A synthetic method for 8-(2-hydroxybenzamido) sodium octanoate

Abstract

The invention discloses a novel method for synthesizing 8-(2-hydroxybenzamide) sodium caprylate, which belongs to the field of pharmaceutical synthesis technology. The method comprises the following steps: cyclization of suberic acid with acetic anhydride and then ring opening with alcohol to obtain compound 2; reaction of compound 2 with ammonium bicarbonate under the activation of di-tert-butyl dicarbonate to obtain compound 3; imidization of compound 3 with di-tert-butyl dicarbonate to obtain compound 4; reduction of compound 4 under the conditions of sodium borohydride and boron trifluoride tetrahydrofuran to obtain compound 5; deprotection of compound 5 in acid to obtain compound 6; condensation reaction of compound 6 with a salicylic acid derivative in the presence of a base to obtain compound 7; and hydrolysis of compound 7 in a base to obtain SNAC. The main raw materials used in the present invention are cheap and easy to obtain, high yield per step, low total cost, mild conditions, simple operation, and suitable for large-scale industrial production; the method can obtain multiple products with high product purity, flexible product lines, and good application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for synthesizing a salt of 8-aminocaprylic acid or an ester and sodium 8-(2-hydroxybenzamido)caprylate. Background Art

[0002] Sodium 8-(2-hydroxybenzamido)octanoate (SNAC) is a chemically synthesized fatty acid derivative. It is a highly effective molecule selected by Emisphere from a variety of penetration enhancers. Its structure is shown below:

[0003]

[0004] SNAC is a non-covalent chelating agent based on a salicylic acid structure. Its molecular design, through its amphiphilic structure, enhances drug lipophilicity and local pH regulation and protection. SNAC forms non-covalent complexes with target drugs (such as peptides and polysaccharides), masking their hydrophilic groups and thereby enhancing their ability to penetrate passively across cells. In the gastric environment, SNAC temporarily increases the local microenvironmental pH by binding to the drug, inhibiting pepsin activity and reducing drug degradation. Furthermore, SNAC offers significant safety advantages, with no mucosal damage or long-term toxicity observed clinically, thus overcoming the toxic and side effect bottleneck of traditional enhancers.

[0005] SNAC has achieved technological transformation in multiple fields. In the treatment of metabolic diseases, as a key excipient for oral semaglutide tablets, SNAC enables the bioavailability of GLP-1 receptor agonists to reach a therapeutic level, and a daily dose of 2.5 mg can achieve blood sugar control and weight management. In the treatment of bisphosphonate malabsorption, SNAC has been successfully used to treat gastrointestinal diseases caused by abnormal phosphate metabolism by enhancing intestinal absorption efficiency, significantly improving the convenience of medication for patients. In the delivery of heparin and insulin, preclinical studies have shown that SNAC can increase the oral absorption rate of heparin to within the therapeutic window, providing a non-injection alternative for anticoagulant therapy.

[0006] The synthesis methods of SNAC reported in the literature can be summarized into three methods.

[0007] Method 1 uses the formate ester of salicylic acid amide as a starting material, undergoes a substitution reaction with ethyl 8-bromooctanoate, and then hydrolyzes it with sodium hydroxide to produce SNAC (CN114195730). This method is limited by the high price and limited availability of the key raw material, ethyl 8-bromooctanoate.

[0008] Method 2 uses 8-aminooctanoic acid as the key raw material, reacting it with methyl salicylate for a condensation reaction, followed by hydrolysis with sodium hydroxide to produce SNAC. This method is original and is also the method adopted by most pharmaceutical companies (WO2022 / 162132). However, the synthetic processes for 8-aminooctanoic acid reported in the literature have the following limitations: some do not undergo purification, resulting in low purity of inorganic salts in the 8-aminooctanoic acid (CN 118307424); others add additional reagents, such as di-tert-butyl dicarbonate, to purify the 8-aminooctanoic acid, followed by desalination to obtain free 8-aminooctanoic acid. The additional purification step results in a loss of yield and increases the raw material cost of the 8-aminooctanoic acid (CN 118561711).

[0009] Method three uses a salt of 8-aminooctanoic acid as a key raw material and reacts it with a salicylic acid derivative to prepare SNAC. Currently, there are few publications using 8-aminooctanoic acid salts as substrates. Patent CN 111978193 uses N,N-carbonyldiimidazole (CDI) as a condensing agent to condense 8-aminooctanoic acid ethyl ester hydrochloride with salicylic acid to produce SNAC. The problem with this process is that the condensing agent CDI is relatively expensive and has low atom economy. The imidazole can cause harm to the environment, especially to water bodies, making wastewater treatment difficult and inconsistent with the concept of green chemistry. Summary of the Invention

[0010] Technical problems solved by the present invention:

[0011] Current synthesis methods for sodium 8-(2-hydroxybenzamido)octanoate primarily use ethyl 8-bromooctanoate or 8-aminooctanoic acid as key raw materials. The high material cost of ethyl 8-bromooctanoate results in high production costs for SNAC, making it difficult to sustain commercial competition under high-intensity conditions. 8-aminooctanoic acid is prone to intermolecular dimerization and is difficult to remove. Obtaining high-purity 8-aminooctanoic acid is a complex process requiring purification with di-tert-butyl dicarbonate and a desalting step, which can lead to product losses.

[0012] Analysis of the above issues:

[0013] 8-Aminooctanoic acid is prepared from the hydrolysis of 8-aminooctanoic acid salts. From a chemical synthesis perspective, the best approach is to use the precursor of 8-aminooctanoic acid, namely its salt, as the substrate. This strategy offers the advantages of lower cost for the salt of 8-aminooctanoic acid and eliminates the step of hydrolysis to prepare 8-aminooctanoic acid, further reducing raw material costs. Furthermore, the salt of 8-aminooctanoic acid can be precipitated from the system, resulting in higher purity. From the perspective of preparing SNAC, using 8-aminooctanoic acid salt as a substrate is superior to using the salt of 8-aminooctanoic acid ester, as the salt of 8-aminooctanoic acid ester is prone to producing impurities from intermolecular amine ester exchange during condensation with salicylic acid fragments, which can affect the quality of the final SNAC product.

[0014] The technical solutions of the present invention are as follows:

[0015] A method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt, using suberic acid as a raw material, and the synthesis path is as follows:

[0016] ,

[0017] Wherein, Acid is one of an inorganic acid or an organic acid; the inorganic acid is one of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably hydrochloric acid; the organic acid is one of benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid;

[0018] R1 is methyl or ethyl, R2 is one of H, methyl, and ethyl;

[0019] When R2 is H, compound 6 is 8-aminocaprylate; when R2 is methyl or ethyl, compound 6 is 8-aminocaprylate;

[0020] The steps include:

[0021] Step 1: Suberic acid is cyclized with acetic anhydride and then ring-opened with alcohol to obtain compound 2;

[0022] Step 2: Compound 2 reacts with ammonium bicarbonate under the activation of di-tert-butyl dicarbonate to obtain compound 3;

[0023] Step 3: Compound 3 is imidized with di-tert-butyl dicarbonate to obtain compound 4;

[0024] Step 4: Compound 4 is reduced under the conditions of sodium borohydride and boron trifluoride tetrahydrofuran to obtain compound 5;

[0025] Step 5: Compound 5 is deprotected in acid to obtain compound 6.

[0026] A method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate (SNAC) using 8-aminocaprylate or 8-aminocaprylate as a raw material, and the synthesis route is as follows:

[0027] ,

[0028] Wherein, Acid is one of an inorganic acid or an organic acid; the inorganic acid is one of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably hydrochloric acid; the organic acid is one of benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid;

[0029] R2 is one of H, methyl, and ethyl, preferably H;

[0030] When R2 is H, compound 6 is 8-aminocaprylate; when R2 is methyl or ethyl, compound 6 is 8-aminocaprylate;

[0031] Compound It is a salicylic acid derivative, X is one of halogen, OH, OMe, and OEt; the halogen is preferably Cl;

[0032] The steps include:

[0033] Step 6: When compound 6 is an 8-aminocaprylate salt, it undergoes a condensation reaction with a salicylic acid derivative in the presence of a base to obtain compound 7; when compound 6 is an 8-aminocaprylate salt, it first undergoes a condensation reaction with a salicylic acid derivative in the presence of a base, and then the ester group is hydrolyzed to obtain compound 7;

[0034] Step 7: Compound 7 is neutralized with sodium hydroxide, sodium bicarbonate or sodium carbonate to obtain SNAC.

[0035] Furthermore, step 1 includes two stages: in the first stage, the molar ratio of suberic acid, acetic anhydride, and 4-dimethylaminopyridine is 1:7.4:0.05, and the reaction temperature is 140-150°C; in the second stage, the molar ratio of suberic acid and triethylamine is 1:4.0, the mass volume ratio of suberic acid, methanol, and toluene is 1:4.0:1.0, and the reaction temperature of the second stage is 50-60°C.

[0036] Furthermore, in step 2, the molar ratio of compound 2, di-tert-butyl dicarbonate, ammonium bicarbonate, and pyridine is 1: 1.1: 2.0: 0.1; the reaction temperature is 10-20° C.; and the solvent is tetrahydrofuran.

[0037] Furthermore, in step 3, the molar ratio of compound 3, di-tert-butyl dicarbonate, triethylamine, and DMAP is 1:1.1:1.5:0.1; the reaction temperature is 20-30°C; and the reaction solvent is tetrahydrofuran.

[0038] Furthermore, in step 4: in the first stage, the molar ratio of compound 4, sodium borohydride, and boron trifluoride tetrahydrofuran is 1: 1.6: 1.6; in the second stage, R2 in compound 5 obtained under the conditions of a molar ratio of compound 4 to sodium hydroxide of 1: 3.0 and a reaction temperature of 20-30° C. is H; R2 in compound 5 obtained without the addition of sodium hydroxide is methyl or ethyl.

[0039] Furthermore, in the step 5, the volume ratio of xylene to acid is 1: 1.0-3.0; the reaction temperature is 80-90° C.; and the reaction solvent is xylene.

[0040] Furthermore, in step six:

[0041] 1) When the salicylic acid derivative is salicylate (X = OMe or OEt): the reaction solvent is methanol, the base is sodium methoxide; the molar ratio of compound 6, salicylate, and sodium methoxide is 1:1.0:4.5, and the reaction temperature is 65°C;

[0042] 2) When the salicylic acid derivative is salicylic acid (X=OH): the reaction solvent is toluene and the base is triethylamine; the reaction is divided into two stages: in the first stage, the molar ratio of compound 6, condensing agent, and triethylamine is 1:2.0:2.2; the reaction temperature is 10-20°C; in the second stage, the molar ratio of compound 6 and triethylamine is 1:3.3, and the reaction temperature is 90-100°C; the condensing agent is one of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, and pivaloyl chloride;

[0043] 3) When the salicylic acid derivative is a salicylic acid halide (X=Cl): the reaction solvent is dichloromethane, the base is triethylamine; the molar ratio of compound 6 to triethylamine is 1:3.3; and the reaction temperature is 0-10°C.

[0044] Furthermore, in step seven, the molar ratio of compound 7 to sodium hydroxide is 1:1.0; the reaction temperature is 45-55° C.; and the reaction solvents are isopropanol and water.

[0045] The present invention also provides a method for preparing a monoester of a diacid from a diacid, wherein the diacid includes succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, etc. Taking suberic acid as an example, the preparation method of suberic acid monoester from suberic acid comprises firstly forming a cyclic transition state by reacting suberic acid with acetic anhydride at high temperature, and then ring-opening the monoester with an alcohol. The preparation route is as follows:

[0046] ,

[0047] Wherein R1 is an alkyl group, preferably a methyl group or an ethyl group; based on this principle, the corresponding monoester can also be prepared from other diacids.

[0048] Beneficial effects:

[0049] (1) This patent provides a method for synthesizing salts of 8-aminooctanoic acid or its esters and SNAC. The main raw materials of this process are cheap and readily available, the yield per step is high, the total cost is low, the process conditions are mild, the operation is simple, and it is suitable for production scale-up. The products obtained by this process are very pure, with the purity of 8-aminooctanoic acid hydrochloride being >99.90% and the purity of SNAC being >99.90%, and both being pure white in color.

[0050] (2) This patented method can produce multiple products with high purity, including 8-aminocaprylic acid hydrochloride, 8-aminocaprylic acid methyl ester hydrochloride, 8-aminocaprylic acid ethyl ester hydrochloride and SNAC. This method has a flexible product line and good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 is the HNMR of compound 6c.

[0052] Figure 2 This is the liquid chromatography of compound 6c.

[0053] Figure 3 is the HNMR of compound 6a.

[0054] Figure 4 This is the liquid chromatography of compound 6a.

[0055] Figure 5 is the HNMR of compound 6b.

[0056] Figure 6 This is the liquid chromatography of compound 6b.

[0057] Figure 7 is the HNMR of SNAC.

[0058] Figure 8 Liquid chromatography of SNAC. DETAILED DESCRIPTION

[0059] To make the technical solutions and advantages of the present invention more clearly apparent, the technical solutions of the present invention are described clearly and completely below with reference to the following examples. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer were followed. Reagents or instruments used, for which the manufacturer is not specified, are commercially available conventional products or services.

[0060] A specific reaction route for synthesizing SNAC is given below:

[0061]

[0062] Example 1 - Preparation of Compound 2a

[0063]

[0064] Suberic acid (100.0 g, 0.574 mol, 1.0 eq), acetic anhydride (434.8 g, 4.258 mol, 7.4 eq), and 4-dimethylaminopyridine (DMAP) (3.51 g, 0.029 mol, 0.05 eq) were added to a reaction flask and reacted at 140-150°C under nitrogen until complete. The acetic anhydride and acetic acid were evaporated under reduced pressure, and the residue was added toluene (100 mL) and stirred to dissolve. This solution was slowly added dropwise to a mixture of methanol (400 mL) and triethylamine (231.9 g, 2.296 mol, 4.0 eq) at 10-20°C. After addition, the reaction was continued at 50-60°C for 6 h. The solvent was evaporated under reduced pressure, and water (500 mL) was added. The pH was adjusted to 3 with 3N HCl, and the mixture was extracted with toluene (300 mL x 3). The organic phases were combined and concentrated under reduced pressure to give compound 2a (99.4 g, 0.528 mol) in a yield of 92%.

[0065] Example 2 - Preparation of Compound 3a

[0066]

[0067] Compound 2a (90.0 g, 0.478 mol, 1.0 eq), ammonium bicarbonate (75.5 g, 0.956 mol, 2.0 eq), pyridine (3.80 g, 0.048 mol, 0.1 eq), and tetrahydrofuran (450 mL) were added to a reaction flask. Di-tert-butyl dicarbonate (41.5 g, 0.526 mol, 1.1 eq) was slowly added dropwise at a temperature of 10-20°C. The reaction was continued for 12 hours. Methyl tert-butyl ether (540 mL) was added, and the organic phase was washed with 1N hydrochloric acid (450 mL), saturated sodium carbonate solution (270 mL), and water (270 mL), respectively. The organic phase was concentrated under reduced pressure to yield compound 3a (76.9 g, 0.411 mol) in an 86% yield.

[0068] Example 3 - Preparation of Compound 4a

[0069]

[0070] Compound 3a (70.0 g, 0.374 mol, 1.0 eq), DMAP (4.51 g, 0.037 mol, 0.1 eq), triethylamine (56.7 g, 0.561 mol, 1.5 eq), and tetrahydrofuran (350 mL) were added to a reaction flask. Di-tert-butyl dicarbonate (89.7 g, 0.411 mol, 1.1 eq) was slowly added dropwise at 20-30°C. The reaction was continued for 12 h. The mixture was concentrated under reduced pressure, and water (350 mL) and dichloromethane (350 mL) were added. The pH of the aqueous phase was adjusted to 3-4 with 3N HCl, and the layers were separated. The aqueous phase was extracted with dichloromethane (350 mL). The organic phases were combined and concentrated under reduced pressure to yield compound 4a (103.2 g, 0.359 mol) in a 96% yield.

[0071] Example 4 - Preparation of Compound 5c

[0072]

[0073] Compound 4a (100 g, 0.348 mol, 1.0 eq) and tetrahydrofuran (1000 mL) were added to a reaction flask. Sodium borohydride (21.2 g, 0.557 mol, 1.6 eq) was added portionwise. Boron trifluoride in tetrahydrofuran (77.98 g, 0.557 mol, 1.6 eq) was added dropwise at 20-30°C. The reaction was continued for 8 hours. The reaction mixture was poured into ice water (800 g) in portions and the solvent was evaporated under reduced pressure. The residue was added with water (400 g) and sodium hydroxide (41.76 g, 1.044 mol, 3.0 eq) and stirred at 20-30°C for 8 hours. The reaction mixture was extracted with ethyl acetate (300 mL) to remove impurities. The aqueous phase was adjusted to pH 2-3 with 3N HCl and extracted with ethyl acetate (400 mL x 3). The organic phases were combined and concentrated under reduced pressure to give compound 5c (74.9 g, 0.289 mol) in a yield of 83%.

[0074] Example 5 - Preparation of Compound 5a

[0075]

[0076] Compound 4a (100 g, 0.348 mol, 1.0 eq) and tetrahydrofuran (1000 mL) were added to a reaction flask. Sodium borohydride (21.2 g, 0.557 mol, 1.6 eq) was added portionwise. Boron trifluoride in tetrahydrofuran (77.98 g, 0.557 mol, 1.6 eq) was added dropwise at 20-30°C. The reaction was continued for 8 hours. The reaction solution was poured into ice water (800 g) in batches and the solvent was evaporated under reduced pressure. Water (400 g) was added to the concentrated residue, and the aqueous phase was adjusted to pH 2-3 with 3N HCl. The resulting phase was extracted with ethyl acetate (400 mL x 3). The organic phases were combined and concentrated under reduced pressure to yield compound 5a (80.9 g, 0.296 mol) in an 85% yield.

[0077] Example 6 - Preparation of Compound 5b

[0078]

[0079] Compound 4b (104.9 g, 0.348 mol, 1.0 eq) and tetrahydrofuran (1000 mL) were added to a reaction flask. Sodium borohydride (21.2 g, 0.557 mol, 1.6 eq) was added portionwise. Boron trifluoride in tetrahydrofuran (77.98 g, 0.557 mol, 1.6 eq) was added dropwise at 20-30°C. The reaction was continued for 8 hours. The reaction solution was poured portionwise into ice water (800 g) and the solvent was evaporated under reduced pressure. Water (400 g) was added to the concentrated residue, and the aqueous phase was adjusted to pH 2-3 with 3N HCl. The resulting phase was extracted with ethyl acetate (400 mL x 3). The organic phases were combined and concentrated under reduced pressure to yield compound 5b (86.0 g, 0.299 mol) in an 86% yield.

[0080] Example 7 - Preparation of Compound 6c

[0081]

[0082] Concentrated hydrochloric acid (140 mL) was added to the reaction flask and heated to 80-90°C. Compound 5c (70.0 g, 0.270 mol, 1.0 eq) dissolved in xylene (140 mL) was added dropwise. The reaction was allowed to proceed for 5 h, and the temperature was then lowered to 0-10°C. The reaction solution was filtered and dried to obtain compound 6c (45.4 g, 0.232 mol) with a yield of 86% and a purity greater than 99.90%. Its HNMR and liquid chromatography results were as follows: Figure 1 and 2 shown.

[0083] Example 8 - Preparation of Compound 6a

[0084]

[0085] Concentrated hydrochloric acid (140 mL) was added to the reaction flask and heated to 80-90°C. Compound 5a (73.8 g, 0.270 mol, 1.0 eq) dissolved in xylene (140 mL) was added dropwise. The reaction was allowed to proceed for 5 h, and the temperature was then lowered to 0-10°C. The reaction solution was filtered and dried to obtain compound 6a (47.0 g, 0.224 mol) with a yield of 83% and a purity greater than 99.90%. Its HNMR and liquid chromatography results were as follows: Figure 3 and 4 shown.

[0086] Example 9 - Preparation of Compound 6b

[0087]

[0088] Concentrated hydrochloric acid (140 mL) was added to the reaction flask and heated to 80-90°C. Compound 5b (77.6 g, 0.270 mol, 1.0 eq) dissolved in xylene (140 mL) was added dropwise. The reaction was allowed to react for 5 h, and the temperature was lowered to 0-10°C. The reaction solution was filtered and dried to obtain compound 6b (49.5 g, 0.221 mol) with a yield of 82% and a purity greater than 99.50%. Its HNMR and liquid chromatography results were as follows: Figure 5 and 6 shown.

[0089] Example 10 - Preparation of Compound 7

[0090]

[0091] Methanol (277 g) and 30% sodium methoxide (828 g, 4.599 mol, 4.5 eq) were added to a reaction flask. Compound 6c (200.0 g, 1.022 mol, 1.0 eq) was added portionwise, along with methyl salicylate (155.4 g, 1.022 mol, 1.0 eq). The temperature was raised to 65°C and the reaction was continued for 40 h. The temperature was then lowered to 20°C, and water (1000 g) was added. The pH was adjusted to 4 with concentrated hydrochloric acid. The product was filtered and dried to afford compound 7 (259.8 g, 0.930 mol) in a 91% yield.

[0092] Example 11 - Preparation of Compound 7

[0093]

[0094] Methanol (277 g) and 30% sodium methoxide (828 g, 4.599 mol, 4.5 eq) were added to a reaction flask. Compound 6c (200.0 g, 1.022 mol, 1.0 eq) was added portionwise, along with ethyl salicylate (169.9 g, 1.022 mol, 1.0 eq). The temperature was raised to 65°C and the reaction was continued for 40 h. The temperature was then lowered to 20°C, and water (1000 g) was added. The pH was adjusted to 4 with concentrated hydrochloric acid. The product was filtered and dried to afford compound 7 (259.5 g, 0.928 mol) in a 91% yield.

[0095] Example 12 - Preparation of Compound 7

[0096]

[0097] Salicylic acid (100 g, 0.724 mol, 1.0 eq), triethylamine (160.9 g, 1.593 mol, 2.2 eq), and toluene (700 mL) were added to a reaction flask. Methyl chloroformate (136.8 g, 1.448 mol, 2.0 eq) was added dropwise at a temperature of 10-20°C. The reaction was continued for 5 h. Compound 6c (141.7 g, 0.724 mol, 1.0 eq) and triethylamine (219.4 g, 2.172 mol, 3.3 eq) were added, and the temperature was raised to 90-100°C for 10 h. The temperature was then lowered to 20-30°C, washed with 3N HCl, and the layers separated. The organic phase was concentrated under reduced pressure to remove the solvent. Sodium hydroxide (115.8 g, 2.896 mol, 4.0 eq) and water (1000 mL) were added and stirred at 20-30°C for 4 h. The mixture was separated, and the aqueous phase was retained. Concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 4. The mixture was filtered and dried to obtain compound 7 (167.8 g, 0.601 mol) in an 83% yield.

[0098] Example 13 - Preparation of Compound 7

[0099]

[0100] Salicylic acid (100 g, 0.724 mol, 1.0 eq), triethylamine (160.9 g, 1.593 mol, 2.2 eq), and toluene (700 mL) were added to a reaction flask. Ethyl chloroformate (157.1 g, 1.448 mol, 2.0 eq) was added dropwise at a temperature of 10-20°C. The reaction was continued for 5 h. Compound 6c (141.7 g, 0.724 mol, 1.0 eq) and triethylamine (219.4 g, 2.172 mol, 3.3 eq) were added, and the temperature was raised to 90-100°C for 10 h. The temperature was then lowered to 20-30°C, washed with 3N HCl, and the mixture was separated. The organic phase was concentrated under reduced pressure to remove the solvent. Sodium hydroxide (115.8 g, 2.896 mol, 4.0 eq) and water (1000 mL) were added and stirred at 20-30°C for 4 h. The mixture was separated, and the aqueous phase was retained. Concentrated hydrochloric acid was added to adjust the pH to 4. The product was filtered and dried to obtain compound 7 (165.8 g, 0.594 mol) in an 82% yield.

[0101] Example 14 - Preparation of Compound 7

[0102]

[0103] Salicylic acid chloride (160.0 g, 1.022 mol, 1.0 eq) was dissolved in dichloromethane (500 mL) and added dropwise to a mixture of compound 6c (200.0 g, 1.022 mol, 1.0 eq), triethylamine (340.6 g, 3.373 mol, 3.3 eq), and dichloromethane (1000 mL). The temperature was controlled at 0-10°C. After 6 hours of reaction, the mixture was poured into 3N HCl for extraction. The organic phase was concentrated under reduced pressure to remove the solvent, yielding compound 7 (225.5 g, 0.807 mol) in a 79% yield.

[0104] Example 15 - Preparation of Compound 7

[0105]

[0106] Salicylic acid (100 g, 0.724 mol, 1.0 eq), triethylamine (160.9 g, 1.593 mol, 2.2 eq), and toluene (700 mL) were added to a reaction flask. Pivaloyl chloride (174.6 g, 1.448 mol, 2.0 eq) was added dropwise at a temperature of 10-20°C. The reaction was continued for 5 h. Compound 6c (141.7 g, 0.724 mol, 1.0 eq) and triethylamine (219.4 g, 2.172 mol, 3.3 eq) were added, and the temperature was raised to 90-100°C for 10 h. The temperature was then lowered to 20-30°C, washed with 3N HCl, and the mixture was separated. The organic phase was concentrated under reduced pressure to remove the solvent. Sodium hydroxide (115.8 g, 2.896 mol, 4.0 eq) and water (1000 mL) were added and stirred at 20-30°C for 4 h. The liquids were separated, and the aqueous phase was retained. Concentrated hydrochloric acid was added to adjust the pH to 4. The product was filtered and dried to obtain compound 7 (151.7 g, 0.543 mol) in a 75% yield.

[0107] Example 16 - Preparation of Compound 7

[0108]

[0109] Methanol (277 g) and 30% sodium methoxide (828 g, 4.599 mol, 4.5 eq) were added to a reaction flask. Compound 6a (214.3 g, 1.022 mol, 1.0 eq) was added portionwise, along with methyl salicylate (155.4 g, 1.022 mol, 1.0 eq). The temperature was raised to 65°C and the reaction was allowed to react for 40 h. The temperature was then lowered to 20°C, and water (1000 g) was added. The mixture was stirred at 20-30°C for 4 h. The pH was adjusted to 4 with concentrated hydrochloric acid. The product was filtered and dried to afford compound 7 (239.8 g, 0.858 mol) in an 84% yield.

[0110] Example 17 - Preparation of SNAC

[0111]

[0112] Compound 7 (200 g, 0.716 mol, 1.0 eq) and isopropanol (680 mL) were added to a reaction flask. A solution of sodium hydroxide (28.6 g, 0.716 mol, 1.0 eq) and water (120 mL) was added. The temperature was raised to 45-55°C and the reaction was allowed to proceed for 1 h. The temperature was lowered to 25°C, seed crystals (0.2 g) were added, the mixture was stirred for 2 h, isopropanol (560 mL) was added, and the mixture was stirred at 0-5°C for 4 h. The mixture was filtered and dried to obtain compound SNAC (200.6 g, 0.666 mol) with a yield of 93% and a purity of 99.92%. Its HNMR and liquid chromatography results were as follows: Figure 7 and 8 shown.

Claims

1. A method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt, characterized in that: Using suberic acid as raw material, the synthesis route is as follows: ， Wherein, Acid is one of an inorganic acid or an organic acid; the inorganic acid is one of hydrochloric acid, sulfuric acid, and phosphoric acid; the organic acid is one of benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid; R1 is methyl or ethyl, R2 is one of H, methyl, and ethyl; When R2 is H, compound 6 is 8-aminocaprylate; when R2 is methyl or ethyl, compound 6 is 8-aminocaprylate; The steps include: Step 1: Suberic acid is cyclized with acetic anhydride and then ring-opened with alcohol to obtain compound 2; Step 2: Compound 2 reacts with ammonium bicarbonate under the activation of di-tert-butyl dicarbonate to obtain compound 3; Step 3: Compound 3 is imidized with di-tert-butyl dicarbonate to obtain compound 4; Step 4: Compound 4 is reduced under the conditions of sodium borohydride and boron trifluoride tetrahydrofuran to obtain compound 5; Step 5: Compound 5 is deprotected in acid to obtain compound 6; The step 1 includes two stages: in the first stage, the molar ratio of suberic acid, acetic anhydride, and 4-dimethylaminopyridine is 1:7.4:0.05, and the reaction temperature is 140-150°C; in the second stage, the molar ratio of suberic acid and triethylamine is 1:4.0, and the mass volume ratio of suberic acid, methanol, and toluene is 1:4.0:1.0, and the reaction temperature in the second stage is 50-60°C; In step 4, in the first stage, the molar ratio of compound 4, sodium borohydride, and boron trifluoride tetrahydrofuran is 1:1.6:1.6; in the second stage, the molar ratio of compound 4 to sodium hydroxide is 1:3.0, and the reaction temperature is 20-30°C, wherein R2 of compound 5 is H; in the compound 5 obtained without the addition of sodium hydroxide, R2 is methyl or ethyl.

2. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, wherein: In the step 2, the molar ratio of compound 2, di-tert-butyl dicarbonate, ammonium bicarbonate, and pyridine is 1: 1.1: 2.0: 0.1; the reaction temperature is 10-20° C.; and the solvent is tetrahydrofuran.

3. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, wherein: In the step 3, the molar ratio of compound 3, di-tert-butyl dicarbonate, triethylamine, and DMAP is 1: 1.1: 1.5: 0.1; the reaction temperature is 20-30° C.; and the reaction solvent is tetrahydrofuran.

4. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, wherein: In the step 5, the volume ratio of xylene to acid is 1: 1.0-3.0; the reaction temperature is 80-90° C.; and the reaction solvent is xylene.

5. A method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate, comprising first preparing 8-aminocaprylate or 8-aminocaprylate ester salt by the method of claim 1, and then synthesizing 8-aminocaprylate or 8-aminocaprylate ester salt as a raw material according to the following route: ， in, Acid is one of an inorganic acid or an organic acid; the inorganic acid is one of hydrochloric acid, sulfuric acid, and phosphoric acid; the organic acid is one of benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid; R2 is one of H, methyl, and ethyl; When R2 is H, compound 6 is 8-aminocaprylate; when R2 is methyl or ethyl, compound 6 is 8-aminocaprylate; Compound is a salicylic acid derivative, X is one of halogen, OH, OMe, and OEt; The steps include: Step 6: Compound 6 undergoes condensation reaction with a salicylic acid derivative in the presence of a base to obtain compound 7; Step 7: Compound 7 is neutralized with sodium hydroxide, sodium bicarbonate or sodium carbonate to obtain SNAC.

6. The method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate according to claim 5, wherein: In the step six: 1) When the salicylic acid derivative is salicylate, i.e., X is OMe or OEt: the reaction solvent is methanol, the base is sodium methoxide; the molar ratio of compound 6, salicylate, and sodium methoxide is 1:1.0:4.5, and the reaction temperature is 65°C; 2) When the salicylic acid derivative is salicylic acid, i.e., X is OH: the reaction solvent is toluene, and the base is triethylamine; the reaction is divided into two stages: in the first stage, the molar ratio of compound 6, condensing agent, and triethylamine is 1:2.0:2.2; the reaction temperature is 10-20°C; in the second stage, the molar ratio of compound 6 and triethylamine is 1:3.3, and the reaction temperature is 90-100°C; the condensing agent is one of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, and pivaloyl chloride; 3) When the salicylic acid derivative is a salicylic acid halide, that is, X is a halogen: the reaction solvent is dichloromethane, the base is triethylamine; the molar ratio of compound 6 to triethylamine is 1:3.3; and the reaction temperature is 0-10°C.

7. The method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate according to claim 5, wherein: In step seven, the molar ratio of compound 7 to sodium hydroxide is 1:1.0; the reaction temperature is 45-55° C.; and the reaction solvents are isopropanol and water.

8. A method for preparing suberic acid monoester from suberic acid, comprising first reacting suberic acid with acetic anhydride at 140-150°C to form a cyclic transition state, followed by ring opening with methanol or ethanol at 50-60°C to obtain compound 2. The preparation route is as follows: ， Wherein R1 is methyl or ethyl.

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