Pyrrole sulfonic acid compound salt form as well as preparation method and application thereof

Abstract

The invention provides a pyrrole sulfonic acid compound salt form as well as a preparation method and application thereof, and relates to 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy) benzenesulfonyl)-1H-pyrrole-3-yl)-N-methylamine organic acid salt which is prepared by the following steps: suspending pamoxamic acid and water, heating and stirring, slowly adding inorganic alkali, and keeping heating until the solution is clear; the preparation method comprises the following steps: slowly dropwise adding an aqueous solution of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy) benzenesulfonyl)-1H-pyrrole-3-yl)-N-methylamine hydrochloride, heating, and carrying out a stirring reaction to obtain a reaction solution containing a target product; and cooling to precipitate a crude product of the target product from the reaction liquid, filtering, washing and drying to obtain the target product. By developing the low-solubility salt form, the effect of changing the water solubility of the medicine can be achieved, so that the release time of the patent medicine is effectively controlled, and the clinical medication requirement of continuous acid inhibition is met.

Description

A pyrrolidine sulfonic acid compound salt form and its preparation method and application

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on March 15, 2023, with patent application number 202310249748.4, entitled “A Pyrrolyl Sulfonic Acid Compound Salt Form, Preparation Method, and Use Thereof.” The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present application relates to the technical field of organic chemical synthesis, and in particular to a pyrrole sulfonic acid compound salt, a preparation method, and an application thereof. Background Art

[0003] Gastric acid-related diseases are the most common type of digestive system diseases. They refer to a general term for a class of digestive tract diseases caused by excessive gastric acid secretion or special sensitivity to gastric acid. Common digestive system diseases include gastroesophageal reflux disease, peptic ulcer, Zollinger-Ellison syndrome and non-steroidal anti-inflammatory drugs.

[0004] Since 1988, proton pump inhibitors, represented by omeprazole, have been widely used clinically to treat peptic ulcers, reflux esophagitis, and Zollinger-Ellison syndrome by inhibiting gastric acid secretion. However, long-term clinical application has revealed limitations in the pharmacokinetics and pharmacodynamics of existing proton pump inhibitors. These include the influence of dosing time on efficacy; slow onset of nocturnal acid breakthrough; instability under acidic conditions (necessitating enteric-coated formulations); and dependence on CYP450 enzymes, leading to significant inter-individual variability.

[0005] Potassium-Competitive Acid Blockers (P-CABs) competitively inhibit H + / K + -K in ATPase + Compared with traditional proton pump inhibitors, P-CABs have the characteristics of lipophilicity, weak alkalinity, high dissociation constant and stability under low pH conditions. In an acidic environment, P-CABs react with H + / K + -ATPase binding, preventing H + P-CABs are transported and secreted into the stomach cavity, rapidly raising the pH in the stomach. Animal experiments and clinical studies have shown that P-CABs take effect quickly, achieving maximum therapeutic effect within 1 hour. They also have the advantage of a linear correlation between blood concentration and oral dosage, making it easier to achieve optimal acid suppression.

[0006] To achieve sustained acid suppression, for example, for more than two days, the formulation needs to be developed into a long-acting injection. Long-acting injections, while achieving long-term, steady drug release, reduce the frequency of dosing and systemic adverse reactions caused by fluctuations in blood drug concentrations, significantly improving patients' quality of life. Because these formulations commonly exhibit a significant burst release effect, the large amount of drug released in a short period of time can adversely affect medication safety. Controlling burst release is both a key and challenging aspect of research and optimization for these formulations.

[0007] Long-acting injectables (LAIs) are complex injectables, generally including microspheres, liposomes, nanosuspensions, micelles, and in situ gel implants. They can be administered via conventional syringes and needles, remaining at the injection site for an extended period and continuously releasing the drug. In situ forming gel implants (ISFGIs) are prepared by mixing the drug with a matrix material dissolved in an organic solvent and injecting it into the body. The drug undergoes a solid or semi-solid phase transition due to environmental stimuli at the injection site, forming a liquid formulation that forms a local drug reservoir. In situ gel implants offer advantages such as a simple preparation process, low cost, and high encapsulation efficiency. However, due to the need for an organic solvent, in situ gel implants require a certain amount of time to solidify after injection, and without any physical barrier before gel formation, they typically experience a greater initial burst release than microspheres. Related toxicity issues and the burst release effect limit the development and application of in situ gel implants.

[0008] Patent CN107814758A discloses a method for preparing a pyrrole sulfonic acid compound salt with ideal purity and stability, thereby effectively treating gastric acid-related diseases and meeting various clinical medication needs. However, the method still fails to meet the requirements of a long-acting injection in terms of controlling the burst release effect of the finished drug.

[0009] How to suppress the burst release effect of drugs, thereby effectively controlling the release time of the finished drug and meeting the clinical medication needs for continuous acid suppression, is a technical problem that needs to be solved at present.

[0010] Summary of the Invention

[0011] In order to meet the long-term and stable drug release effect required by long-acting injections, the present application provides a pyrrole sulfonic acid compound salt form and its preparation method and application. By developing a low-solubility salt form, the effect of changing the water solubility of the drug can be achieved.

[0012] On the one hand, the present application provides a 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine organic acid salt having the structure shown in Formula I:

[0013] Wherein, n=1 or 0.5, and HA is pamoic acid.

[0014] On the other hand, the present application also provides a method for preparing a salt form of a pyrrole sulfonic acid compound, which is used to prepare the above-mentioned 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine organic acid salt, comprising the following steps:

[0015] (1) dissolving Compound II in an organic solvent, slowly adding pamoic acid at room temperature, and stirring to react to obtain a reaction solution containing a crude solid of Compound I;

[0016] (2) filtering the crude compound I, washing it with an organic solvent, and drying it to obtain compound I;

[0017] Furthermore, the organic solvent is ethyl acetate, methanol, acetone, acetonitrile or tetrahydrofuran, and the volume ratio of the compound II to the organic solvent is 1.3-1.5:4-8.

[0018] Furthermore, the molar ratio of compound III to HA is 1:0.3-2.

[0019] Furthermore, the stirring reaction in step (1) is carried out for a reaction time of 1 to 3 hours, and the drying temperature in step (3) is 30 to 40° C., and the drying time is 3 to 6 hours.

[0020] In other embodiments, the 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine organic acid salt provided herein can also be prepared by the following steps:

[0021] (1) Suspend pamoic acid and water, heat and stir, slowly add inorganic base, and keep heating until the solution is clear;

[0022] (2) slowly adding an aqueous solution of compound III dropwise, heating, and stirring to react to obtain a reaction solution containing compound I;

[0023] (3) cooling the reaction solution to precipitate the crude compound I, filtering, washing with water, and drying to obtain the crude compound I;

[0024] Furthermore, the heating temperature in step (1) and step (2) is 70-80°C.

[0025] Furthermore, the molar ratio of compound III to HA is 1:0.3-2.

[0026] Furthermore, the stirring reaction in step (2) is carried out for a reaction time of 1 to 3 hours, and the drying temperature in step (3) is 30 to 40° C., and the drying time is 3 to 6 hours.

[0027] Finally, the present application also provides the use of the above-mentioned pyrrole sulfonic acid compound salt form in the preparation of sustained-release drugs for gastric acid-related diseases.

[0028] Among them, gastric acid-related diseases include erosive esophagitis, gastric ulcer, duodenal ulcer or Helicobacter pylori eradication indications and other digestive tract diseases caused by excessive gastric acid or special sensitivity to gastric acid.

[0029] Adjusting the hydrophilicity of drugs is an important way to control burst release. For small molecule hydrophilic drugs, it is easy to escape from the internal to the external aqueous phase (organism) and cause obvious burst release. Therefore, adjusting the hydrophilicity of the drug can reduce such escape and help control burst release. The 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine organic acid salt provided by the application is obtained by screening various organic acids to obtain a salt form with higher purity, better stability and lower solubility, thereby effectively controlling the release time of the finished drug and meeting the clinical medication needs of continuous acid suppression. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The following is a brief description of the contents expressed in the drawings of the specification:

[0031] FIG1 is a release curve of the preparation prepared in Example 1 provided in this application. DETAILED DESCRIPTION

[0032] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0033] Example 1

[0034] Disperse pamoic acid (2.34 g, 6.02 mmol) in water (60 mL) at room temperature, heat to 75°C, and stir for 10 minutes. Slowly add a solution of sodium hydroxide (0.48 g, 12.00 mol) in water (4.8 mL). Once the reaction solution becomes clear, slowly add dropwise a mixture of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride (2.34 g, 4.99 mmol) and water (60 mL). After addition, continue heating to 75°C for 2 hours to terminate the reaction. The temperature was slowly lowered to 0°C to solidify and precipitate a crude solid, which was filtered and washed twice with water (2-4 mL of water per gram of crude organic acid salt). The resulting solid was dried in a vacuum drying oven at 35°C for 4 hours to obtain the target compound 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate.

[0035] 1 H NMR (400MHz, DMSO) δ10.10-8.30 (m, 2H), 8.20 (d, J=9.3Hz, 2H), 7.78 (s, 1H), 7.63 (d, J =7.9Hz, 1H), 7.52 (dd, J = 13.4, 6.1Hz, 1H), 7.45 (t, J = 8.1Hz, 1H), 7.29-7.18 (m, 3H), 7. 11-7.06 (m, 3H), 7.00 (t, J=7.3Hz, 1H), 6.84 (s, 1H), 6.48 (s, 1H), 4.69 (s, 1H), 4.01 (s , 2H), 3.95 (t, J=6.4Hz, 2H), 3.44 (d, J=6.2Hz, 2H), 2.55 (s, 3H), 1.92 (p, J=6.2Hz, 2H).

[0036] Example 2

[0037] 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine (2.34 g, 4.99 mmol) was dissolved in ethyl acetate under stirring, using 4-8 mL of ethyl acetate per gram of free amine. Pamoic acid (2.34 g, 6.02 mmol) was added to the reaction system at room temperature of 25°C, and stirred for 2 hours to obtain a crude solid. The solution was filtered, and the solid was washed twice with ethyl acetate. The obtained solid was dried in a vacuum drying oven at 35°C for 4 hours to obtain the target compound 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate.

[0038] Comparative Example 1

[0039] In a 100 mL single-necked flask, 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine (5.0 g, 11.6 mmol) and ethyl acetate (25 mL) were added and dissolved with stirring at room temperature (25 ° C). Fumaric acid (1.6 g, 15.20 mmol) was added to the reaction system, and the mixture was heated to 50 ° C with stirring and stirred at this temperature for 2 h. Solid precipitated, and the solid was filtered out and washed with ethyl acetate (10 mL * 2 times). The obtained solid was dried in a vacuum oven (35 ° C) for 4 hours to give an off-white solid 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine fumarate.

[0040] Saturation solubility test of different salt types in different pH media

[0041] Take 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride, add appropriate amounts of pH 1.0 hydrochloride solution, pH 2.0 hydrochloride solution, pH 3.8 acetate buffer, pH 4.5 acetate buffer, pH 5.8 phosphate buffer, and pH 6.8 phosphate buffer to prepare supersaturated solutions, place the sample in a constant temperature water bath shaker and shake for 24 hours at a shaking frequency of 150 rpm and a water bath temperature of 37°C;

[0042] Separately, 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine organic acid salts prepared in Example 1 and Comparative Example 1 were added with appropriate amounts of PBS (pH 7.4) and 0.5% Tween 80 in PBS (pH 7.4), respectively, to prepare supersaturated solutions. The samples were shaken in a constant-temperature water bath at 150 rpm for 24 hours. The water bath temperature was tested at both room temperature and 37°C. The samples were removed and filtered through a 0.45 μm polyethersulfone membrane. The filtrate was collected and the solution concentration was determined by high-performance liquid chromatography. The test results are shown in Table 1.

[0043] Instruments used:

[0044] Dual-function constant temperature water bath oscillator (manufacturer: Huanyu Scientific Instrument Factory);

[0045] BS124S Sartorius electronic balance (manufacturer: Sartorius).

[0046] Table 1 Saturated solubility test results of different salt types in different pH media

[0047] As can be seen from the test results in Table 1, the saturated solubility of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride in pH 1.0 solution is the lowest (2.66 mg / ml), and the solubility is relatively high in pH 2.0-6.8 solution; the solubility of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate and fumarate is greatly reduced compared with 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride, and the saturated solubility is slightly increased after adding 0.5% Tween 80%. The solubility of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate increased, but was still far lower than that of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride. At the same time, compared with fumarate, the solubility of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate was further reduced. In the absence of surfactant, the solubility of pamoate in PBS (pH 7.4) solution was as low as 0.06 mg / ml.

[0048] The saturated solubility of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate in solutions of varying pH was further investigated. Supersaturated solutions of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate were prepared by adding appropriate amounts of solutions containing 0.5% or 1.0% Tween 80 at different pH values ​​(pH 1.0 hydrochloride solution, pH 2.0 hydrochloride solution, pH 3.8 acetate buffer, pH 4.5 acetate buffer, pH 5.5 phosphate buffer, pH 6.8 phosphate buffer, and pH 6.8 phosphate buffer). The samples were shaken in a constant temperature water bath at 150 rpm for 24 hours, and the saturated solubility at room temperature was investigated. The sample was taken out and filtered through a 0.45 μm polyethersulfone membrane. The filtrate was taken and the concentration of the solution was detected by high performance liquid chromatography. The results are shown in Table 2.

[0049] Table 2 Saturated solubility of pamoate in media with different pH values ​​containing 0.5% Tween 80 / 1.0% Tween 80

[0050] The results in Table 2 show that there is no significant difference in the solubility of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoic acid in solutions containing 0.5% and 1.0% Tween 80 at different pH values. The saturation solubility of both solutions is significantly lower than that of other existing salt forms, further confirming the low solubility of pamoate. The low solubility of pamoate increases the potential for its development into a sustained-release or long-acting formulation.

[0051] Release rate test of different salt forms in preparations

[0052] Take 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine hydrochloride and 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate, and mix the raw materials and excipients according to the weight ratio shown in Table 3 and stir until clear. The active ingredient in the final preparation is 10% based on the free base content.

[0053] Table 3 Ratio of raw materials and auxiliary materials of finished medicines

[0054] Experimental animal species: Beagle dogs, 6 dogs in each group, administered with a dose of 9.1 mg / kg.

[0055] Blood samples were collected from the forelimb vein at 0.25 h, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, 120 h, 168 h, 216 h, 264 h, and 336 h after administration. Approximately 1.0 mL of blood was collected per sample and anticoagulated with EDTA-2K. Blood samples were placed on ice and centrifuged within 1 h to separate plasma (centrifugation conditions: 6000 g, 3 min, 2-8°C). Plasma samples were stored at -80°C until analysis. The release profiles of the formulation in experimental animals are shown in Figure 1.

[0056] As shown in Figure 1, during the first few hours of release, the plasma concentration of the pamoate salt formulation is significantly lower than that of the hydrochloride salt formulation. Lower plasma concentrations during the burst release are crucial for avoiding API-induced side effects. During the middle phase of release, the plasma concentrations of the two salts gradually approach each other. In the latter stages of release, the plasma concentration of the hydrochloride salt formulation is below the detection limit by 200 hours, while the plasma concentration of the pamoate salt formulation remains below the detection limit after 300 hours. Therefore, the pamoate salt formulation can achieve a lower burst release while allowing for a longer dosing period.

[0057] Stability investigation and accelerated long-term testing:

[0058] The present invention investigates the stability of 1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)phenylsulfonyl)-1H-pyrrol-3-yl)-N-methylamine pamoate. Samples were tested under high temperature (60°C), high humidity (92.5% RH), and light conditions. Sample solutions were prepared as follows: A suitable amount of the product was dissolved in a solvent of acetonitrile and water (50:50) and diluted to a concentration of approximately 2.1 mg of pamoate per ml. A control solution was prepared by precisely measuring an appropriate amount of the test solution and diluting it with a solvent to a concentration of approximately 2.1 μg of pamoate per ml. A sensitive solution was prepared by precisely measuring an appropriate amount of the control solution and diluting it with a solvent to a concentration of approximately 1.05 μg of pamoate per ml. System suitability solution: Accurately weigh 1-[5-(2-fluorophenyl)-1H-pyrrol-3-yl]-N-methylmethanamine (H008-imp-1), (Z)-1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylformimine oxide (H008-imp-3), 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol- 3-yl]-N,N-dimethylmethanamine (H008-imp-5), 3-(3-methoxypropoxy)benzenesulfonamide (H008-imp-17), 5-(2-fluorophenyl)-1-methyl-1H-pyrrole-3-carbaldehyde (H008-imp-18), N-{[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]methyl}-3-(3-methoxypropoxy)-N-methylbenzenesulfonamide (H008-i imp-19), N-{[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]methyl}-N-methylformamide (H008-imp-20), 1-[5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]methyl}-N-methylmethanamine (H008-imp-22), 5-(2-fluorophenyl)-1-{[3-(3-methoxypropoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl]methyl}-N-methylformamide Appropriate amounts of a reference substance (1-(5-(2-fluorophenyl)-1-3-(3-methoxypropoxy)benzenesulfonyl)-1H-pyrrole-3-yl)-N-methylamine hydrochloride) were dissolved in a solvent and diluted to produce a solution containing approximately 7.5 μg of each impurity and 1.6 mg of kepasin hydrochloride per 1 ml. Purity was determined by HPLC. The test results are shown in Tables 4 and 5 below.

[0059] Table 4 Influencing factors test

[0060] Under the influencing factors, the impurities showed an increasing trend after 30 days at high temperature, and the total impurities increased from 0.62% to 6.65%; under light conditions, H008-imp-17 increased from undetectable to 0.10%, unknown single impurities increased from 0.17% to 1.50%, and total impurities increased from 0.62% to 3.77%, while there were no significant changes in other materials; after 30 days at high humidity, there were no significant changes except for H008-imp-19, unknown single impurities, unknown total impurities and total impurities.

[0061] Table 5 Accelerated and long-term tests

[0062] Under accelerated conditions, H008-02-imp-1 increased from 0.05% to 0.15% in the accelerated period, H008-imp-17 increased from undetected to 0.09%, H008-imp-3 increased from undetected to 0.05%, H008-imp-20 increased from undetected to 0.08%, H008-imp-19 increased from undetected to 0.79%, unknown single impurities increased from 0.17% to 0.46%, unknown total impurities increased from 0.57% to 2.39%, and total impurities increased from 0.62% to 3.71% in the long-term period. In the long-term period, except for H008-imp-19 (which increased from undetected to 0.07%), unknown single impurities (which increased from 0.17% to 0.19%), unknown total impurities (which increased from 0.57% to 1.30%), and total impurities (which increased from 0.62% to 1.56%), there were no significant changes in other contents.

[0063] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A pyrrole sulfonic acid compound salt type, in, It has the structure shown in Formula I: Wherein, n=1 or 0.5, HA is pamoic acid.

2. A method for preparing a pyrrole sulfonic acid compound salt, for preparing the pyrrole sulfonic acid compound salt according to claim 1, in, The steps include: (1) dissolving compound II in an organic solvent, slowly adding HA at room temperature, stirring and reacting to obtain a reaction solution containing a crude solid of compound I; (2) filtering the crude compound I, washing it with an organic solvent, and drying it to obtain compound I; Wherein, HA is pamoic acid, and n=1 or 0.

5.

3. A method for preparing a pyrrole sulfonic acid compound salt according to claim 2, in, The organic solvent is ethyl acetate, methanol, acetone, acetonitrile or tetrahydrofuran.

4. A method for preparing a pyrrole sulfonic acid compound salt according to claim 2, in, The volume ratio of the compound II to the organic solvent is 1.3-1.5:4-8.

5. A method for preparing a pyrrole sulfonic acid compound salt, for preparing the pyrrole sulfonic acid compound salt according to claim 1, in, The steps include: (1) HA and water are suspended, heated and stirred, and an inorganic base is slowly added, and the mixture is heated until the solution becomes clear; (2) slowly adding an aqueous solution of compound III dropwise, heating, and stirring to react, thereby obtaining a reaction solution containing compound I; (3) cooling the reaction solution to precipitate a crude compound I, filtering, washing with water, and drying to obtain a crude compound I; Wherein, HA is pamoic acid, and n=1 or 0.

5.

6. A method for preparing a pyrrole sulfonic acid compound salt according to claim 5, in, The heating temperature in step (1) and step (2) is 70-80°C.

7. A method for preparing a pyrrole sulfonic acid compound salt according to claim 2 or 5, in, The molar ratio of the compound II or compound III to HA is 1:0.3-2.

8. A method for preparing a pyrrole sulfonic acid compound salt according to claim 2 or 5, in, The reaction time of the stirring reaction is 1 to 3 hours, the drying temperature is 30 to 40° C., and the drying time is 3 to 6 hours.

9. Use of a pyrrole sulfonic acid compound salt according to any one of claims 1 to 8 in the preparation of sustained-release drugs for gastric acid-related diseases.

10. Use of a pyrrole sulfonic acid compound salt according to claim 9, in, The gastric acid-related diseases include erosive esophagitis, gastric ulcer, duodenal ulcer or Helicobacter pylori eradication indications.

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