A process for the preparation of sodium 8-(2-hydroxybenzoylamino)octanoate
By using a heterogeneous Lewis acid-catalyzed amidation and in-situ saponification tandem reaction with an electron-deficient arylboronic acid catalyst supported on porous silicon, the problems of difficult reaction control, catalyst separation difficulties, and high waste treatment in the synthesis of sodium 8-(2-hydroxybenzoylamino)octanoate were solved, realizing an efficient and environmentally friendly preparation process that meets the requirements for pharmaceutical purity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU STERRIC CHEM IND
- Filing Date
- 2026-04-15
- Publication Date
- 2026-08-04
AI Technical Summary
In the existing technology, the synthesis process of sodium 8-(2-hydroxybenzoylamino)octanoate has problems such as difficulty in controlling the violent reaction conditions, poor mass transfer of the catalytic system, difficulty in solid-liquid separation, and high cost of waste treatment, resulting in low product yield and purity that is difficult to meet pharmaceutical requirements.
A porous silica-supported electron-deficient arylboronic acid catalyst was used to achieve amidation and saponification reactions in tandem via heterogeneous Lewis acid catalysis. 3-fluoro-4-vinylphenylboronic acid on SBA-15 mesoporous molecular sieve was used as the catalytic center, and the catalyst was prepared by combining mercapto-olefin click chemistry, thereby reducing the temperature and improving the purity.
The preparation of sodium 8-(2-hydroxybenzoylamino)octanoate with high yield (91.6%-94.9%) and high purity (99.76%-99.89%) was achieved, which simplified the subsequent purification steps, reduced production costs and environmental pressure, and is in line with the development direction of green chemistry.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediates technology, specifically to a method for preparing sodium 8-(2-hydroxybenzoylamino)octanoate. Background Technology
[0002] Sodium 8-(2-hydroxybenzoylamino)octanoate (SNAC) is a commercially promising oral absorption enhancer for macromolecular drugs. In recent years, with the widespread use of oral GLP-1 receptor agonists such as semaglutide, SNAC, as a key pharmaceutical excipient, can significantly improve the permeability of polypeptide and protein macromolecular drugs in the gastrointestinal tract and resist pepsin degradation, resulting in explosive growth in market demand.
[0003] Currently, the industrial synthesis of SNAC mainly involves the ring-opening amidation reaction of cassalan (i.e., 2H-1,3-benzoxazine-2,4(3H)-dione) with 8-aminooctanoic acid under alkaline conditions. However, existing synthetic processes and technologies suffer from the following significant defects and technical bottlenecks: (1) Violent reaction conditions and difficult-to-control side reactions: Traditional batch reactor processes rely heavily on strong alkalis (such as large excess sodium hydroxide) and continuous high-temperature heating (usually reflux at 100℃-130℃). Under such intense thermodynamic driving, cassalane is prone to hydrolysis and ring-opening to generate salicylic acid byproducts; at the same time, high temperature can also cause the generated SNAC to undergo a certain degree of dimerization or thermal degradation. These side reactions not only significantly reduce the yield of the target product, but also produce impurities that are highly similar in structure to SNAC, making the subsequent crystallization and purification steps extremely cumbersome and difficult to meet the stringent requirements for purity (>99.5%) of pharmaceutical excipients.
[0004] (2) Poor mass transfer and low efficiency of traditional catalytic systems: In order to reduce the reaction temperature, some studies have attempted to introduce conventional homogeneous acid-base catalysts. Although this can alleviate the thermal degradation caused by high temperature to some extent, homogeneous catalysts cannot be effectively separated from the high-viscosity product mother liquor, which easily leads to the residue of heavy metals or organic impurities. Conventional supported heterogeneous catalysts, due to their lack of specific activation ability for the substrate (single acidic or basic site), have extremely low catalytic conversion rates at lower temperatures, and the reaction time is often as long as 15-20 hours or more, resulting in low industrial production efficiency.
[0005] (3) Difficult solid-liquid separation and high cost of waste treatment: In heterogeneous catalysis trials, the viscosity of the reaction system (especially in the later stages of the reaction) increases dramatically, making it extremely difficult to recover micron- or nano-sized solid catalysts using traditional centrifugation or pressure filtration methods. This not only easily causes filter membrane clogging but also leads to the loss of a large amount of catalyst with the mother liquor. This increases both the cost of catalyst loss and the environmental protection pressure of waste liquid decolorization and impurity removal (extremely high E-factor), seriously deviating from the development orientation of "green, low-carbon, and sustainable" in the modern pharmaceutical industry.
[0006] Therefore, there is an urgent need to develop a novel catalytic synthesis system to solve the above-mentioned technical problems. Summary of the Invention
[0007] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing sodium 8-(2-hydroxybenzoylamino)octanoate.
[0008] To achieve the above objectives, the present invention provides the following technical solution: A method for preparing sodium 8-(2-hydroxybenzoylamino)octanoate includes the following steps: An organic solvent, salicylic acid, 8-aminooctanoate, and a porous silica-supported electron-deficient arylboronic acid catalyst are mixed and heated to 110-140℃ for amidation reaction. After the reaction is completed, an alkaline aqueous solution is added for saponification to form a salt. The product is then obtained by crystallization and drying.
[0009] The 8-aminooctanoate is one of methyl 8-aminooctanoate or ethyl 8-aminooctanoate.
[0010] The molar ratio of salicylic acid to 8-aminooctanoate is 1:(1.0-1.2).
[0011] The organic solvent is one of toluene and xylene.
[0012] The amidation reaction takes 4-10 hours.
[0013] The mass concentration of the alkaline aqueous solution is 10-20%.
[0014] The salt formation reaction takes 1-3 hours.
[0015] The porous silicon-supported electron-deficient arylboronic acid catalyst is prepared by the following method: SBA-15 mesoporous molecular sieve was reacted with a thiol-containing silane coupling agent under reflux in an anhydrous organic solvent to obtain thiolized SBA-15; thiolized SBA-15 was reacted with 3-fluoro-4-vinylphenylboronic acid under the action of an initiator to carry out a thiol-alkene click chemical reaction, followed by washing and drying to obtain the final product.
[0016] The mercapto-containing silane coupling agent is (3-mercaptopropyl)trimethoxysilane.
[0017] The initiator is AIBN.
[0018] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include: The core mechanism of this preparation process is a tandem reaction of heterogeneous Lewis acid-catalyzed amidation and in-situ saponification. 3-fluoro-4-vinylphenylboronic acid, immobilized on SBA-15 mesopores, serves as a specific catalytic center, utilizing the strong electron-withdrawing effect of fluorine atoms to impart strong electron-deficient properties to boron. This successfully overcomes the reaction inertia problem caused by intramolecular hydrogen bonding in salicylic acid, promoting the dehydration of the carboxyl group to form a highly reactive acyloxyborane intermediate. Subsequently, 8-aminooctanoic acid ester initiates a nucleophilic attack to rapidly construct an amide bond. Finally, ester hydrolysis occurs via the addition of alkali at a cooling temperature, leading to direct saponification to obtain the target sodium salt. The synthetic process described in this application has the advantages of high yield and high purity, and is easy to industrialize. Attached Figure Description
[0019] Figure 1 SEM image of the catalyst prepared in Example 1; Figure 2 The FTIR spectrum of the catalyst prepared in Example 1; Figure 3 The XRD diffraction pattern of the catalyst prepared in Example 1. Detailed Implementation
[0020] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.
[0021] Example 1: Preparation of porous silicon-supported electron-deficient arylboronic acid catalyst 10g of SBA-15 mesoporous molecular sieve (two-dimensional hexagonal channels, average pore size 8nm, specific surface area 650m²) was used. 2 (g) was dispersed in 100 mL of anhydrous toluene and ultrasonically dispersed for 30 min to form a uniform suspension; under nitrogen protection, 3.0 g of (3-mercaptopropyl)trimethoxysilane was added, and the mixture was stirred and refluxed for 12 h. After filtration, the filter cake was washed successively with 50 mL of toluene and 50 mL of anhydrous ethanol, and dried under vacuum at 70 °C for 10 h to obtain thiolized SBA-15.
[0022] The obtained mercaptolated SBA-15 and 2.5 g of 3-fluoro-4-vinylphenylboronic acid were dispersed in 100 mL of anhydrous tetrahydrofuran and ultrasonically dispersed for 15 min. Then, 0.1 g of initiator azobisisobutyronitrile (AIBN) was added, and the reaction system was bubbled with high-purity nitrogen in an ice bath for 30 min to completely remove oxygen and prevent free radical quenching. Under a nitrogen atmosphere, the system was heated to 70 °C and reacted with stirring for 10 h. After filtration, the filter cake was washed successively with 50 mL of anhydrous ethanol, 50 mL of acetone, and 50 mL of anhydrous ethanol. The powder was then vacuum dried at 60 °C for 10 h to obtain the catalyst powder. ICP-OES analysis showed that the boron content was 2.4 wt%.
[0023] pass Figure 2 It can be seen that pure SBA-15 exhibits a typical strong absorption band (~1100 cm⁻¹) in the Si-O-Si framework. -1 ); Thioylated SBA-15 at 2560 cm -1 The presence of the characteristic SH vibration at 1480 cm⁻¹ confirms the successful introduction of the thiol group; in the final catalyst spectrum, this SH peak completely disappears, proving that the thiol-alkene "click reaction" has been completed. The 1480 cm⁻¹ peak is clearly visible in the spectrum. -1 The C=C skeletal vibration of fluorinated aromatic rings and 1320 cm -1 The presence of BO characteristic vibrations confirms the successful preparation of the catalyst.
[0024] In small-angle X-ray diffraction (XRD) patterns, pure SBA-15 exhibited three characteristic reflection peaks corresponding to the (100), (110), and (200) crystal planes, confirming its highly ordered two-dimensional hexagonal mesoporous structure. After grafting electron-deficient arylboronic acid, these three core diffraction peaks of the catalyst remained clear and in the same position, indicating that despite the high-density loading of large-volume organic groups within the pores, the mesoporous framework of the molecular sieve maintained extremely high structural stability and did not collapse, ensuring the smooth entry and exit of the reaction substrate and its access to the catalytic active sites on the pore walls.
[0025] Example 2 Preparation of sodium 8-(2-hydroxybenzoylamino)octanoate In a 500 mL reaction flask equipped with a water separator, thermometer, and mechanical stirrer, 100 mL of toluene, 13.8 g (0.1 mol) of salicylic acid, 17.3 g (0.1 mol) of methyl 8-aminooctanoate, and 0.5 g of porous silica-supported electron-deficient arylboronic acid catalyst were added sequentially. The mixture was stirred and heated to 110 °C for 10 h, with water continuously separated using the water separator. The filtrate was cooled to 60 °C, and 44 g of a 10% sodium hydroxide aqueous solution was added dropwise over 20 min. After the addition was completed, the system temperature was maintained, and the saponification reaction to form a salt was carried out for 1 h. The mixture was then distilled under reduced pressure to constant weight, and 200 mL of acetone was added. The mixture was cooled to 5 °C, and a white solid precipitated. The solid was filtered, washed twice with 20 mL of icy acetone each time, and dried under vacuum at 60 °C for 12 h to obtain 27.6 g of sodium 8-(2-hydroxybenzoylamino)octanoate, with a yield of 91.6% and a liquid phase purity of 99.76%.
[0026] Example 3 Preparation of sodium 8-(2-hydroxybenzoylamino)octanoate In a 500 mL reaction flask equipped with a water separator, thermometer, and mechanical stirrer, 100 mL of xylene, 13.8 g (0.1 mol) of salicylic acid, 20.6 g (0.11 mol) of ethyl 8-aminooctanoate, and 0.6 g of porous silica-supported electron-deficient arylboronic acid catalyst were added sequentially. The mixture was stirred and heated to 125 °C for 6 h. Water generated during the reaction was continuously separated using the water separator. The filtrate was cooled to 65 °C, and 32 g of a 15% sodium hydroxide aqueous solution was added dropwise over 20 min. After the addition was completed, the system temperature was maintained, and the saponification reaction to form a salt was carried out for 2 h. The mixture was then distilled under reduced pressure to constant weight, and 200 mL of acetone was added. The mixture was cooled to 5 °C, and a white solid precipitated. The solid was filtered, washed twice with 20 mL of icy acetone each time, and dried under vacuum at 60 °C for 12 h to obtain 28.4 g of sodium 8-(2-hydroxybenzoylamino)octanoate, with a yield of 94.3% and a liquid phase purity of 99.89%. The 1H NMR data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ:12.50 (s, 1H), 8.86 (t, J = 5.5 Hz, 1H), 7.91 (dd, J = 8.0, 1.5 Hz, 1H), 7.37(ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 6.95 – 6.87 (m, 2H), 3.29 (q, J = 6.5 Hz, 2H), 1.94 (t, J = 7.5 Hz, 2H), 1.55 – 1.46 (m, 4H), 1.35 – 1.20 (m, 6H).
[0027] Example 4 Preparation of sodium 8-(2-hydroxybenzoylamino)octanoate In a 500 mL reaction flask equipped with a water separator, thermometer, and mechanical stirrer, 100 mL of xylene, 13.8 g (0.1 mol) of salicylic acid, 22.4 g (0.12 mol) of ethyl 8-aminooctanoate, and 0.5 g of porous silica-supported electron-deficient arylboronic acid catalyst were added sequentially. The mixture was stirred and heated to reflux for 4 h, with water continuously separated using the water separator. The filtrate was cooled to 65 °C, and 26 g of a 20% sodium hydroxide aqueous solution was added dropwise over 20 min. After the addition was completed, the system temperature was maintained, and the saponification reaction was allowed to proceed for 3 h. The mixture was then distilled under reduced pressure to constant weight, and 200 mL of acetone was added. The mixture was cooled to 5 °C, and a white solid precipitated. The solid was filtered, washed twice with 20 mL of icy acetone each time, and dried under vacuum at 60 °C for 12 h to obtain 28.6 g of sodium 8-(2-hydroxybenzoylamino)octanoate, with a yield of 94.9% and a liquid phase purity of 99.84%.
[0028] Comparative Example 1 The preparation method of sodium 8-(2-hydroxybenzoylamino)octanoate is basically the same as that in Example 3, except that a different porous silica-supported electron-deficient arylboronic acid catalyst is used. The preparation method of this comparative example is as follows: 10g of SBA-15 mesoporous molecular sieve (rod-shaped structure, average pore size 8nm, specific surface area 650m²) was added. 2 (g) was dispersed in 100 mL of anhydrous toluene and ultrasonically dispersed for 30 min to form a uniform suspension; under nitrogen protection, 3.0 g of (3-mercaptopropyl)trimethoxysilane was added, and the mixture was stirred and refluxed for 12 h. After filtration, the filter cake was washed successively with 50 mL of toluene and 50 mL of anhydrous ethanol, and dried under vacuum at 70 °C for 10 h to obtain thiolized SBA-15.
[0029] The obtained mercaptolated SBA-15 and 2.5 g of 4-vinylphenylboronic acid were dispersed in 100 mL of anhydrous tetrahydrofuran and ultrasonically dispersed for 15 min. Then, 0.1 g of initiator azobisisobutyronitrile (AIBN) was added, and the reaction system was bubbled with high-purity nitrogen in an ice bath for 30 min to completely remove oxygen and prevent free radical quenching. Under a nitrogen atmosphere, the system was heated to 70 °C and reacted with stirring for 10 h. After filtration, the filter cake was washed successively with 50 mL of anhydrous ethanol, 50 mL of acetone, and 50 mL of anhydrous ethanol. The mixture was then vacuum dried at 60 °C for 10 h to obtain catalyst powder.
[0030] The final yield of sodium 8-(2-hydroxybenzoylamino)octanoate was 19.3 g.
[0031] Comparative Example 2 The preparation method of sodium 8-(2-hydroxybenzoylamino)octanoate is basically the same as that in Example 3, except that a different porous silica-supported electron-deficient arylboronic acid catalyst is used. The preparation method of this comparative example is as follows: 10g of SBA-16 molecular sieve (cage-like structure, specific surface area 720m²) was added. 2 (g) was dispersed in 100 mL of anhydrous toluene and ultrasonically dispersed for 30 min to form a uniform suspension; under nitrogen protection, 3.0 g of (3-mercaptopropyl)trimethoxysilane was added, and the mixture was stirred and refluxed for 12 h. After filtration, the filter cake was washed successively with 50 mL of toluene and 50 mL of anhydrous ethanol, and dried under vacuum at 70 °C for 10 h to obtain thiolized SBA-16.
[0032] The obtained mercaptolated SBA-16 and 2.5 g of 3-fluoro-4-vinylphenylboronic acid were dispersed in 100 mL of anhydrous tetrahydrofuran and ultrasonically dispersed for 15 min. Then, 0.1 g of initiator azobisisobutyronitrile (AIBN) was added, and the reaction system was bubbled with high-purity nitrogen in an ice bath for 30 min to completely remove oxygen and prevent free radical quenching. Under a nitrogen atmosphere, the system was heated to 70 °C and reacted with stirring for 10 h. After filtration, the filter cake was washed successively with 50 mL of anhydrous ethanol, 50 mL of acetone, and 50 mL of anhydrous ethanol. The mixture was then vacuum dried at 60 °C for 10 h to obtain catalyst powder.
[0033] The final yield of sodium 8-(2-hydroxybenzoylamino)octanoate was 25.4 g.
[0034] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.
Claims
1. A method for preparing sodium 8-(2-hydroxybenzoylamino)octanoate, characterized in that, Includes the following steps: An organic solvent, salicylic acid, 8-aminooctanoate, and a porous silica-supported electron-deficient arylboronic acid catalyst are mixed and heated to 110-140℃ for amidation reaction. After the reaction is completed, an alkaline aqueous solution is added for saponification to form a salt. The product is then obtained by crystallization and drying.
2. The preparation method according to claim 1, characterized in that, The 8-aminooctanoate is one of methyl 8-aminooctanoate or ethyl 8-aminooctanoate.
3. The preparation method according to claim 1, characterized in that, The molar ratio of salicylic acid to 8-aminooctanoate is 1:(1.0-1.2).
4. The preparation method according to claim 1, characterized in that, The organic solvent is one of toluene and xylene.
5. The preparation method according to claim 1, characterized in that, The amidation reaction takes 4-10 hours.
6. The preparation method according to claim 1, characterized in that, The mass concentration of the alkaline aqueous solution is 10-20%.
7. The preparation method according to claim 1, characterized in that, The salt formation reaction takes 1-3 hours.
8. The preparation method according to claim 1, characterized in that, The porous silicon-supported electron-deficient arylboronic acid catalyst was prepared by the following method: SBA-15 mesoporous molecular sieve was reacted with a thiol-containing silane coupling agent under reflux in an anhydrous organic solvent to obtain thiolized SBA-15; thiolized SBA-15 was reacted with 3-fluoro-4-vinylphenylboronic acid under the action of an initiator to carry out a thiol-alkene click chemical reaction, followed by washing and drying to obtain the final product.
9. The preparation method according to claim 8, characterized in that, The mercapto-containing silane coupling agent is (3-mercaptopropyl)trimethoxysilane.
10. The preparation method according to claim 8, characterized in that, The initiator is AIBN.