperature with stirring for 1.5-3.5 hours. Then, slowly raise the temperature to 38-45℃ over 35-60 minutes and maintain this temperature with stirring for 20-60 minutes. Then, slowly lower the temperature to 25-35℃ over 95-120 minutes, and then raise the temperature again over 35-60 minutes. The internal temperature was slowly raised to 38–45°C within 0 min and kept at this temperature with stirring for 20–40 min. Then, the internal temperature was slowly lowered to 25–35°C within 95–120 min. This cycle was repeated 3 times. Then, the internal temperature was slowly lowered to 5–15°C within 65–90 min and kept at this temperature with stirring for 4–8 h. The crystals were collected by centrifugation and dried at 95–105°C for 14–20 h. The crystals were then pulverized and sieved, and dried again at 95–105°C for 5–6 h to obtain 9.7 g of SNAC powder solid, with a molar yield of 89.33% and an HPLC purity of 99.97%.

[0041] Example 2

[0042] Preparation of intermediate compound (I): Under nitrogen protection, 100 ml of a prepared mixture of N-methylpyrrolidone and hydrochloric acid aqueous solution (pH = 3.5), 12 mg of BHT, and 24 g of ethyl 2,4-dioxo-1,3-benzoxazinyl octanoate (71.99 mmol) were added to a reaction vessel. The mixture was heated to 60–70 °C and stirred for 6–8 h. The solution was concentrated under reduced pressure until no flow was observed to obtain crude compound (I). Acetonitrile was added and recrystallized 1–2 times. The solution was dried under reduced pressure at 65–75 °C for 10–15 h to obtain 19.4 g of white SNAC free acid solid of compound (I), with a molar yield of 96.7% and an HPLC purity of 99.95%.

[0043] Preparation of SNAC: 100 ml of isopropanol and 3.6 g of NaHCO3 were added to a reaction vessel and heated to dissolve. Then, 10 g of compound (I) prepared by the above method was added, and the mixture was stirred at 70–75 °C for 1–2 h. The reaction solution was then transferred to a crystallization vessel, and the temperature was slowly lowered to 30–40 °C. 8 mg of SNAC hydrate seed crystals were mixed with a small amount of purified water and added to the crystallization vessel. The temperature was adjusted to 25–35 °C and stirred for 1.5–3 h. The temperature was then raised to 38–45 °C at a heating rate of 0.1 °C / min and stirred for 20–40 min. The temperature was then lowered to 25–35 °C at a cooling rate of 0.08 °C / min, and then raised to 38–45 °C again at a heating rate of 0.1 °C / min. The mixture was heated to ℃ and stirred for 20–40 min, then the internal temperature was lowered to 25–35℃ at a cooling rate of 0.08℃ / min. This cycle was repeated twice. Then, the internal temperature of the crystallizer was lowered to 5–15℃ at a cooling rate of 0.2℃ / min and stirred for 4–8 h. The crystals were collected by centrifugation and dried at 95–105℃ for 14–20 h. The crystals were then pulverized and sieved, and dried at 95–105℃ for 5–6 h to obtain 10.6 g of SNAC powder solid, with a molar yield of 97.61% and an HPLC purity of 100.00%.

[0044] Example 3

[0045] Preparation of intermediate compound (I): Under nitrogen protection, 100 ml of a prepared mixture of acetonitrile and p-toluenesulfonic acid aqueous solution (pH = 5), 11 mg of BHT, and 35 g of 0.1 mol of 2,4-dioxo-1,3-benzoxazinyl octanoate were added to a reaction vessel. The mixture was heated to 65–75 °C and stirred for 7–10 h. The solution was concentrated under reduced pressure until no flow was observed to obtain crude compound (I). Acetonitrile was added and recrystallized 1–2 times. The solution was dried under reduced pressure at 65–75 °C for 10–15 h to obtain 26.5 g of off-white solid compound (I), with a molar yield of 94.9% and an HPLC purity of 99.91%.

[0046] Preparation of SNAC: Add 10g of the compound of formula (I) prepared by the above method and 50ml of isopropanol to a reaction vessel. Raise the temperature to 40-50℃, and slowly add NaOH aqueous solution (1.45g NaOH dissolved in 6ml water) dropwise while stirring. After the addition is complete, adjust the temperature inside the reaction vessel to 70-80℃ and maintain this temperature with stirring for 1-2 hours. Transfer the reaction solution to a crystallization vessel and slowly lower the temperature inside the crystallization vessel to 30-40℃. Mix 10mg of SNAC hydrate seed crystals with a small amount of purified water and add them to the crystallization vessel. Adjust the temperature inside the crystallization vessel to 25-35℃ and maintain this temperature with stirring for 1.5-3.5 hours. Then add an additional 20ml of isopropanol, raise the temperature inside the crystallization vessel to 38-45℃ at a heating rate of 0.1℃ / min, and maintain this temperature with stirring for 20-60 minutes. Then lower the temperature inside the crystallization vessel to 25-35℃ at a cooling rate of 0.08℃ / min. The internal temperature was then raised to 38–45°C at a heating rate of 0.1°C / min and held at this temperature with stirring for 20–60 min. The internal temperature was then lowered to 25–35°C at a cooling rate of 0.08°C / min. This cycle was repeated twice. The internal temperature of the crystallizer was then lowered to 5–15°C at a cooling rate of 0.2°C / min and held at this temperature with stirring for 4–8 h. The crystals were collected by centrifugation and dried at 95–105°C for 14–20 h. The crystals were then pulverized, sieved, and dried again at 95–105°C for 5–6 h to obtain 9.9 g of SNAC powder solid, with a molar yield of 91.17% and HPLC purity of 100%.

[0047] Example 4

[0048] Preparation of intermediate compound (I): Under nitrogen protection, 100 ml of a prepared aqueous mixture of dimethyl sulfoxide and trifluoroacetic acid (pH = 4), 18 mg of BHT, and 28 g of ethyl 2,4-dioxo-1,3-benzoxazine octanoate (83.99 mmol) were added to a reaction vessel. The mixture was heated to 90–100 °C and stirred for 4–6 h. The solution was concentrated under reduced pressure until no flow was observed to obtain crude compound (I). Acetonitrile was added and recrystallized 1–2 times. The solution was dried under reduced pressure at 65–75 °C for 10–15 h to obtain 22.05 g of off-white solid compound (I), with a molar yield of 94.0% and an HPLC purity of 99.91%.

[0049] Preparation of SNAC: 100 ml of isopropanol and 3.6 g of NaHCO3 were added to a reaction vessel and heated to 70–75 °C until dissolved. 10 g of compound (I) prepared by the above method was added, and the mixture was kept at 70–75 °C with stirring for 1–2 h. The reaction solution was transferred to a crystallization vessel, and the temperature inside the crystallization vessel was slowly lowered to 30–40 °C. 8 mg of SNAC hydrate seed crystals were mixed with a small amount of purified water and added to the crystallization vessel. The temperature inside the crystallization vessel was adjusted to 25–35 °C and kept at this temperature with stirring for 1.5–3 h. The temperature inside the crystallization vessel was then raised to 38–45 °C at a heating rate of 0.1 °C / min and kept at this temperature with stirring for 20–40 min. The temperature inside the crystallization vessel was then lowered to 25–35 °C at a cooling rate of 0.08 °C / min, and then raised to 38–45 °C again at a heating rate of 0.1 °C / min. The mixture was heated to ℃ and stirred for 20–40 min, then the internal temperature was lowered to 25–35℃ at a cooling rate of 0.08℃ / min. This cycle was repeated twice. Then, the internal temperature of the crystallizer was lowered to 5–15℃ at a cooling rate of 0.2℃ / min and stirred for 4–8 h. The crystals were collected by centrifugation and dried at 95–105℃ for 14–20 h. The crystals were then pulverized and sieved, and dried at 95–105℃ for 5–6 h to obtain 9.8 g of SNAC powder solid, with a molar yield of 90.24% and an HPLC purity of 99.97%.

[0050] Example 5

[0051] Preparation of intermediate compound (I): Under nitrogen protection, 5 g of sulfonic acid resin, 100 ml of acetonitrile aqueous solution (acetonitrile to water ratio of 9:1), 6 mg of BHT and 30 g of ethyl 2,4-dioxo-1,3-benzoxazine octanoate (89.99 mmol) were added to a reaction vessel. The mixture was heated to 65-75 °C and stirred for 7-10 h, then filtered. The filtrate was concentrated under reduced pressure until no flow was observed to obtain crude SNAC free acid. Acetonitrile was added and recrystallized 1-2 times. The product was dried under reduced pressure at 65-75 °C for 10-15 h to obtain 23.7 g of off-white SNAC free acid solid, with a molar yield of 94.4% and an HPLC purity of 99.93%.

[0052] Preparation of SNAC: Add 10g of the compound of formula (I) prepared by the above method and 50ml of isopropanol to a reaction vessel. Raise the temperature to 40-50℃, and slowly add NaOH aqueous solution (1.45g NaOH dissolved in 6ml water) dropwise while stirring. After the addition is complete, adjust the temperature inside the reaction vessel to 70-80℃ and maintain this temperature with stirring for 1-2 hours. Transfer the reaction solution to a crystallization vessel and slowly lower the temperature inside the crystallization vessel to 30-40℃. Mix 10mg of SNAC hydrate seed crystals with a small amount of purified water and add them to the crystallization vessel. Adjust the temperature inside the crystallization vessel to 25-35℃ and maintain this temperature with stirring for 1.5-3 hours. Then add an additional 20ml of isopropanol and slowly raise the temperature to 38-45℃ over 35-60 minutes while maintaining this temperature with stirring for 20-60 minutes. Then slowly lower the temperature to 25-35℃ over 95-120 minutes. The internal temperature was slowly raised to 38–45°C over 35–60 min and kept at this temperature with stirring for 20–60 min. Then, the internal temperature was slowly lowered to 25–35°C over 95–120 min. This cycle was repeated 3 times. Then, the internal temperature was slowly lowered to 5–15°C over 65–90 min and kept at this temperature with stirring for 4–8 h. The crystals were collected by centrifugation and dried at 95–105°C for 14–20 h. The crystals were then pulverized and sieved, and dried again at 95–105°C for 5–6 h to obtain 9.9 g of SNAC powder solid, with a molar yield of 91.17% and HPLC purity of 100%.

[0053] Example 6

[0054] Preparation of intermediate compound (I): Under nitrogen protection, 100 ml of a mixture of N,N-dimethylformamide and acetic acid aqueous solution (pH = 4.5), 9 mg of BHT, and 35 g of 0.1 mol of 2,4-dioxo-1,3-benzoxazine octanoate were added to a reaction vessel. The mixture was heated to 90–100 °C and stirred for 4–6 h. The solution was concentrated under reduced pressure until no flow was observed to obtain crude SNAC free acid. Acetonitrile was added and recrystallized 1–2 times. The solution was dried under reduced pressure at 65–75 °C for 10–15 h to obtain 26.7 g of white solid compound (I), with a molar yield of 95.6% and an HPLC purity of 99.94%.

[0055] Preparation of SNAC: Add 10g of the compound of formula (I) prepared by the above method and 50ml of isopropanol to a reaction vessel. Raise the temperature to 40-50℃, and slowly add NaOH aqueous solution (1.45g NaOH dissolved in 6ml water) dropwise while stirring. After the addition is complete, adjust the temperature inside the reaction vessel to 70-80℃ and maintain the temperature while stirring for 1-2 hours. Transfer the reaction solution to a crystallization vessel and slowly lower the temperature inside the crystallization vessel to 30-40℃. Mix 10mg of SNAC hydrate seed crystals with a small amount of purified water and add it to the crystallization vessel. Adjust the temperature inside the crystallization vessel to 25-35℃ and maintain the temperature while stirring for 1.5-3 hours. Then add an additional 20ml of isopropanol and raise the temperature inside the crystallization vessel to 38-45℃ at a heating rate of 0.1℃ / min and maintain the temperature while stirring for 20-40 minutes. Then lower the temperature inside the crystallization vessel to 25-35℃ at a cooling rate of 0.08℃ / min, and then raise the temperature again at a heating rate of 0.1℃ / min. The internal temperature was raised to 38–45°C and kept at this temperature with stirring for 20–40 min. Then, the internal temperature was lowered to 25–35°C at a cooling rate of 0.08°C / min. This cycle was repeated 3 times. Then, the internal temperature of the crystallizer was lowered to 5–15°C at a cooling rate of 0.2°C / min and kept at this temperature with stirring for 4–8 h. The crystals were collected by centrifugation and dried at 95–105°C for 14–20 h. The crystals were then pulverized and sieved, and dried again at 95–105°C for 5–6 h to obtain 10.0 g of SNAC powder solid, with a molar yield of 92.09% and an HPLC purity of 100%.

[0056] Comparative Example 1

[0057] SNAC free acid was prepared according to the method of Example 1 of patent CN101506147B, except that 22 mg of EDTA (0.08 mmol) was replaced with 1% BHT. The results showed that the obtained SNAC free acid solid was light pink in color.

[0058] Comparative Example 2

[0059] Preparation of the intermediate compound of formula (I) prepared by the above method: Under nitrogen protection, 100 ml of purified water and 14.4 g of NaOH solid (0.36 mol) were added to the reaction vessel and stirred to dissolve. Then, 30 g of ethyl 2,4-dioxo-1,3-benzoxazine octanoate (89.99 mmol) and 6 mg of BHT were added. The mixture was heated to 92-100 °C and stirred for 1-2 h. After cooling to room temperature, the pH was adjusted to 4.0-4.5 with hydrochloric acid and stirred to induce crystallization. The crude product of formula (I) was obtained by filtration. Acetonitrile was added and recrystallized 1-2 times to obtain 23.0 g of light pink solid with HPLC purity of 98.20%.

[0060] Comparative Example 3

[0061] Preparation of intermediate compound (I): Under nitrogen protection, 100 ml of purified water and 14.4 g of NaOH solid (0.36 mol) were added to a reaction vessel and stirred to dissolve. Then, 30 g of ethyl 2,4-dioxo-1,3-benzoxazine octanoate (89.99 mmol) was added. The mixture was heated to 92–100 °C and stirred for 1–2 h. After cooling to room temperature, the pH was adjusted to 4.0–4.5 with hydrochloric acid and stirred to induce crystallization. The mixture was filtered to obtain crude compound (I). Acetonitrile was added and recrystallized 1–2 times to obtain 22.9 g of light pink solid with an HPLC purity of 98.15%.

[0062] Comparative Example 4

[0063] Preparation of intermediate compound (I): Under nitrogen protection, 30 g of ethyl 2,4-dioxo-1,3-benzoxazine octanoate (89.99 mmol), 150 mL of ethanol, and 3.7 g of hydrochloric acid were added to a reaction vessel. The reaction was carried out overnight at 50 °C. The crude product of compound (I) was concentrated and recrystallized with 74 mL of acetonitrile to obtain 19.7 g of light pink compound (I) with an HPLC purity of 97.6%.

[0064] The particle size of the SNAC products obtained in the embodiments of the present invention was determined by a laser particle size analyzer. The particle size distribution diagrams of Examples 2 and 6 are shown below. Figures 5-6 As shown, the particle size distribution exhibits a normal distribution with a single peak, and the average crystal particle size D... 50 The particle size is 20-25 μm, indicating that the crystallization is more complete and the crystallinity is high. The resulting product is a crystalline substance with large and uniform particle size.

[0065] HPLC detection conditions in this embodiment of the invention: Instrument: Agilent 1260 series HPLC; Column: Welch AQ-C18, 250 mm × 4.6 mm, 5 μm; Mobile phase A: 0.1% (v / v) phosphoric acid solution; Mobile phase B: acetonitrile; Column temperature: 30℃; Detection wavelength: 210 nm; Flow rate: 1.0 ml / min; Injection volume: 10 μL. Elution gradient:

[0066]

[0067] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a sodium N-(8-[2-hydroxybenzoyl]amino)octanoate intermediate of formula (I), characterized in that, The compound of formula (II) was obtained by hydrolysis in a polar solvent in the presence of an acid catalyst and 2,6-di-tert-butyl-p-cresol. ， In compound (II), R is a straight-chain or branched alkyl group.

2. The method according to claim 1, characterized in that, The polar solvent is selected from one or more of water, methanol, ethanol, acetonitrile, diethyl ether, acetone, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide, N-methylpyrrolidone, dimethyl sulfoxide, and methyl tert-butyl ether.

3. The method according to claim 1, characterized in that, The acid catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, formic acid, acetic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, citric acid, acidic resin, and acidic molecular sieve.

4. The method according to claim 1, characterized in that, The amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.01 to 0.3% of the amount of compound (II).

5. The method according to claim 4, characterized in that, The amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.02 to 0.1% of the amount of compound (II).

6. The method according to claim 5, characterized in that, The amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.02 to 0.05% of the amount of compound (II).

7. The method according to claim 1, characterized in that, The pH value of the mixture of acid catalyst and polar solvent is 1~5.

8. The method according to claim 7, characterized in that, The pH value of the mixture of acid catalyst and polar solvent is 3-5.

9. The method according to claim 1, characterized in that, In the compound of formula (II), R is ethyl, and the amount of 2,6-di-tert-butyl-p-cresol used is 0.01 to 0.1% of the amount of compound of formula (II) by weight.

10. The method according to claim 9, characterized in that, The amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.02 to 0.07% of the amount of compound (II).

11. The method according to claim 10, characterized in that, The amount of 2,6-di-tert-butyl-p-cresol used, by weight, is 0.03 to 0.05% of the amount of compound (II).

12. The method according to claim 9, characterized in that, The polar solvent is selected from one or more of water, methanol, ethanol, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; the acid catalyst is hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or p-toluenesulfonic acid.

13. A method for preparing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, characterized in that, Including the following steps: (a) The compound of formula (I) is prepared by the method according to any one of claims 1-12; (b) The obtained compound of formula (I) reacts with a sodium-containing base in an organic solvent to produce sodium N-(8-[2-hydroxybenzoyl]amino)octanoate; 。 14. The method according to claim 13, characterized in that, The sodium-containing alkali is one or a combination of sodium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate; the organic solvent is one or a combination of methanol, ethanol, isopropanol, butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, 1,4-dioxane, tetrahydrofuran, acetonitrile, and acetone.

15. The method according to claim 14, characterized in that, The sodium-containing alkali is sodium hydroxide or sodium bicarbonate.

16. The method according to claim 14, characterized in that, The organic solvent is isopropanol.

17. The method according to claim 13, characterized in that, The process includes the following steps: the mixture of compound (I) and sodium-containing alkali after reaction is transferred to a crystallization vessel, the temperature inside the crystallization vessel is adjusted to 30-40℃, N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium hydrate seed crystals are added for programmed temperature-controlled dynamic crystallization, centrifugation, and drying to obtain the finished product; the programmed temperature-controlled dynamic crystallization process is as follows: after the seed crystals are added, the temperature inside the crystallization vessel is adjusted to 25-35℃ and kept at this temperature and stirred for 1.5-3.5h, then the temperature is slowly increased to 38-45℃ and kept at this temperature and stirred for 20-60min, then the temperature is slowly decreased to 25-35℃, then the temperature is slowly increased to 38-45℃ and kept at this temperature and stirred for 20-60min, then the temperature is slowly decreased to 25-35℃, and this cycle is repeated 2-4 times, and then the temperature inside the crystallization vessel is slowly decreased from 25-35℃ to 5-15℃ and kept at this temperature and stirred for 4-8h.

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