Compound containing fatty acid salt structure and solid composition and application thereof

Abstract

The invention provides a compound containing a fatty acid salt structure as well as a solid composition and application of the compound. The chemical structural general formula of the compound is as shown in formulas (I), (II), (III) and (IV): # imgabs0. In addition to being used as an oral accelerator of polypeptide or protein drugs to improve oral bioavailability and contribute to oral absorption of the polypeptide or protein drugs, the pharmaceutical composition can also be used as an auxiliary material to improve tablet compressibility, the hardness of the obtained tablet meets expectation, the disintegration time is ideal, and the dissolution characteristic meets the requirement.

Description

Technical Field

[0001] The present invention belongs to the field of drug development, and specifically relates to four types of aromatic derivatives containing fatty acid salt structures and solid compositions and applications thereof. The solid compositions composed of aromatic derivatives and polypeptide drugs can meet the clinical application of oral administration of polypeptide drugs. Background Art

[0002] Compared with small molecule chemical drugs, protein and peptide drugs (PPDs) have the advantages of high biological activity, strong specificity, strong solubility and low toxicity. They treat or prevent diseases by regulating physiological or pathological processes. With the rapid development of biotechnology, they are increasingly being developed and applied in the treatment of clinical diseases. Although parenteral administration is the most commonly used route of administration for PPDs, patient compliance is often poor. Compared with injection, oral administration has advantages in patient compliance, safety, long-term dosage and manufacturing cost. However, compared with small molecule drugs, the widespread application of PPDs is limited by stability and absorption.

[0003] The development of new oral absorption-enhancing technologies has become a way to improve the bioavailability of PPDs, and the number of oral peptide and protein preparations currently launched is increasing. From 2001 to 2006, Emisphere, a US company, conducted the first Phase I and Phase II clinical trials of oral insulin preparations, and the studies showed that there was no significant difference between oral preparations and placebo. In 2014, ORMD-0801, developed by Oramed, an Israeli company, was approved by the US FDA for Phase III clinical trials. Emisphere has developed an oral absorption enhancer, sodium N-[8-(2-hydroxybenzamido)] caprylate (SNAC), which was first used to improve the oral absorption of insulin and was eventually used to improve the oral absorption of semaglutide. In 2019, semaglutide tablets (trade name Rybelsus), the world's first oral glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk of Denmark, were approved by the US FDA for the treatment of type 2 diabetes. Subsequently, in 2020, octreotide oral enteric-coated capsules (trade name Mycapssa) were prepared by introducing transient permeability enhancer (TPE) technology and were also approved by the US FDA.

[0004] However, there are currently few types of oral polypeptide absorption enhancers used clinically, and the bioavailability of the oral polypeptide absorption enhancers that have been marketed is low, only 1-3%. At the same time, the coefficient of variation is extremely large, which greatly affects the clinical use effect of polypeptide drugs. Therefore, the development of new oral absorption enhancers has important clinical application value. Summary of the invention

[0005] In order to overcome the shortcomings and deficiencies of the prior art, the present invention aims to provide an aromatic derivative containing a fatty acid salt structure and a solid composition and application thereof. The compound molecules have the dual characteristics of hydrophilicity and lipophilicity and can be used as an oral absorption enhancer for polypeptide and protein biomacromolecules.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] The first object of the present invention is to provide four types of aromatic derivatives containing fatty acid salt structures, whose general chemical structures are shown in formula (I), (II), (III) and (IV):

[0008]

[0009] In the compound of formula (I):

[0010] When X 1 =C, R 1 =OH, n = 5, 6 or 11, when n = 5, 11, R 2 =-COONa, when n = 6, R 2 =-SO 3 Na;

[0011] When X 1 =N, R 1 =NH 2 , n = 7, R 2 =-COONa;

[0012] In the compound described by formula (II):

[0013] n = 5, 7;

[0014] In the compound of formula (III):

[0015] When R 1 =H, n=5, 7, two identical side chain substituents are located at the meta position and ortho position; when n=5, two identical side chain substituents are located at the ortho position; when n=7, two identical side chain substituents are located at the ortho position and meta position;

[0016] When R 1 =-OH, n = 7, and two identical side chain substituents are located at the meta position;

[0017] In the compound of formula (IV):

[0018] n=5,7.

[0019] Further, the compound structure is shown below:

[0020]

[0021]

[0022]

[0023] The second object of the present invention is to provide the use of the above four types of aromatic derivatives containing fatty acid salt structures or their pharmaceutically acceptable salts in oral absorption enhancers for polypeptide or protein drugs.

[0024] The third object of the present invention is to provide a pharmaceutical composition comprising any one or a combination of the above four types of aromatic derivatives containing fatty acid salt structures or pharmaceutically acceptable salts thereof.

[0025] Furthermore, the pharmaceutically acceptable salt is a combination of one or more of sulfate, carboxylate, oxalate, maleate, fumarate, succinate, gluconate, tartrate, and pyruvate.

[0026] Furthermore, the D90 particle size range of the four types of aromatic derivatives containing fatty acid salt structures or pharmaceutically acceptable salts thereof is 70 to 180 μm;

[0027] Preferably, the D90 particle size range of the four types of aromatic derivatives containing fatty acid salt structures or pharmaceutically acceptable salts thereof is 90 to 160 μm.

[0028] Furthermore, the pharmaceutical composition also includes a polypeptide or protein biomacromolecule drug;

[0029] Preferably, the polypeptide and protein biomacromolecule drugs are GLP-1 receptor agonists or GLP-1 receptor agonist analogs.

[0030] The fourth object of the present invention is to provide the use of the above four types of aromatic derivatives containing fatty acid salt structures or their pharmaceutically acceptable salts or the above pharmaceutical compositions in the preparation of drugs for treating type II diabetes, obesity or non-alcoholic fatty liver disease.

[0031] The fifth object of the present invention is to provide a method for preparing the above four types of aromatic derivatives containing fatty acid salt structures, the preparation method comprising the following steps:

[0032] The preparation method of the compound of formula (I) is:

[0033] (1) using 1,3-benzoxazine-2,4-dione, ethyl 6-bromohexanoate / bromoethanol and sodium carbonate as raw materials and DMF as solvent, reacting at 70° C. to generate the corresponding amide ester intermediate A; or

[0034] Using 12-aminododecanoic acid and 2-(formyl chloride) phenyl acetate as raw materials and water as solvent, in the presence of sodium hydroxide to prepare intermediate A; or

[0035] Using 8-aminooctanoic acid methyl ester hydrochloride and 2-aminopyridine-3-carboxylic acid as raw materials and DMF as solvent, in the presence of diisopropylethylamine, HATU and DIPEA, intermediate A was prepared;

[0036] (2) using the amide ester intermediate A of step (1) as a raw material, hydrolyzing the ester in the presence of sodium hydroxide solution and hydrochloric acid to prepare an amide fatty acid intermediate B;

[0037] (3) using the amide fatty acid intermediate B of step (2) and sodium bicarbonate as raw materials and water as solvent to prepare an amide fatty acid salt product of formula (I);

[0038] The preparation method of the compound described in formula (II) is:

[0039] (1) using difatty acid monoester and aminophenol as raw materials and dichloromethane as solvent, reacting at room temperature to generate the corresponding amide ester intermediate A;

[0040] (2) using the amide ester intermediate A of step (1) as a raw material, using methanol as a solvent, and hydrolyzing the ester in the presence of sodium hydroxide and hydrochloric acid to prepare an amide fatty acid intermediate B;

[0041] (3) using the amide fatty acid intermediate B of step (2) and sodium bicarbonate as raw materials and water as solvent to prepare an amide fatty acid salt product of formula (II);

[0042] Preferably, when n=7, the difatty acid monoester described in step (1) is azelaic acid monomethyl ester, and when n=5, it is pimelic acid monomethyl ester;

[0043]

[0044] The preparation method of the compound of formula (III) is:

[0045] (1) using amino fatty acid and alcohol as raw materials and thionyl chloride as solvent, reacting under heating conditions to generate the corresponding fatty acid ester amine salt intermediate B;

[0046] (2) using the fatty acid ester amine salt intermediate of step (1), phthalic acid or phthaloyl chloride as raw materials, using dichloromethane as solvent, and preparing a phthalamide intermediate C in the presence of triethylamine or HATU or DIPEA;

[0047] (3) using the phthalamide intermediate C of step (2) as a raw material, water or ethanol as a solvent, and preparing the phthalamide intermediate D in the presence of sodium hydroxide or Pd / C and hydrogen;

[0048] (4) using the phthalamide intermediate D of step (3) as a raw material and water as a solvent, in the presence of sodium hydroxide or sodium bicarbonate, to prepare the phthalamide product E of formula (III);

[0049] Preferably, when n=7, the amino fatty acid described in step (1) is 8-aminooctanoic acid, and when n=5, the amino fatty acid described in step (1) is 6-aminohexanoic acid;

[0050] Preferably, the phthalic acid in step (2) is phthalic acid or 2-hydroxyisophthalic acid;

[0051] Preferably, the phthaloyl chloride in step (2) is phthaloyl chloride;

[0052] The specific synthesis route is as follows:

[0053]

[0054] The preparation method of the compound of formula (IV) is:

[0055] (1) using phthalic anhydride and amino fatty acid as raw materials and acetic acid as solvent, reacting at 145° C. to generate the corresponding phthalimido fatty acid intermediate B;

[0056] (2) Using the phthalimido fatty acid product B of step (1) and sodium bicarbonate as raw materials, acetone and water as solvents, and preparing the phthalimido fatty acid sodium product C at 0-10°C.

[0057] Preferably, when n=7, the amino fatty acid described in step (1) is preferably 8-aminooctanoic acid, and when n=5, the amino fatty acid described in step (1) is 6-aminohexanoic acid.

[0058] The specific synthesis route is as follows:

[0059]

[0060] The technical solution of the present invention has the following beneficial effects compared with the prior art:

[0061] The four types of aromatic derivatives containing fatty acid salt structures described in the present invention can not only serve as oral enhancers for polypeptide or protein drugs to improve oral bioavailability and facilitate oral absorption of polypeptide or protein drugs, but also as excipients to improve tablet compressibility. The hardness of the obtained tablets meets expectations, the disintegration time is ideal, and the dissolution characteristics meet the requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 : Drug concentration-time curve of semaglutide enteric-coated capsules (WXBD-024 excipient);

[0063] Figure 2 : Drug concentration-time curve of semaglutide enteric-coated capsules (WXBD-029 excipient); DETAILED DESCRIPTION

[0064] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0065] The synthesis of four Class I compounds is described below in conjunction with the examples.

[0066] Example 1: Synthesis of Compound 1

[0067]

[0068] Synthesis of intermediate A: 1,3-benzoxazine-2,4-dione (10.0 g, 61.3 mmol), ethyl 6-bromohexanoate (13.76 g, 54.8 mmol) and sodium carbonate (13.0 g, 122.7 mmol) were added to 150 ml of DMF solution. The mixed solution was stirred at 70 ° C for 10 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to 15 ° C and then poured into 150 ml of water. The aqueous phase was extracted with dichloromethane (2×100 ml), the organic phase was collected, and concentrated under reduced pressure at 45 ° C to obtain a crude product. The crude product was separated by column with petroleum ether / ethyl acetate (70:30) to obtain 15.1 g of intermediate A. LC-MS (ESI) calcd for C 16 H 20 NO 5 , [M+H] + m / z 306.1341, found 306.

[0069] Synthesis of intermediate B: Intermediate A (17 g, 55.7 mmol) and sodium hydroxide solution (139.3 ml, 278.4 mmol) were heated to reflux at 95°C for 5 h. After the reaction was completed, the reaction solution was cooled to 15°C, the pH was adjusted to 2-3 with hydrochloric acid solution, filtered, the solid was collected, and freeze-dried to obtain 19.8 g of intermediate B. LC-MS (ESI) calculation for C 13 H 18 NO 4 ,[M+H] + m / z 252.1236, found 252. 1 H NMR (400MHz, DMSO-d6) δ12.7(s,1H),11.98(s,1H),8.7(s,1H),7.8(m,1H),7.4(m,1H),6.85(m,2H),3.25(m,2H),2.18(m,2H),1.65-1.20(m,6H).

[0070] Synthesis of compound 1: Intermediate B (19.638 g, 78.2 mmol), NaHCO 3 A mixed solution of (6.57 g, 78.2 mmol) and 200 ml of water was stirred at 45°C for 2 hours. The reaction mixture was then stirred at 45°C under reduced pressure for 3 hours. Finally, the reaction solution was cooled to 15-20°C, filtered, and the filtrate was freeze-dried to obtain 19.1 g of a white solid. LC-MS (ESI) calculation for C 13 H 17 NNaO 4 ,[M+H] + m / z 274.1055, found 274. 1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.81-7.78(m,1H),7.17-7.15(m,1H),6.77-6.75(m,1H), 6.60-6.56(m,1H),3.28-3.24(m,2H),2.04-2.01(m,2H),1.52-1.47(m,4H),1.33-1.29(m,2H).

[0071] Example 2: Synthesis of Compound 2

[0072]

[0073] Synthesis of intermediate A: 1,3-benzoxazine-2,4-dione (20 g, 122.4 mmol), 6-bromohexanol (20 g, 110.4 mmol) and sodium carbonate (26.2 g, 247.2 mmol) were added to 200 ml of DMF solution. The mixed solution was stirred at 70 ° C for 18 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to 15 ° C and then poured into 1000 ml of water. Filter, collect the white solid, and freeze-dry to obtain 18 g of white solid, namely intermediate A. LCMS (ESI) calculation for C 14 H 17 NO 4 [M+H] + m / z264.3, found264.

[0074] Synthesis of intermediate B: At 0-5°C, under nitrogen protection, add chlorosulfonic acid (13.28g, 114mmol) to a dichloromethane solution (145ml) of intermediate A (20g, 76.0mmol) and triethylamine (11.54g, 114mmol). The reaction solution was stirred at 15-20°C for 4h, cooled to 15°C after the reaction, and then poured into 150ml of water. The aqueous phase was extracted with a mixed solvent of dichloromethane / methanol (10:1) (2×150ml). The organic phase was collected and concentrated under reduced pressure at 45°C to obtain a crude product. The crude product was separated by column with a mixed solvent of dichloromethane / methanol (10:1) to obtain 28.7g of solid, i.e., intermediate B. LCMS (ESI) calculation for C 14 H 17 NO 7 S[M+H] + m / z 344.3, found 344.

[0075] Synthesis of Intermediate C: After the reaction, the reaction solution was poured into 100 ml of water, and the aqueous phase was extracted twice with dichloromethane. The pH of the aqueous phase was adjusted to pH 2, and then sodium chloride was added until the aqueous phase reached saturation. Finally, the aqueous phase was extracted twice with acetonitrile, and the acetonitrile was removed by vacuum concentration, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent to obtain 15.8 g, which is Intermediate C. LCMS (ESI) calculation for C 13 H 19 NO 6 S[M+H] + m / z 318.3, found 318. 1H NMR (400MHz, DMSO-d6) δ8.84(t,J=5.2Hz,1H),7.85(d,J=8.2Hz,1H),7.39(t,J=7.7Hz,1H),6.87(t ,J=7.3Hz,2H),3.69(t,J=6.5Hz,2H),3.28(dd,J=13.0,6.6Hz,2H),1.59-1.44(m,4H),1.32(s,4H).

[0076] Synthesis of compound 2: Intermediate C (15.5 g, 48.8 mmol), NaHCO 3 A mixed solution of (4.1 g, 48.8 mmol) and 300 ml of water was stirred at 25°C for 3 h. After the reaction was completed, the mixture was filtered and the filtrate was freeze-dried to obtain 15.7 g of a white solid. LCMS (ESI) calculation for C 13 H 19 NO 6 SNa[M+H] + m / z 340.3, found 318. 1 H NMR (400MHz, DMSO) δ9.89 (s, 1H), 7.83-7.73 (m, 1H), 7.20 (t, J = 7.1Hz, 1H), 6.85-6.5 2(m,2H),3.70(t,J=6.6Hz,2H),3.27(t,J=6.8Hz,2H),1.46(dd,J=42.5,36.3Hz,8H).

[0077] Example 3: Synthesis of Compound 3

[0078]

[0079] Synthesis of Intermediate A: A mixture of 12-aminododecanoic acid (31.5 g, 145 mmol) and sodium hydroxide (1 M, 400 mL) was mechanically stirred in an ice-water bath, and then 2-(formyl chloride) phenyl acetate (30 g, 151 mmol) was added in batches over 7 hours to keep the temperature of the reaction solution at 5°C. After the addition, the reaction was continued at 5°C for 12 hours. After the reaction was completed, the pH was adjusted to 6.5 with 1 M hydrochloric acid, filtered, and 16.5 g of solid was collected, namely Intermediate A. 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.77(m,1H),7.28(m,1H),6.85(m,1H),6 .65(m,1H),3.25(m,2H),2.18(m,2H),1.65-1.48(m,4H).1.43-1.15(m,14H).

[0080] Synthesis of compound 3: Intermediate A (16.5 g, 49.3 mmol) was added to 100 ml of isopropanol. NaOH (1.97 g, 49.3 mmol) was added under stirring at 50°C and then reacted for 2 h. The reaction solution was concentrated under reduced pressure and frozen to precipitate 17.1 g of a white solid. LCMS (ESI) calculation for C 19 H 30 NO 4 [M-Na+2H] + m / z 336.2175, found 336. 1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.77(m,1H),7.18(m,1H),6.85(m,1H),6 .65(m,1H),3.25(m,2H),2.18(m,2H),1.65-1.48(m,4H),1.43-1.15(m,14H).

[0081] Example 4: Synthesis of Compound 4

[0082]

[0083] Synthesis of Intermediate A: Add diisopropylethylamine (37.43 g, 36.2 mmol) to a DMF solution of 2-aminopyridine-3-carboxylic acid, then add HATU (19.27 g, 50.6 mmol) to activate for 30 minutes. Then add 8-aminooctanoic acid methyl ester hydrochloride (7.59 g, 36.2 mmol), and stir the reaction solution at 25°C overnight. After the reaction is completed, dilute the reaction solution with 90 ml of saturated brine and extract with ethyl acetate (3×50 ml). Collect the organic phase, dry it with anhydrous sodium sulfate, filter it, and distill it under reduced pressure to obtain a brown solid, namely Intermediate A. LCMS (ESI) calculation for C 15 H 24 N 3 O 3 [M+H] + m / z 294.1818, found 294.

[0084] Synthesis of Intermediate B: Add Intermediate A (25 g, 85 mmol) to a mixed solution of sodium hydroxide (3.4 g, 85 mmol) and 60 ml of tetrahydrofuran, and stir at room temperature overnight. Then adjust the pH of the reaction solution to 5-7 with acetic acid, filter, and obtain 13.5 g of Intermediate B solid. 1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.37(m,1H),8.07(m,1H),7.78(m,1H),6.95( s,2H),6.55(m,1H),3.25(m,2H),2.18(m,2H),1.65-1.48(m,4H).1.43-1.15(m,6H).

[0085] Synthesis of compound 4: Intermediate B (13.5 g, 15.6 mmol) was added to 100 ml of isopropanol. NaOH (0.624 g, 15.6 mmol) was added under stirring at 50°C and then reacted for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure and frozen to precipitate 14.0 g of a white solid product. LCMS (ESI) calculation for C 14 H 22 N 3 O 3 [M-Na+2H] + m / z 280.1661,found280.1H NMR(400MHz,DMSO-d6)δ8.47(m,1H),8.07(m,1H),7.78(m,1H),6.95(s,2H), 6.55(m,1H),3.25(m,2H),1.88(m,2H),1.65-1.48(m,4H),1.43-1.15(m,6H).

[0086] The synthesis of two Class II compounds is described below in conjunction with the examples.

[0087] Example 5: Synthesis of Compound 5

[0088]

[0089] Synthesis of intermediate A: Add methyl azelate (10 g, 49.48 mmol), diisopropylethylamine (10.65 g, 82.56 mmol) and HATU (18.8 g, 49.48 mmol) to a dichloromethane solution (225 ml) of 2-aminophenol (4.5 g, 41.28 mmol). Activate the reaction solution at 0 °C for 1 hour, then warm to room temperature and stir at room temperature for 8 hours. After the reaction is completed, add 200 ml of dichloromethane to the reaction solution. Wash the organic phase with water and precipitate with anhydrous MgSO 4 The crude product was obtained after drying and concentration under reduced pressure. The crude product was separated by column with petroleum ether / ethyl acetate (70:30) as eluent to obtain 28.8 g of product. 1H NMR (400 MHz, CDCl 3)δ7.48(s,1H),7.11-7.04(m,1H),7.03-6.97(m,2H),6.88-6.84(m,1H),3.67(s, 3H),2.48-2.44(m,2H),2.33-2.30(m,2H),1.74-1.59(m,4H),1.39-1.34(m,6H).

[0090] Synthesis of intermediate B: A mixture of intermediate A (28.8 g, 98.24 mmol), sodium hydroxide solution (2M, 110 mL) and methanol (50 mL) was stirred at 55°C for 5 h. After the reaction, the reaction solution was cooled to 15°C, the pH was adjusted to 2 with 2M hydrochloric acid solution, filtered, and the residue was separated by column, the eluent was dichloromethane / methanol (90:10), and 17 g was obtained. LCMS (ESI): calculated for C 15 H 22 NO 4 [M+H] + m / z 280.1549, found 280.

[0091] Synthesis of compound 5: Intermediate B (17 g, 60.9 mmol), NaHCO 3 A mixed solution of (5.12 g, 60.9 mmol) and 170 ml of water was stirred at 40°C for 2 hours. The reaction solution was then stirred at 45°C under reduced pressure for 4 hours. Finally, the reaction solution was cooled to 20°C, activated carbon was added for decolorization for 1 hour, filtered, and the filtrate was freeze-dried to obtain 15.5 g of a white solid. LCMS (ESI): calculation for C 15 H 22 NO 4 [M-Na+2H] + m / z 280.1549, found 280. 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),7.77-7.75(m,1H),6.86-6.78(m,2H),6.64-6 .60(m,1H),2.34-2.30(m,2H),1.91(m,2H),1.57-1.45(m,4H),1.39-1.26(m,6H).

[0092] Example 6: Synthesis of Compound 6

[0093]

[0094] Synthesis of Intermediate A: The method is the same as that of Example 5, except that monomethyl azelaic acid ester is replaced by monomethyl pimelate. LCMS (ESI) calculation for C 14 H 20 NO 4 [M+H] + m / z 266.1392, found 266.2.

[0095] Synthesis of intermediate B: The method is the same as that of the synthesis of intermediate B in Example 5, except that the corresponding intermediate A is replaced. 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.72(s,1H),9.24(s,1H),7.66(d,J=7.6Hz,1H),6.93(t,J=7.8Hz,1H),6.85(d,J =8.0Hz,1H),6.75(t,J=7.6Hz,1H),2.38(t,J=7.4Hz,2H),2.21(t,J=7.4Hz,2H),1.65-1.50(m,4H),1.39-1.26(m,2H).

[0096] Synthesis of compound 6: The method is the same as the synthesis of compound 5 in Example 5, except that the corresponding intermediate B is replaced. 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),7.77(d,J=7.6Hz,1H),6.84(t,J=7.2Hz,1H),6.74(d,J=7.6Hz,1H),6.63 (t,J=7.6Hz,1H),2.31(t,J=7.6Hz,2H),1.94(t,J=6.8Hz,2H),1.64-1.46(m,4H),1.30(dd,J=14.4,7.2Hz,2H).

[0097] The synthesis of four Class III compounds is described below in conjunction with examples, but the embodiments of the invention are not limited thereto.

[0098] Example 7: Synthesis of Compound 7

[0099]

[0100] Synthesis of intermediate A: 8-aminooctanoic acid (20.0, 125.7 mmol, 1 eq) was dissolved in 50 mL of methanol, and thionyl chloride (30 mL, 410 mmol, 3.3 eq) was added dropwise at 0°C. The mixture was heated under reflux overnight to react. After the reaction, the solvent was removed by rotary evaporation to obtain 21.2 g of a white solid. 1H NMR (400MHz, DMSO-d6) δ8.15(s,2H),4.5(s,1H),3.58(s,3H),2.75(m,2H),2.35(m,2H),1.48-1.44(m,4H),1.31-1.28(m,6H).

[0101] Synthesis of intermediate B: Dissolve isophthaloyl chloride (40 g, 193 mmol) in 100 ml of dichloromethane, then add dropwise to a dichloromethane solution (100 ml) containing 8-aminooctanoic acid methyl ester hydrochloride (85.4 g, 492 mmol) and triethylamine (99.2 g, 980 mmol) at 0°C. Warm the reaction solution to room temperature and stir overnight at room temperature to react. After the reaction is completed, remove the solvent by rotary evaporation to obtain 28.3 g of a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.6(m,2H),8.25(m,1H),7.9(m,2H),7.5(t,1H),3. 55(s,6H),3.25(m,4H),2.25(m,4H),1.48-1.44(m,8H),1.31-1.28(m,12H).

[0102] Synthesis of Intermediate C: Add Intermediate C (28.3 g, 59.5 mmol) to an aqueous solution of sodium hydroxide (5.96 g, 149 mmol). Stir the reaction solution overnight. Adjust the pH of the reaction solution to 1-2 with 2M hydrochloric acid, and filter to obtain 20.1 g of solid. 1 H NMR(400MHz,DMSO-d6)δ11.91(m,2H),8.6(m,2H),8.2(m,1H),7.9(m,2H),7.5( m,1H),3.26-3.21(m,4H),2..2(m,4H),1.48-1.44(m,8H),1.31-1.28(m,12H).

[0103] Synthesis of compound 7: Intermediate C (20.1 g, 45.2 mmol) was added to 50 ml of isopropanol. NaOH (1.81 g, 45.2 mmol) was added under stirring at 50°C and stirred for 2 hours. The solvent was removed by concentration under reduced pressure to obtain 18.6 g of a white solid. LCMS (ESI) calculation for C 24 H 37 N 2 O 6 [M-2Na+3H] + m / z 449.26, found 449. 1H NMR (400MHz, D2O) δ7.95(s,1H), 7.81(m,2H), 7.53-7.49(t,1H), 3.31-3.28(m,4H), 2.09-2.06(m,4H), 1.53-1.42(m,8H), 1.27-1.21(m,12H).

[0104] Example 8: Synthesis of Compound 8

[0105]

[0106] Synthesis of intermediate A: 2-hydroxyisophthalic acid (10 g, 54.9 mmol), HATU (50.1 g, 131 mmol) and diisopropylethylamine (42.576 g, 314.43 mmol) were dissolved in 500 ml of dichloromethane, stirred and reacted for 1 hour at 20-25 ° C under nitrogen protection, and then 8-aminooctanoic acid methyl ester hydrochloride (27.634 g, 131.77 mmol) was added and stirred and reacted for 72 hours at room temperature. After the reaction was completed, the reaction solution was cooled to 15 ° C and then poured into 150 ml of water. The aqueous phase was extracted with dichloromethane (2×100 ml), and the organic phase was collected and concentrated under reduced pressure at 45 ° C. The crude product was separated by column with ethyl acetate / petroleum ether (50:50) to obtain 10.1 g of solid. LCMS (ESI) calculation for C 26 H 41 N 2 O 7 [M+H] + m / z 493.62, found 493.

[0107] Synthesis of intermediate B: Add intermediate A (25 g, 51 mmol) to an aqueous solution of sodium hydroxide. Stir the reaction solution at 20°C for 2 hours. After the reaction, cool the reaction solution to 5°C, adjust the pH of the reaction solution to 2-3 with hydrochloric acid solution, filter, and separate the crude product with dichloromethane / methanol (90:10) to obtain 18 g of solid. LCMS (ESI) calculation for C 24 H 37 N 2 O 7 [M+H] + m / z 465.2601, found 465. 1H NMR(400MHz,DMSO-d6)δ14.91(s,1H),11.97(s,2H),8.74-8.72(m,2H),8.01-7.99(m,2H),7. 01-6.99(m,1H),3.30-3.29(m,4H),2.21-2.17(m,4H),1.55-1.51(m,8H),1.47-1.29(m,12H).

[0108] Synthesis of compound 8: Intermediate B (17 g, 36.6 mmol), NaHCO 3 A mixture of (6.15 g, 73.2 mmol) and 340 mL of water was stirred at 45°C for 2 h. Then, the mixture was stirred at 45°C under reduced pressure for 3 h. After filtration, 17.5 g of a white solid was obtained. LCMS (ESI) calculation for C 24 H 37 N 2 O 7 [M-2Na+3H] + m / z 465.26, found 465. 1 HNMR(400MHz,DMSO-d6)δ11.83-11.81(m,2H),7.80-7.78(m,2H),6.17-6.13(m,1 H),3.26-3.21(m,4H),2.04-2.00(m,4H),1.48-1.44(m,8H),1.31-1.28(m,12H).

[0109] Example 9: Synthesis of Compound 9

[0110]

[0111] Synthesis of intermediate A: 8-aminooctanoic acid (30 g, 188.4 mmol) was dissolved in benzyl alcohol [203.74 g, 1984 mmol], and thionyl chloride (72 g, 621.6 mmol) was added dropwise at 0°C. The mixture was reacted at 70°C for 4 hours. After the reaction, the reaction solution was poured into 1000 ml of petroleum ether to precipitate a white solid. The white solid was filtered and dried to obtain 38 g of a white solid. 1 H NMR (400MHz, DMSO) δ7.93 (s, 2H), 7.43-7.29 (m, 2H), 5.08 (s, 2H), 2.74 (d, J = 7.5H z, 1H), 2.35 (t, J = 7.4Hz, 1H), 1.53 (dd, J = 14.0, 7.0Hz, 2H), 1.26 (d, J = 1.4Hz, 3H).

[0112] Synthesis of intermediate B: Dissolve intermediate A (35.6 g, 124.2 mmol) and triethylamine (29.9 g, 295.5 mmol) in 200 ml of dichloromethane, add phthaloyl chloride (12 g, 59.1 mmol) dropwise at 0 ° C under nitrogen protection, and stir at 15 ° C for 4 hours. After the reaction, pour the reaction solution into 250 ml of water. The aqueous phase is extracted with dichloromethane (2×100 ml), and the organic phase is collected and concentrated under reduced pressure at 45 ° C. The crude product is separated by column with ethyl acetate / petroleum ether (50:50) to obtain 31 g of solid. LCMS (ESI) calculation for C 38 H 49 N 2 O 6 [M+H] + m / z 629.8, found 629.

[0113] Intermediate C: Add Intermediate B (30 g, 47.7 mmol) and Pd / C (2.03, 19 mmol) to 300 ml of ethanol, stir and react for 4 hours at room temperature under a hydrogen pressure of 1 atm. Filter, and concentrate the filtrate under reduced pressure at 45°C to obtain a crude product. The crude product was separated by column with dichloromethane / methanol (90:10) to obtain 18.8 g of solid. 1 H NMR (400MHz, DMSO) δ11.98 (s, 2H), 8.19 (t, J = 5.6Hz, 2H), 7.48-7.39 (m, 4H), 3.16 (dd,J=12.8,6.7Hz,4H),2.19(t,J=7.4Hz,4H),1.52-1.42(m,8H),1.28(s,12H).

[0114] Synthesis of compound 9: The method is the same as that of compound 8 in Example 8, except that the corresponding intermediate C is replaced. LCMS (ESI) calculation for C 24 H 37 N 2 O 6 [M-2Na+3H] + m / z 449.2652, found 449. 1 H NMR (400MHz, MeOD) δ7.41 (s, 4H), 3.24-3.17 (m, 4H), 2.06 (t, J = 7.6Hz, 4H), 1.51 (s, 8H), 1.29 (s, 12H).

[0115] Example 10: Synthesis of Compound 10

[0116]

[0117] Synthesis of intermediate A: 6-aminocaproic acid (50.0 g, 0.38 mol) was dissolved in benzyl alcohol (206 g, 1.91 mol), and thionyl chloride (150 g, 1.26 mol) was added dropwise at 0°C. The mixture was reacted at 70°C for 4 hours. After the reaction, the reaction solution was poured into 1000 ml of a mixed solution of petroleum ether / ethyl acetate in equal proportions to precipitate a white solid. The white solid was filtered and dried to obtain 69.4 g of a white solid. LCMS (ESI) calculation for C 13 H 20 NO 2 [M-HCl+H] + m / z 222.1494, found 222.15.

[0118] Synthesis of intermediate B: Dissolve intermediate A (40.0 g, 154 mmol) and triethylamine (38.9 g, 385 mmol) in 200 ml of dichloromethane, add phthaloyl chloride (14.7 g, 72.2 mmol) dropwise at 0 ° C under nitrogen protection, and stir at 15 ° C for 4 hours. After the reaction is completed, pour the reaction solution into 250 ml of water. The aqueous phase is extracted with dichloromethane (2×100 ml), and the organic phase is collected and concentrated under reduced pressure at 45 ° C. The crude product is separated by column with ethyl acetate / petroleum ether (50:50) to obtain 31 g of solid. 1 H NMR(400MHz, DMSO-d6)δ8.18(t,J=5.6Hz,2H),7.48-7.40(m,4H),7.39-7.27(m,10H),5.08(s,4H ),3.15(dd,J=12.8,6.8Hz,4H),2.36(t,J=7.2Hz,4H),1.63-1.52(m,4H),1.52-1.41(m,4H),1.40 -1.22(m,4H).

[0119] Synthesis of Intermediate C: Add Intermediate B (32 g, 55.9 mmol) and Pd / C (3.2 g) to 300 ml of ethanol, stir and react for 12 hours at room temperature under a hydrogen pressure of 1 atm. Filter, and concentrate the filtrate under reduced pressure at 45°C to obtain a crude product. The crude product was separated by column with dichloromethane / methanol (90:10) to obtain 20.9 g of solid. LCMS (ESI) calculation for C 24 H 37 N 2 O 6 [M-2Na+3H] + m / z 449.2652, found 449.1 H NMR (400MHz, MeOD) δ7.41 (s, 4H), 3.24-3.17 (m, 4H), 2.06 (t, J = 7.6Hz, 4H), 1.51 (s, 8H), 1.29 (s, 12H).

[0120] Synthesis of compound 10: NaHCO 3 The aqueous solution (100 ml) of (8.96 g, 107 mmol) was added dropwise to the aqueous solution (100 ml) of intermediate D4 (20.9 g, 53.3 mmol). The reaction solution was stirred at 20°C for 4 h. After the reaction was completed, the filtrate was lyophilized and dried under reduced pressure at 50°C for 3 days to obtain 22.5 g of a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.25(t,J=5.2Hz,2H),7.44(s,4H),3.15(dd,J=12.8,6.8Hz,4H),1.89(t,J=7.2Hz,4H),1.50-1.39(m,8H),1.32-1.22(m,4H).

[0121] The synthesis of two Class IV compounds is described in detail below:

[0122] Example 11: Synthesis of Compound 11

[0123]

[0124] Synthesis of intermediate A: Phthalic anhydride (10 g, 67.5 mmol), 8-aminooctanoic acid (16.1 g, 101.3 mmol) and 200 ml of acetic acid were heated and stirred at 145°C for 3 hours. After the reaction was completed, the reaction solution was evaporated at 55°C to remove the solvent to obtain a crude product. The crude product was dispersed in 125 ml of water, filtered, and the filter residue was collected and freeze-dried to obtain 15 g of a white solid. 1 H NMR (400MHz, DMSO) δ11.96(s,1H),7.92-7.78(m,4H),3.56(t,J=7.1Hz,2H),2.17(t,J=7.4Hz,2H),1.65-1.41(m,4H),1.25(d,J=10.2Hz,6H).

[0125] Synthesis of compound 11: NaHCO was added dropwise to an acetone solution (150 ml) of intermediate A (14.7 g, 50.8 mmol) at 5-10 °C. 3(4.27 g, 50.8 mmol) in aqueous solution (150 ml). After the addition was complete, the reaction solution was stirred at 20°C under reduced pressure for 4 hours. Filter, collect the filtrate, and freeze-dry to obtain 15.3 g of a white solid. LCMS (ESI) calculation for C 16 H 18 NO 4 Na[M+H] + m / z 312.3, found 312. 1 H NMR (400MHz, DMSO) δ7.92-7.77(m,2H),3.55(t,J=7.1Hz,2H),1.81(t,J=7.4Hz,1H),1.46(dq,J=21.5,7.1Hz,2H),1.20(dd,J=16.5,8.1Hz,3H).

[0126] Example 12: Synthesis of Compound 12

[0127]

[0128] Synthesis of intermediate A: Phthalic anhydride (20.0 g, 135 mmol), 6-aminocaproic acid (26.6 g, 202.5 mmol) and 400 ml of acetic acid were heated and stirred at 145 ° C for 3 hours. The reaction was monitored by LC-MS. After the reaction was completed, the reaction mixture was poured into 800 ml of water and slurried for 30 minutes. Filter, slurry the filter residue in 800 ml of water for 30 minutes, and repeat this filtering and slurrying step 3 times. The filter residue was dried under reduced pressure at 50 ° C for 2 days to obtain 33.7 g of white solid. 1 H NMR (400MHz, DMSO) δ11.97(s,1H),7.84(t,J=6.8Hz,4H),3.55(t,J=6.8Hz,2H),2.18(t,J=7.2Hz,2H),1.66-1.46(m,4H),1.36-1.18(m,2H).

[0129] Synthesis of compound 12: NaHCO was added dropwise to an acetone solution (200 ml) of intermediate A (20.0 g, 76.5 mmol) at 0 °C. 3 (6.43 g, 76.5 mmol) in an aqueous solution (200 ml). The reaction solution was stirred at 20°C under reduced pressure for 4 hours. The filtrate was collected by filtration, freeze-dried, and dried under reduced pressure at 50°C to obtain 21.27 g of a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ7.89-7.80(m,4H),3.54(t,J=7.2Hz,2H),1.83(t,J=7.6Hz,2H),1.61-1.50(m,2H),1.49-1.39(m,2H),1.29-1.17(m,2H).

[0130] Example 13: Particle size distribution of excipient compounds

[0131] The particle size distribution of the sample was measured using a laser particle size diffractometer. The results are shown in Table 1:

[0132] Table 1: Excipient compounds and API particle size test results

[0133]

[0134] The particle size of the auxiliary compound with a particle size close to or greater than 180 μm shown in Table 1 is controlled, and the target particle size distribution D90 is controlled to be approximately 70 to 180 μm, preferably 90 to 160 μm. The processing method and results are shown in Table 2:

[0135] Table 2: Particle size control studies of excipient compounds

[0136]

[0137] Subsequent experiments showed that the particle size of the excipient compound should be moderate so that the prepared oral solid preparation has better bioavailability. If the particle size distribution exceeds the expected range, its bioavailability will be affected.

[0138] Example 14: Preparation of compositions of different excipient compounds and semaglutide

[0139] The excipient compounds obtained in Examples 1 to 12 were respectively mixed with semaglutide according to the following prescription ratios to prepare oral solid tablets, and the physicochemical properties and in vitro dissolution behavior of the prepared tablets were tested.

[0140] The prescription design is as follows:

[0141]

[0142] According to the above prescription, the raw materials are prepared into tablets under the following process. According to the prescription amount, microcrystalline cellulose (101), povidone K90, magnesium stearate, semaglutide, and auxiliary compound are respectively passed through a 60-mesh sieve and put into a ziplock bag for manual mixing for 5 minutes, and the total mixed material is obtained after mixing; the material is placed in a tablet press, and the tablet weight is about 405 mg, and the expected target hardness is 80-100N.

[0143] The physical properties of the finished products are studied and the results are as follows:

[0144] Table 3: Physical properties of self-developed tablets with different excipient compounds and povidone dosage

[0145]

[0146]

[0147] By comparing the above test results, it can be seen that the above 12 different excipient compounds can prepare samples with similar expected formulation composition, appearance size and thickness.

[0148] The dissolution of the above tablets in pH 2.5 and pH 6.8 media was tested, wherein the dissolution medium of pH 2.5 was hydrogen phthalate buffer solution + 0.05% Brij35, and the dissolution medium of pH 6.8 was phosphate buffer solution + 0.05% Brij35, the medium volume was 500 ml, the temperature was controlled at 37±0.5°C, the paddle method was used, the rotation speed was 70 rpm, and the dissolution phenomenon of the semaglutide oral tablets that have been on the market was compared. The test results are as follows:

[0149] Table 4: Dissolution test results

[0150]

[0151] Through the comparison of dissolution tests, it can be seen that in the two groups of dissolution media, the self-developed tablets and the marketed semaglutide oral tablets have similar dissolution characteristics.

[0152] Example 15: Pharmacokinetic properties of semaglutide enteric-coated capsules prepared using WXBD-024 (code 6) as an excipient compound in rats

[0153] Four eight-week-old male SD rats weighing about 280 g were administered via the duodenum at a dose of two capsules (about 3.6 mg / kg) per rat. Whole blood was collected from the rats before administration and 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 hours after administration, and plasma was prepared. The plasma drug concentration was determined according to the method described in Tables 5 and 6.

[0154] Table 5: Chromatographic parameters (UPLC)

[0155]

[0156]

[0157] The pharmacokinetic curve of semaglutide enteric-coated capsules prepared with WXBD-024 excipients after intraduodenal administration in rats is shown in Figure 1 The pharmacokinetic parameters are shown in Table 7.

[0158] Table 7: Pharmacokinetic parameters of semaglutide enteric-coated capsules (n=4)

[0159]

[0160] Note: AUC and Cmax in the table are the geometric means of four rats.

[0161] Comprehensive drug concentration-time curve and pharmacokinetic parameters show that WXBD-024 excipient can improve the oral bioavailability of semaglutide more than the original excipient SNAC.

[0162] Example 16: Pharmacokinetic properties of semaglutide enteric-coated capsules prepared with WXBD-029 (code 12) as excipient in rats

[0163] The experimental animals, dosing, blood collection time points and detection methods were the same as those in Example 15.

[0164] The pharmacokinetic curve of semaglutide enteric-coated capsules prepared with WXBD-029 excipients after intraduodenal administration in rats is shown in Figure 2 The pharmacokinetic parameters are shown in Table 8.

[0165] Table 8: Pharmacokinetic parameters of semaglutide enteric-coated capsules (n=4)

[0166]

[0167] Note: AUC and Cmax in the table are the geometric means of four rats.

[0168] Comprehensive drug concentration-time curve and pharmacokinetic parameters show that semaglutide enteric-coated capsules prepared with WXBD-029 excipient are helpful for oral absorption of semaglutide API.

[0169] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Four types of aromatic derivatives containing fatty acid salt structures, characterized in that: Its general chemical structure is shown in formula (I), (II), (III), (IV): In the compound of formula (I): When X1=C, R1=OH, n=5, 6 or 11, when n=5, 11, R2=-COONa, when n=6, R2=-SO3Na; When X1=N, R1=NH2, n=7, R2=-COONa; In the compound described by formula (II): n＝5、7； In the compound of formula (III): When R1=H, n=5, 7, two identical side chain substituents are located at the meta position and ortho position; when n=5, two identical side chain substituents are located at the ortho position; when n=7, two identical side chain substituents are located at the ortho position and meta position; When R1 = -OH, n = 7, and two identical side chain substituents are located at the meta position; In the compound of formula (IV): n＝5、7。 2. The four types of aromatic derivatives containing fatty acid salt structures according to claim 1, characterized in that: The compound structure is shown below:

3. Use of the four types of aromatic derivatives containing fatty acid salt structures or pharmaceutically acceptable salts thereof as claimed in claim 1 in oral absorption enhancers for polypeptide or protein drugs.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises any one or a combination of multiple of the four types of aromatic derivatives containing fatty acid salt structures or pharmaceutically acceptable salts thereof as described in claim 1.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutically acceptable salt is a combination of one or more of sulfate, carboxylate, oxalate, maleate, fumarate, succinate, gluconate, tartrate, and pyruvate.

6. The pharmaceutical composition according to claim 4, characterized in that The D90 particle size range of the four types of aromatic derivatives containing fatty acid salt structures or their pharmaceutically acceptable salts is 70 to 180 μm. Preferably, the D90 particle size range of the four types of aromatic derivatives containing fatty acid salt structures or their pharmaceutically acceptable salts is 90 to 160 μm.

7. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition also includes a polypeptide or protein biomacromolecule drug. Preferably, the polypeptide and protein biomacromolecule drug is a GLP-1 receptor agonist or a GLP-1 receptor agonist analog.

8. Use of the four types of aromatic derivatives containing fatty acid salt structures or pharmaceutically acceptable salts thereof according to claim 1 or the pharmaceutical composition according to claim 4 in the preparation of drugs for treating type II diabetes, obesity or non-alcoholic fatty liver disease.

9. The method for preparing the four types of aromatic derivatives containing fatty acid salt structures as claimed in claim 1, characterized in that: The preparation method comprises the following steps: The preparation method of the compound of formula (I) is: (1) using 1,3-benzoxazine-2,4-dione, ethyl 6-bromohexanoate / bromoethanol and sodium carbonate as raw materials and DMF as solvent, reacting at 70° C. to generate the corresponding amide ester intermediate A; or Using 12-aminododecanoic acid and 2-(formyl chloride) phenyl acetate as raw materials and water as solvent, in the presence of sodium hydroxide to prepare intermediate A; or Using 8-aminooctanoic acid methyl ester hydrochloride and 2-aminopyridine-3-carboxylic acid as raw materials and DMF as solvent, in the presence of diisopropylethylamine, HATU and DIPEA, intermediate A was prepared; (2) using the amide ester intermediate A of step (1) as a raw material, hydrolyzing the ester in the presence of sodium hydroxide solution and hydrochloric acid to prepare an amide fatty acid intermediate B; (3) using the amide fatty acid intermediate B of step (2) and sodium bicarbonate as raw materials and water as solvent to prepare an amide fatty acid salt product of formula (I); The preparation method of the compound described in formula (II) is: (1) using difatty acid monoester and aminophenol as raw materials and dichloromethane as solvent, reacting at room temperature to generate the corresponding amide ester intermediate A; (2) using the amide ester intermediate A of step (1) as a raw material, using methanol as a solvent, and hydrolyzing the ester in the presence of sodium hydroxide and hydrochloric acid to prepare an amide fatty acid intermediate B; (3) using the amide fatty acid intermediate B of step (2) and sodium bicarbonate as raw materials and water as solvent to prepare an amide fatty acid salt product of formula (II); Preferably, when n=7, the difatty acid monoester described in step (1) is azelaic acid monomethyl ester, and when n=5, it is pimelic acid monomethyl ester; The preparation method of the compound of formula (III) is: (1) using amino fatty acid and alcohol as raw materials and thionyl chloride as solvent, reacting under heating conditions to generate the corresponding fatty acid ester amine salt intermediate B; (2) using the fatty acid ester amine salt intermediate of step (1), phthalic acid or phthaloyl chloride as raw materials, using dichloromethane as solvent, and preparing a phthalamide intermediate C in the presence of triethylamine or HATU or DIPEA; (3) using the phthalamide intermediate C of step (2) as a raw material, water or ethanol as a solvent, and preparing the phthalamide intermediate D in the presence of sodium hydroxide or Pd / C and hydrogen; (4) using the phthalamide intermediate D of step (3) as a raw material and water as a solvent, in the presence of sodium hydroxide or sodium bicarbonate, to prepare the phthalamide product E of formula (III); Preferably, when n=7, the amino fatty acid described in step (1) is 8-aminooctanoic acid, and when n=5, the amino fatty acid described in step (1) is 6-aminohexanoic acid; Preferably, the phthalic acid in step (2) is phthalic acid or 2-hydroxyisophthalic acid; Preferably, the phthaloyl chloride in step (2) is phthaloyl chloride; The preparation method of the compound of formula (IV) is: (1) using phthalic anhydride and amino fatty acid as raw materials and acetic acid as solvent, reacting at 145° C. to generate the corresponding phthalimido fatty acid intermediate B; (2) using the phthalimido fatty acid product B of step (1) and sodium bicarbonate as raw materials, acetone and water as solvents, and preparing a phthalimido fatty acid sodium product C at 0-10° C.; Preferably, when n=7, the amino fatty acid described in step (1) is preferably 8-aminooctanoic acid, and when n=5, the amino fatty acid described in step (1) is 6-aminohexanoic acid.

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