Novel synthesis method of 8-(2-hydroxybenzamido) sodium caprylate

Abstract

The invention discloses a novel synthesis method of 8-(2-hydroxybenzamido) sodium caprylate, and belongs to the technical field of medicine synthesis. Comprising the following steps: cyclizing suberic acid and acetic anhydride, and performing ring opening with alcohol to obtain a compound 2; the compound 2 reacts with ammonium bicarbonate under activation of di-tert-butyl dicarbonate to obtain a compound 3; carrying out imidization on the compound 3 and di-tert-butyl dicarbonate ester to obtain a compound 4; reducing the compound 4 under the condition of sodium borohydride and boron trifluoride tetrahydrofuran to obtain a compound 5; deprotecting the compound 5 in acid to obtain a compound 6; carrying out condensation reaction on the compound 6 and a salicylic acid derivative in the presence of alkali to obtain a compound 7; and hydrolyzing the compound 7 in alkali to obtain SNAC. The method has the advantages of cheap and easily available main raw materials, high yield in each step, low total cost, mild conditions and simple operation, and is suitable for large-scale industrial production; according to the method, multiple products can be obtained, the product purity is high, the product line is flexible, and the method has good application prospects.

Description

Technical Field

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

[0002] Sodium 8-(2-hydroxybenzamido) caprylate (SNAC for short) 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] SNAC is a non-covalent chelating agent based on the structure of salicylic acid. Its molecular design achieves enhanced drug lipophilicity and local pH regulation and protection through amphiphilic structure design. SNAC forms non-covalent complexes with target drugs (such as peptides and polysaccharides), masking their hydrophilic groups, thereby enhancing transcellular passive permeability. In the gastric environment, SNAC temporarily increases the local microenvironment pH by binding to the drug, inhibiting pepsin activity and reducing drug degradation. In addition, SNAC has obvious safety advantages. No mucosal damage or long-term toxicity has been observed in clinical practice, breaking through the bottleneck of toxic and side effects of traditional promoters.

[0004] SNAC has achieved technological transformation in many 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 treatable level, and a daily dose of 2.5 mg can achieve blood sugar control and weight management. In terms 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 terms of heparin and insulin delivery, 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.

[0005] The synthesis methods of SNAC reported in the literature can be summarized into three methods.

[0006] Method 1 is to use the formate ester of salicylic acid amide as raw material, undergo substitution reaction with ethyl 8-bromooctanoate, and then hydrolyze with sodium hydroxide to obtain SNAC (CN114195730). The limitation of this method is that the key raw material ethyl 8-bromooctanoate is expensive, difficult to obtain, and has a high cost.

[0007] Method 2 is to use 8-aminocaprylic acid as the key raw material to undergo a condensation reaction with methyl salicylate, and then hydrolyze with sodium hydroxide to obtain SNAC. This method is an original research method and is also the method adopted by most pharmaceutical companies (WO2022 / 162132). However, the synthesis process of 8-aminocaprylic acid reported in the literature has the following limitations: some do not have a purification operation, which will result in 8-aminocaprylic acid containing inorganic salts with low purity (CN 118307424); in order to purify 8-aminocaprylic acid, other reagents such as di-tert-butyl dicarbonate are added, and then the salt is dissolved to obtain free 8-aminocaprylic acid. The extra purification steps will lose the yield and increase the raw material cost of 8-aminocaprylic acid (CN 118561711).

[0008] Method three is to use the salt of 8-aminocaprylic acid as the key raw material to react with salicylic acid derivatives to prepare SNAC. Currently, there are few literatures using the salt of 8-aminocaprylic acid as a substrate. Patent CN 111978193 uses N,N-carbonyldiimidazole (CDI) as a condensation agent to condense 8-aminocaprylic acid ethyl ester hydrochloride with salicylic acid to obtain SNAC. The problem with this process is that the condensation agent CDI is relatively expensive and has low atom economy. Imidazole will cause harm to the environment, especially water bodies, making waste liquid treatment difficult, which does not conform to the concept of green chemistry. Summary of the invention

[0009] Technical problems solved by the present invention: The current synthesis method of sodium 8-(2-hydroxybenzamido)octanoate mainly uses 8-bromooctanoate ethyl ester or 8-aminooctanoic acid as key raw materials. The material cost of 8-bromooctanoate ethyl ester is relatively high, resulting in a high production cost of SNAC, which is difficult to support commercial competition under high intensity. 8-aminooctanoic acid is prone to intermolecular dimerization and is not easy to remove. The operation of obtaining high-purity 8-aminooctanoic acid is relatively cumbersome, and it needs to be purified by di-tert-butyl dicarbonate and desalting steps, which will cause product loss and other problems.

[0010] Analysis of the above issues: 8-aminocaprylic acid is prepared from the hydrolysis of 8-aminocaprylic acid salt. From the perspective of chemical synthesis, the best solution is to use the precursor of 8-aminocaprylic acid, that is, the salt of 8-aminocaprylic acid as a substrate. The advantage of this strategy is that the cost of 8-aminocaprylic acid salt is lower, and the step of preparing 8-aminocaprylic acid by hydrolysis can be omitted, thereby further reducing the cost of raw materials, and 8-aminocaprylic acid salt can be precipitated from the system with higher purity; from the perspective of preparing SNAC, using 8-aminocaprylic acid salt as a substrate is better than 8-aminocaprylic acid ester salt, because 8-aminocaprylic acid ester salt is easy to produce intermolecular amine ester exchange impurities during the condensation process with salicylic acid fragments, affecting the quality of the final product SNAC.

[0011] The technical solution of the present invention is as follows: 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: , 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; R 1 is methyl or ethyl, R 2 is one of H, methyl, and ethyl; When R 2 When R is H, compound 6 is 8-aminocaprylate; when R 2 When it 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 is reacted 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.

[0012] A method for synthesizing sodium 8-(2-hydroxybenzamide) caprylate SNAC, using 8-aminocaprylate or 8-aminocaprylate ester as a raw material, and the synthesis path 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, preferably hydrochloric acid; the organic acid is one of benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid; R 2 is one of H, methyl and ethyl, preferably H; When R 2 When R is H, compound 6 is 8-aminocaprylate; when R 2 When it 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 halogen is preferably Cl; The steps include: Step 6: When compound 6 is 8-aminocaprylic acid 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 8-aminocaprylic acid ester 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; Step 7: Compound 7 is neutralized with sodium hydroxide, sodium bicarbonate or sodium carbonate to obtain SNAC.

[0013] Furthermore, step one includes two stages: in the first stage, the molar ratio of suberic acid, acetic anhydride, and 4-dimethylaminepyridine 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.

[0014] Furthermore, 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.

[0015] Furthermore, in the step three: 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.

[0016] Further, in the 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 to obtain R in compound 5 2 is H; R in compound 5 obtained without adding sodium hydroxide 2 It is methyl or ethyl.

[0017] 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.

[0018] Furthermore, in step six: 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; 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, condensation 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; wherein the condensation agent is one of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, and pivaloyl chloride; 3) When the salicylic acid derivative is 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; the reaction temperature is 0-10°C.

[0019] 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.

[0020] 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 method for preparing a monoester of suberic acid from suberic acid comprises firstly forming a cyclic transition state by reacting suberic acid with acetic anhydride at a high temperature, and then ring-opening the monoester with an alcohol, and the preparation route is as follows: , 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.

[0021] Beneficial effects: (1) This patent provides a new method for synthesizing 8-aminocaprylic acid or its ester salt and SNAC. The main raw materials of this process are cheap and easy to obtain, the yield of each 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 product obtained by this process is very pure, the purity of 8-aminocaprylic acid hydrochloride is>99.90%, the purity of SNAC is>99.90%, and the color is pure white; (2) This patented method can obtain multiple products with high purity, including 8-aminocaprylic acid hydrochloride, 8-aminocaprylic acid methyl ester hydrochloride, 8-aminocaprylic acid ethyl ester hydrochloride and SNAC, etc. This method has a flexible product line and good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the HNMR of compound 6c.

[0023] Figure 2 This is the liquid chromatography of compound 6c.

[0024] Figure 3 is the HNMR of compound 6a.

[0025] Figure 4 This is the liquid chromatography of compound 6a.

[0026] Figure 5 is the HNMR of compound 6b.

[0027] Figure 6 This is the liquid chromatography of compound 6b.

[0028] Figure 7 is the HNMR of SNAC.

[0029] Figure 8 Liquid chromatography of SNAC. DETAILED DESCRIPTION

[0030] In order to make the technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described in conjunction with the embodiments below. If no specific conditions are specified in the embodiments, the conditions are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products or services that can be purchased commercially.

[0031] A specific reaction route for synthesizing SNAC is given below, as shown below:

[0032] Example 1 - Preparation of Compound 2a

[0033] Suberic acid (100.0 g, 0.574 mol, 1.0 eq), acetic anhydride (434.8 g, 4.258 mol, 7.4eq), 4-dimethylaminopyridine (DMAP) (3.51 g, 0.029 mol, 0.05eq) were added to the reaction flask, and the reaction was completed at 140-150℃ under nitrogen protection. The acetic anhydride and acetic acid were concentrated under reduced pressure, and the residue was added toluene (100 mL) and stirred to dissolve. The solution was slowly dripped into a mixture of methanol (400 mL) and triethylamine (231.9 g, 2.296 mol, 4.0 eq), and the temperature was controlled at 10-20℃. After the dripping, the reaction was continued at 50-60℃ for 6 h. The solvent was concentrated under reduced pressure, water (500 mL) was added, pH=3 was adjusted with 3N HCl, and 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) with a yield of 92%.

[0034] Example 2 - Preparation of Compound 3a

[0035] 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 the reaction flask. Di-tert-butyl dicarbonate (41.5 g, 0.526 mol, 1.1 eq) was slowly added dropwise, the temperature was controlled at 10-20°C, and the reaction was continued for 12 hours after the addition. 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 obtain compound 3a (76.9 g, 0.411 mol) with a yield of 86%.

[0036] Example 3 - Preparation of Compound 4a

[0037] Compound 3a (70.0 g, 0.374 mol, 1.0 eq), DMAP (4.51 g, 0.037 mol, 0.1eq), triethylamine (56.7 g, 0.561 mol, 1.5 eq), and tetrahydrofuran (350 mL) were added to the reaction flask. Di-tert-butyl dicarbonate (89.7 g, 0.411 mol, 1.1 eq) was slowly added dropwise at a temperature of 20-30°C. After addition, 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 phases were separated. The aqueous phase was extracted with dichloromethane (350 mL). The organic phases were combined and concentrated under reduced pressure to obtain compound 4a (103.2 g, 0.359 mol) with a yield of 96%.

[0038] Example 4 - Preparation of Compound 5c

[0039] 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 in batches, boron trifluoride tetrahydrofuran (77.98 g, 0.557 mol, 1.6 eq) was added dropwise at 20-30°C, and the reaction was continued for 8 h. The reaction solution was poured into ice water (800 g) in batches, and the solvent was concentrated under reduced pressure. Water (400 g) and sodium hydroxide (41.76 g, 1.044 mol, 3.0 eq) were added to the concentrated residue and stirred at 20-30°C for 8 h. The reaction solution was extracted with ethyl acetate (300 mL) to remove impurities, and the aqueous phase was adjusted to pH = 2-3 with 3N HCl and extracted with ethyl acetate (400 mL x3). The organic phases were combined and concentrated under reduced pressure to give compound 5c (74.9 g, 0.289 mol) with a yield of 83%.

[0040] Example 5 - Preparation of Compound 5a

[0041] 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 in batches, boron trifluoride tetrahydrofuran (77.98 g, 0.557 mol, 1.6 eq) was added dropwise at 20-30°C, and the reaction was continued for 8 hours after the addition. The reaction solution was poured into ice water (800 g) in batches and the solvent was concentrated under reduced pressure. Water (400 g) was added to the concentrated residue, the aqueous phase was adjusted to pH = 2-3 with 3N HCl, and extracted with ethyl acetate (400 mL x3). The organic phases were combined and concentrated under reduced pressure to obtain compound 5a (80.9 g, 0.296 mol) with a yield of 85%.

[0042] Example 6 - Preparation of Compound 5b

[0043] 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 in batches, boron trifluoride tetrahydrofuran (77.98 g, 0.557 mol, 1.6 eq) was added dropwise at 20-30°C, and the reaction was continued for 8 hours after the addition. The reaction solution was poured into ice water (800 g) in batches and the solvent was concentrated under reduced pressure. Water (400 g) was added to the concentrated residue, the aqueous phase was adjusted to pH = 2-3 with 3N HCl, and extracted with ethyl acetate (400 mL x3). The organic phases were combined and concentrated under reduced pressure to obtain compound 5b (86.0 g, 0.299 mol) with a yield of 86%.

[0044] Example 7-Preparation of Compound 6c

[0045] Concentrated hydrochloric acid (140 mL) was added to the reaction flask, heated to 80-90°C, compound 5c (70.0 g, 0.270 mol, 1.0 eq) dissolved in xylene (140 mL) was added dropwise, reacted for 5 h, and cooled 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 were as follows: Figure 1 and 2 shown.

[0046] Example 8 - Preparation of Compound 6a

[0047] Concentrated hydrochloric acid (140 mL) was added to the reaction flask, heated to 80-90°C, compound 5a (73.8 g, 0.270 mol, 1.0 eq) dissolved in xylene (140 mL) was added dropwise, reacted for 5 h, and cooled 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 were as follows: Figure 3 and 4 shown.

[0048] Example 9 - Preparation of Compound 6b

[0049] Concentrated hydrochloric acid (140 mL) was added to the reaction flask, heated to 80-90°C, compound 5b (77.6 g, 0.270 mol, 1.0 eq) dissolved in xylene (140 mL) was added dropwise, reacted for 5 h, and cooled 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 were as follows: Figure 5 and 6 shown.

[0050] Example 10 - Preparation of Compound 7

[0051] Methanol (277 g) and 30% sodium methoxide (828 g, 4.599 mol, 4.5 eq) were added to the reaction flask. Compound 6c (200.0 g, 1.022 mol, 1.0 eq) was added in batches, and methyl salicylate (155.4 g, 1.022 mol, 1.0eq) was added. The temperature was raised to 65°C and the reaction was continued for 40 h. The temperature was lowered to 20°C, water (1000 g) was added, and the pH was adjusted to 4 with concentrated hydrochloric acid. The mixture was filtered and dried to obtain compound 7 (259.8 g, 0.930 mol) with a yield of 91%.

[0052] Example 11 - Preparation of Compound 7

[0053] Methanol (277 g) and 30% sodium methoxide (828 g, 4.599 mol, 4.5 eq) were added to the reaction flask. Compound 6c (200.0 g, 1.022 mol, 1.0 eq) was added in batches, and ethyl salicylate (169.9 g, 1.022 mol, 1.0eq) was added. The temperature was raised to 65°C and the reaction was continued for 40 h. The temperature was lowered to 20°C, water (1000 g) was added, and the pH was adjusted to 4 with concentrated hydrochloric acid. The mixture was filtered and dried to obtain compound 7 (259.5 g, 0.928 mol) with a yield of 91%.

[0054] Example 12 - Preparation of Compound 7

[0055] Add salicylic acid (100 g, 0.724 mol, 1.0 eq), triethylamine (160.9 g, 1.593 mol, 2.2 eq) and toluene (700 mL) to the reaction flask. Add methyl chloroformate (136.8 g, 1.448 mol, 2.0 eq) dropwise, control the temperature at 10-20°C, and react for 5 hours. Add compound 6c (141.7 g, 0.724 mol, 1.0 eq) and triethylamine (219.4 g, 2.172 mol, 3.3 eq), raise the temperature to 90-100°C and react for 10 hours. Lower the temperature to 20-30°C, wash with 3N HCl, and separate the liquids. The organic phase was concentrated under reduced pressure to remove the solvent, and 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 the aqueous phase to adjust the pH to 4, and the compound 7 (167.8 g, 0.601 mol) was obtained by filtration and drying with a yield of 83%.

[0056] Example 13 - Preparation of Compound 7

[0057] Add salicylic acid (100 g, 0.724 mol, 1.0 eq), triethylamine (160.9 g, 1.593 mol, 2.2 eq) and toluene (700 mL) to the reaction flask. Add ethyl chloroformate (157.1 g, 1.448 mol, 2.0 eq) dropwise, control the temperature at 10-20°C, and react for 5 hours. Add compound 6c (141.7 g, 0.724 mol, 1.0 eq) and triethylamine (219.4 g, 2.172 mol, 3.3 eq), raise the temperature to 90-100°C and react for 10 hours. Reduce the temperature to 20-30°C, wash with 3N HCl, and separate the liquids. The organic phase was concentrated under reduced pressure to remove the solvent, and 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, and the mixture was filtered and dried to obtain compound 7 (165.8 g, 0.594 mol) with a yield of 82%.

[0058] Example 14 - Preparation of Compound 7

[0059] Dissolve salicylic acid chloride (160.0 g, 1.022 mol, 1.0 eq) in dichloromethane (500 mL) and drop into 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), and control the temperature at 0-10°C. After reacting for 6 hours, pour into 3N HCl for extraction. The organic phase is concentrated under reduced pressure to remove the solvent to obtain compound 7 (225.5 g, 0.807 mol), with a yield of 79%.

[0060] Example 15 - Preparation of Compound 7

[0061] Add salicylic acid (100 g, 0.724 mol, 1.0 eq), triethylamine (160.9 g, 1.593 mol, 2.2 eq) and toluene (700 mL) to the reaction flask. Add pivaloyl chloride (174.6 g, 1.448 mol, 2.0 eq) dropwise, control the temperature at 10-20°C, and react for 5 hours. Add compound 6c (141.7 g, 0.724 mol, 1.0 eq) and triethylamine (219.4 g, 2.172mol, 3.3 eq), raise the temperature to 90-100°C and react for 10 hours. Reduce the temperature to 20-30°C, wash with 3N HCl, and separate the liquids. The organic phase was concentrated under reduced pressure to remove the solvent, and 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, and the product was filtered and dried to obtain compound 7 (151.7 g, 0.543 mol) with a yield of 75%.

[0062] Example 16 - Preparation of Compound 7

[0063] Methanol (277 g) and 30% sodium methoxide (828 g, 4.599 mol, 4.5 eq) were added to the reaction flask. Compound 6a (214.3 g, 1.022 mol, 1.0 eq) was added in batches, and methyl salicylate (155.4 g, 1.022 mol, 1.0eq) was added. The temperature was raised to 65°C and the reaction was continued for 40 h. The temperature was 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, and the mixture was filtered and dried to obtain compound 7 (239.8 g, 0.858 mol) with a yield of 84%.

[0064] Example 17 - Preparation of SNAC

[0065] Compound 7 (200 g, 0.716 mol, 1.0 eq) and isopropanol (680 mL) were added to the 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 continued 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 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 is reacted 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.

2. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, characterized in that: The step 1 includes two stages: in the first stage, the molar ratio of suberic acid, acetic anhydride and 4-dimethylamine pyridine 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.

3. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, characterized in that: 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.

4. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, characterized in that: 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.

5. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, characterized in that: In the 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., and R2 in the compound 5 obtained is H; R2 in the compound 5 obtained without adding sodium hydroxide is methyl or ethyl.

6. The method for synthesizing 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt according to claim 1, characterized in that: 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.

7. A method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate, using the 8-aminocaprylic acid salt or 8-aminocaprylic acid ester salt prepared according to claim 1 as a raw material, and the synthesis path is as follows: ， 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.

8. A method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate according to claim 7, characterized in that: In step six: 1) When the salicylic acid derivative is salicylate, that is, 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, that is, 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, condensation 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; wherein the condensation agent is one of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, and pivaloyl chloride; 3) When the salicylic acid derivative is 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.

9. A method for synthesizing sodium 8-(2-hydroxybenzamido)octanoate according to claim 7, characterized in that: In the 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.

10. A method for preparing suberic acid monoester from suberic acid, firstly, suberic acid and acetic anhydride form a cyclic transition state at high temperature, and then the monoester is obtained by alcohol ring opening. The preparation route is as follows: ， Wherein R1 is methyl or ethyl.

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