Acetate crystal form of acid-suppressing compound, and preparation method therefor and use thereof

Abstract

Provided are an acetate crystal form of an acid-suppressing compound, and a preparation method therefor and a use thereof. The crystal of the compound comprises crystal form A, and the structural formula of the crystal is as shown in formula (I). The crystal form exhibits good stability, high purity, and excellent physiochemical properties, and requires a simple preparation process. The present invention is suitable for the field of compounds, and can solve the problem in the prior art of poor water solubility in acid-suppressing compounds.

Description

Acetate crystal forms of acid-suppressing compounds, their preparation methods and applications

[0001] This application is based on and claims priority to Chinese application CN application number 202411940449.6 filed on December 26, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to the field of compounds, and more specifically, to an acetate crystal form of an acid-suppressing compound, its preparation method, and its application. Background Technology

[0003] Acid-related diseases are a group of conditions triggered or caused by stomach acid reflux, mainly including peptic ulcers and gastroesophageal reflux disease. In the drug treatment of these diseases, acid-suppressing drugs are the most effective means of treatment in clinical practice. Proton pump inhibitors (PPIs) can directly inhibit H+... + Antacids that inhibit gastric acid secretion by promoting the exchange of potassium ions with potassium, such as omeprazole, lansoprazole, and pantoprazole, are well-known. In recent years, potassium-competitive acid blockers have been used clinically; these are a new type of antacid that competitively and reversibly inhibits potassium ions. + By binding to the proton pump, it blocks the exchange of K+ and H+, thereby inhibiting gastric acid secretion; it is a reversible proton pump inhibitor. Studies have shown that, compared with PPIs, potassium-competitive acid blockers have a more rapid, stronger, and longer-lasting reversible acid-suppressing effect.

[0004] Currently, potassium-competitive acid blockers such as vonoprazan, tegorazan, fexuprazan, revaprazan, and carenoprazan are marketed in various countries. These potassium-competitive acid blockers suffer from side effects such as slow onset of action, unstable acid suppression, and allergic reactions. Therefore, there is an urgent need in this field to develop an acetate crystal form of an acid-suppressing compound with good stability, excellent physicochemical properties, and high purity. Summary of the Invention

[0005] The main objective of this invention is to provide an acetate crystal form of an acid-suppressing compound, its preparation method, and its application, in order to solve the problem of poor water solubility of acid-suppressing compounds in the prior art.

[0006] To achieve the above objectives, according to a first aspect of the present invention, a crystal is provided, the crystal comprising crystal form A, the crystal having a structural formula as shown in formula (I);

[0007] The XRPD pattern of crystal form A includes six or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 26.70°±0.2°, and 27.51°±0.2°.

[0008] Furthermore, the XRPD pattern of crystal form A includes three or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°. 0.2°, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2° and 28.82°±0.2°.

[0009] Furthermore, the XRPD pattern of crystal form A includes five or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, and 17.38°±0.2°. 2°, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2°, and 28.82°±0.2°.

[0010] Furthermore, the XRPD pattern of crystal form A includes 10 or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°. 0.2°, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2°, and 28.82°±0.2°.

[0011] Furthermore, the X-ray powder diffraction pattern of crystal form A may further include one or more 2θ values ​​selected from the group consisting of: 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 20.11°±0.2°, 22.82°±0.2°, and 23.78°±0.2°.

[0012] Furthermore, the XRPD pattern of crystal form A is basically characterized as shown in Figure 1.

[0013] Furthermore, the infrared spectrum of crystal form A is basically characterized as shown in Figure 2.

[0014] Furthermore, crystal form A exhibits no weight loss between 20 and 190°C.

[0015] Furthermore, the DSC endothermic peak of crystal form A is 99±3℃.

[0016] Furthermore, the TGA spectrum of crystal form A is characterized as shown in Figure 3.

[0017] Furthermore, the DSC endothermic peak of crystal form A is 99±3℃.

[0018] Furthermore, the DSC spectrum of crystal form A is basically characterized as shown in Figure 4.

[0019] Furthermore, the solubility of crystal form A is 0.1 to 1 g / mL, preferably 0.3 to 0.8 g / mL, and more preferably 0.4 to 0.6 g / mL.

[0020] Furthermore, the purity of crystal form A is greater than 95%, preferably greater than 97%, and more preferably greater than 99%.

[0021] To achieve the above objectives, according to a second aspect of the present invention, a pharmaceutical composition is provided comprising: (a) the crystals described above, and (b) a pharmaceutically acceptable carrier.

[0022] To achieve the above objectives, according to a third aspect of the present invention, a method for preparing the above-mentioned crystal, wherein the crystal is of crystal form A, is provided; the method includes: (s1) dissolving the compound of formula (II) in an organic solvent and mixing it thoroughly;

[0023] (s2) After adding acetic acid, the reaction was carried out and dried to obtain crystal form A.

[0024] Furthermore, the organic solvent includes one or more of ethyl acetate, isopropyl acetate, ethanol, tetrahydrofuran, methyl tert-butyl ether, acetonitrile, toluene, acetone, dichloromethane, 1,4-dioxane, and 2-methyltetrahydrofuran.

[0025] Furthermore, in step (s2), the reaction after adding acetic acid also includes cooling, filtration, and / or washing.

[0026] Furthermore, it is cooled to -10 to 30°C, preferably -5 to 25°C.

[0027] Furthermore, the washing process utilizes organic solvents.

[0028] Furthermore, the mass ratio of the compound of formula (II) to the organic solvent is 1:1 to 20, preferably 1:2 to 15, and more preferably 1:2 to 10.

[0029] Furthermore, the molar ratio of compound (II) to acetic acid is 1:1 to 5, more preferably 1:1 to 3, and even more preferably 1:1 to 2.

[0030] Furthermore, the mass ratio of compound (II) to acetic acid is 1 to 10:1, more preferably 3 to 8:1, and even more preferably 5 to 7:1.

[0031] Furthermore, the reaction is carried out at 0–40°C, preferably 10–40°C, and more preferably 20–40°C.

[0032] Furthermore, the reaction time is 0.1 to 10 hours, preferably 0.5 to 8 hours, and more preferably 0.5 to 4 hours.

[0033] Furthermore, the drying process is vacuum drying.

[0034] Furthermore, the drying temperature is 20–60°C, preferably 25–55°C, and more preferably 25–50°C.

[0035] Furthermore, the drying time is 3 to 20 hours, preferably 5 to 18 hours, and more preferably 6 to 16 hours.

[0036] To achieve the above objectives, according to a fourth aspect of the present invention, the use of the above-described crystals in the preparation of a medicament or pharmaceutical composition for treating diseases related to excessive gastric acid is provided.

[0037] To achieve the above objectives, according to a fifth aspect of the present invention, a method for treating diseases related to excessive gastric acid is provided, the method comprising: administering a subject a therapeutically effective amount of the above-mentioned crystals.

[0038] To achieve the above objectives, according to a sixth aspect of the present invention, a crystal is provided for treating diseases related to excessive gastric acid.

[0039] The crystals with the structure shown in Formula (I) obtained by applying the technical solution of the present invention have good stability, high purity, excellent physicochemical properties, and simple preparation process. Compared with crystals in the prior art, they are more suitable for industrial production and can be further applied to the preparation of potassium ion competitive acid blockers, as well as to the preparation of drugs for treating erosive esophagitis, gastric ulcers, duodenal ulcers, Helicobacter pylori eradication indications, and related diseases caused by excessive gastric acid. Attached Figure Description

[0040] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0041] Figure 1 shows the XRPD spectrum of the crystal form A compound of Example 1 of this application.

[0042] Figure 2 shows the infrared absorption spectrum of the crystal form A compound of Example 1 of this application.

[0043] Figure 3 shows the TGA spectrum of crystal form A compound of test example 3 of this application.

[0044] Figure 4 shows the DSC spectrum of crystal form A compound of test example 3 of this application. Detailed Implementation

[0045] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present invention will now be described in detail with reference to the embodiments.

[0046] To facilitate understanding of the invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Before describing the invention, it should be understood that the invention is not limited to the specific methods and experimental conditions described, as such methods and conditions can vary. It should also be understood that the terminology used herein is intended only to describe particular embodiments and is not intended to be restrictive; the scope of the invention will be limited only by the appended claims.

[0047] As used herein, the term “comprising” or its variations such as “including” or “comprising” are understood to include the said element or component without excluding other elements or other components.

[0048] The term “about” can refer to a value or composition within an acceptable margin of error for a particular value or composition as determined by a person skilled in the art, depending in part on how the value or composition is measured or determined. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0049] As used herein, unless otherwise stated, any concentration range, percentage range, proportion range, or integer range shall be understood to include any integer value within the range and, where appropriate, its fractional value (e.g., one-tenth and one-hundredth of an integer).

[0050] As used herein, the term “and / or” refers to and covers any and all possible combinations of one or more of the related listed items.

[0051] As used in this article, unless otherwise specified, solvents or solutions are added by pouring directly or adding at a constant rate.

[0052] As used in this article, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0053] As used in this article, the "slow addition" method includes, but is not limited to: adding drop by drop, adding slowly along the container wall, etc.

[0054] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0055] As used in this article, the term "n or more 2θ values ​​selected from the following group" refers to any positive integer including n and greater than n (e.g., n, n+1, ...), where the upper limit Nup is the number of all 2θ peaks in the group. For example, "3 or more" includes not only the positive integers of the upper limit Nup (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ...), but also ranges such as "4 or more", "5 or more", and "6 or more".

[0056] As used herein, the terms "compound of the present invention" and "1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine" are used interchangeably and both refer to the compound of formula (II). The compound of formula (II) is prepared according to the method of patent CN113620930B.

[0057] As used herein, the terms “crystal form of the compound of the present invention,” “acetate crystal form of the compound of the present invention,” or “acetate crystal form of the acid-suppressing compound of the present invention” are used interchangeably and all refer to the crystal form described in the first aspect of the present invention.

[0058] As mentioned in the background section, existing potassium ion competitive acid blockers suffer from side effects such as slow onset of action, unstable acid suppression, and allergic reactions. Based on this, the inventors of this invention, through extensive and in-depth research and numerous experiments and screenings, unexpectedly discovered the aforementioned crystal for the first time. The structural formula of this crystal is shown in formula (I), and the crystal includes crystal form A. This crystal exhibits good stability, high purity, excellent physicochemical properties, and a simple preparation process, making it suitable for preparing potassium ion competitive acid blockers. Therefore, a series of protection schemes are proposed in this application.

[0059] In a first typical embodiment of this application, a crystal is provided, the crystal including crystal form A, the structural formula of the crystal being shown in formula (I);

[0060] The XRPD pattern of crystal form A includes six or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 26.70°±0.2°, and 27.51°±0.2°.

[0061] In a preferred embodiment, the XRPD pattern of crystal form A includes three or more 2θ values ​​selected from the group consisting of: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, and 17.38°. °±0.2°, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2° and 28.82°±0.2°.

[0062] In a preferred embodiment, the XRPD pattern of crystal form A includes five or more 2θ values ​​selected from the group consisting of: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, and 17.38°. ±0.2°, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2°, and 28.82°±0.2°.

[0063] In a preferred embodiment, the XRPD pattern of crystal form A includes 10 or more 2θ values ​​selected from the group consisting of: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 16.54°±0.2°, 16.38°±0.2°, 16.07 ...04°±0.2°, 16.54°±0.2°, 16.38°±0.2°, 16.07°±0.2°, 16.04°±0.2°, 16.04°±0.2°, 16.04°±0.2°, 16.04°±0.2°, 16.04°±0.2°, 16.04°±0.2°, °±0.2°, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2°, and 28.82°±0.2°.

[0064] In a preferred embodiment, the X-ray powder diffraction pattern of crystal form A may further include one or more 2θ values ​​selected from the group consisting of: 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 20.11°±0.2°, 22.82°±0.2°, and 23.78°±0.2°.

[0065] In a preferred embodiment, the XRPD pattern of crystal form A is essentially as shown in Figure 1.

[0066] In a preferred embodiment, the infrared spectrum of crystal form A is essentially as shown in Figure 2.

[0067] In a preferred embodiment, crystal form A exhibits no weight loss at temperatures ranging from 20 to 190°C.

[0068] In a preferred embodiment, the DSC endothermic peak of crystal form A is 99±3℃.

[0069] In a preferred embodiment, the TGA spectrum of crystal form A is characterized as shown in Figure 3.

[0070] In a preferred embodiment, the DSC endothermic peak of crystal form A is 99±3℃.

[0071] In a preferred embodiment, the DSC spectrum of crystal form A is essentially as shown in Figure 4.

[0072] In a preferred embodiment, the solubility of crystal form A is 0.1–1 g / mL, preferably 0.3–0.8 g / mL, and more preferably 0.4–0.6 g / mL.

[0073] In a preferred embodiment, the purity of crystal form A is greater than 95%, preferably greater than 97%, and more preferably greater than 99%.

[0074] In a second typical embodiment of this application, a pharmaceutical composition is provided comprising: (a) the crystals described above, and (b) a pharmaceutically acceptable carrier.

[0075] The pharmaceutical composition of this application contains a therapeutically effective amount of crystals of compound of formula I as described in this invention, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients, and / or diluents. The excipients include odorants, flavoring agents, sweeteners, etc.

[0076] The above-mentioned pharmaceutical composition preferably contains an active ingredient in a weight ratio of 1-99%, preferably in which the compound of general formula I accounts for 65 wt% to 99 wt% of the total weight, and the remainder is a pharmaceutically acceptable carrier, diluent, solution, or saline solution. The compounds and pharmaceutical compositions provided by this invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and can be contained in suitable solid or liquid carriers or diluents and in suitable sterile instruments for injection or infusion.

[0077] Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional pharmaceutical preparation methods. The dosage form contains 1 mg to 700 mg of compound of general formula I per unit volume, preferably 25 mg to 300 mg of compound of general formula I per unit volume.

[0078] The compounds and pharmaceutical compositions of the present invention are suitable for clinical use in mammals, including humans and animals, and can be administered via oral, nasal, skin, lung, or gastrointestinal routes. Oral administration is preferred. The most preferred daily dose is 50-1400 mg / kg body weight, taken as a single dose, or 25-700 mg / kg body weight, divided into multiple doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Generally, a low dose is started, and the dose is gradually increased until the most suitable dose is found.

[0079] In a third typical embodiment of this application, a method for preparing the above-mentioned crystal is provided, wherein the crystal is of crystal form A; the method includes: (s1) dissolving the compound of formula (II) in an organic solvent and mixing it thoroughly;

[0080] (s2) After adding acetic acid, the reaction was carried out and dried to obtain crystal form A.

[0081] In a preferred embodiment, step (s2) further includes cooling, filtering, and / or washing after the acetic acid reaction.

[0082] In a preferred embodiment, the temperature is cooled to -10 to 30°C, more preferably -5 to 25°C.

[0083] In a preferred embodiment, washing is performed using an organic solvent.

[0084] In a preferred embodiment, the mass ratio of the compound of formula (II) to the organic solvent is 1:1 to 20, more preferably 1:2 to 15, and even more preferably 1:2 to 10.

[0085] In a preferred embodiment, the molar ratio of the compound of formula (II) to acetic acid is 1:1 to 5, more preferably 1:1 to 3, and even more preferably 1:1 to 2.

[0086] In a preferred embodiment, the mass ratio of the compound of formula (II) to acetic acid is 1 to 10:1, more preferably 3 to 8:1, and even more preferably 5 to 7:1.

[0087] In a preferred embodiment, the reaction is carried out at 0–40°C, preferably 10–40°C, and more preferably 20–40°C.

[0088] In a preferred embodiment, the reaction time is 0.1 to 10 hours, preferably 0.5 to 8 hours, and more preferably 0.5 to 4 hours.

[0089] In a preferred embodiment, the drying is vacuum drying.

[0090] In a preferred embodiment, the drying temperature is 20–60°C, preferably 25–55°C, and more preferably 25–50°C.

[0091] In a preferred embodiment, the drying time is 3 to 20 hours, preferably 5 to 18 hours, and more preferably 6 to 16 hours.

[0092] In this invention, unless otherwise specified, the drying method used is a conventional drying method in the art. For example, in the embodiments of this invention, drying refers to vacuum drying or atmospheric pressure drying in a conventional drying oven. Generally, the drying time is 0.1–50 h or 1–30 h.

[0093] In a preferred embodiment, the organic solvent includes one or more of ethyl acetate, isopropyl acetate, ethanol, tetrahydrofuran, methyl tert-butyl ether, acetonitrile, toluene, acetone, dichloromethane, 1,4-dioxane, or 2-methyltetrahydrofuran.

[0094] In a fourth typical embodiment of this application, the use of the above-mentioned crystals in the preparation of a medicament or pharmaceutical composition for treating diseases caused by excessive gastric acid is provided.

[0095] In a preferred embodiment, the diseases related to excessive gastric acid mentioned above are selected from the group consisting of: erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, or combinations thereof.

[0096] In a fifth typical embodiment of this application, a method for treating diseases related to excessive gastric acid is provided, the method comprising: administering a subject a therapeutically effective amount of the aforementioned crystals. The aforementioned diseases related to excessive gastric acid are selected from the group consisting of: erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, or combinations thereof.

[0097] In a sixth typical embodiment of this application, a crystal is provided for treating diseases related to excessive stomach acid. These diseases are selected from the group consisting of: erosive esophagitis, gastric ulcer, duodenal ulcer, Helicobacter pylori eradication indications, or combinations thereof.

[0098] Within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0099] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. In the embodiments of the present invention, percentages and parts are calculated by mass, unless otherwise stated in the page number description.

[0100] Example 1

[0101] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g), ethyl acetate (12.0 g), and acetic acid (0.52 g) were added dropwise to a 100 mL single-necked flask. The mixture was stirred at room temperature for 1.0 h, filtered, washed with ethyl acetate (3.0 g), and dried under vacuum at 50 °C for 14 h to obtain 2.72 g of white solid, with a yield of 79.3%.

[0102] The XRPD spectrum of crystal form A is shown in Figure 1. The infrared absorption spectrum of crystal form A is shown in Figure 2 (where the horizontal axis is "cm"). -1 The vertical axis “%T” represents wavenumber, and the vertical axis “%T” represents transmittance. The 2θ values ​​for crystal form A are shown in Table 1.

[0103] Table 1

[0104] Example 2

[0105] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g) and isopropyl acetate (15.0 g) were added to a 100 mL single-necked flask. Acetic acid (0.52 g) was added dropwise while heating to 40 °C. The mixture was stirred for 1.0 h, cooled to room temperature, filtered, washed with isopropyl acetate (6.0 g), and dried under vacuum at 50 °C for 14 h to obtain 2.97 g of white solid, with a yield of 86.5%.

[0106] Example 3

[0107] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g), ethanol (6.0 g), and acetic acid (0.48 g) were added dropwise to a 100 mL single-necked flask. The mixture was stirred at room temperature for 0.5 h, cooled to -10 °C, and stirred for another 1.0 h. After filtration, the mixture was dried under vacuum at 50 °C for 12 h to obtain 2.04 g of a white solid, with a yield of 59.5%.

[0108] Example 4

[0109] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g) and tetrahydrofuran (12.0 g) were added to a 100 mL single-necked flask, and acetic acid (0.52 g) was added dropwise at room temperature. The mixture was stirred at -5 °C for 2.0 h, filtered, and dried under vacuum at 50 °C for 6 h to obtain 2.32 g of white solid, with a yield of 67.6%.

[0110] Example 5

[0111] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g) and methyl tert-butyl ether (21.0 g) were added to a 100 mL single-necked flask. Acetic acid (0.52 g) was added dropwise while heating to 40 °C. The mixture was stirred for 1.0 h, cooled to room temperature, and stirred for another 1.0 h. After filtration, the mixture was washed with methyl tert-butyl ether (6.0 g) and dried under vacuum at 40 °C for 14 h to obtain 3.04 g of white solid, with a yield of 88.6%.

[0112] Example 6

[0113] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g), acetonitrile (18.0 g), and acetic acid (0.48 g) were added dropwise to a 100 mL single-necked flask. The mixture was stirred at room temperature for 1 h, filtered, washed with acetonitrile (6.0 g), and dried under vacuum at 50 °C for 6 h to obtain 2.47 g of white solid, with a yield of 72.0%.

[0114] Example 7

[0115] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g) and toluene (15.0 g) were added to a 100 mL single-necked flask. Acetic acid (0.52 g) was added dropwise while heating to 40 °C. The mixture was stirred for 1.0 h, cooled to room temperature, and stirred for another 2.0 h. The mixture was filtered, washed with toluene (6.0 g), and dried under vacuum at 50 °C for 12 h to obtain 2.77 g of a white solid, with a yield of 80.8%.

[0116] Example 8

[0117] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g), acetone (15.0 g), and acetic acid (0.52 g) were added dropwise to a 100 mL single-necked flask. The mixture was stirred at room temperature for 1.0 h, filtered, washed with acetone (6.0 g), and dried under vacuum at 50 °C for 6 h to obtain 2.44 g of white solid, with a yield of 71.1%.

[0118] Example 9

[0119] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g) and dichloromethane (6.0 g) were added to a 100 mL single-necked flask. Acetic acid (0.51 g) was added dropwise after heating to 35 °C. The mixture was stirred for 1 h, cooled to -5 °C, and stirred for another 1 h. The mixture was filtered and dried under vacuum at 50 °C for 6 h to obtain 1.85 g of a white solid, with a yield of 54.0%.

[0120] Example 10

[0121] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g), 1,4-dioxane (15.0 g), and acetic acid (0.52 g) were added dropwise to a 100 mL single-necked flask. The mixture was stirred at room temperature for 2.0 h, filtered, and dried under vacuum at 50 °C for 6 h to obtain 2.15 g of white solid, with a yield of 62.7%.

[0122] Example 11

[0123] 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine (3.0 g), 2-methyltetrahydrofuran (15.0 g), and acetic acid (0.52 g) were added dropwise to a 100 mL single-necked flask. The mixture was stirred at room temperature for 2.0 h, filtered, washed with 2-methyltetrahydrofuran (6.0 g), and dried under vacuum at 50 °C for 16 h to obtain 2.98 g of white solid, with a yield of 86.9%.

[0124] Comparative Example 1

[0125] Add 5.00 g of 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine, 30 mL of ethyl acetate, and 1.69 g of nitric acid to a 100 mL single-necked flask and stir at room temperature for 1 h. No solid precipitates.

[0126] Test Example 1: Solubility Test of the Crystal Form of the Compound of the Present Invention

[0127] The solubility test method in this test example is performed according to the conventional method.

[0128] The solubility test results of acetate crystal form A, fumarate crystal form A, and hydrochloride crystal form A of this application are shown in Table 2.

[0129] Table 2 Solubility Data

[0130] As shown in Table 2, acetate crystal form A is readily soluble in purified water, and its solubility is much greater than that of fumarate and hydrochloride.

[0131] Test Example 2: Stability Test of the Crystal Form of the Compound of the Present Invention

[0132] The crystal form A of 1-[5-[4-(cyclopropylmethoxy)-2-fluorophenyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine acetate was subjected to an experiment to investigate the effects of high temperature (60℃), high humidity (92.5% RH), and light (4500 lx). Samples were taken on the 5th, 10th, and 30th days for testing, and the results are shown in Table 3.

[0133] Table 3 Stability of Crystal Form A

[0134] Under light (outer aluminum foil bag, inner polyethylene bag) and high humidity conditions, the sample's appearance, related substances, and crystal form remained unchanged. Under light (naked) conditions, the appearance gradually turned yellow, and the related substances increased with the duration of light exposure, while the crystal form remained unchanged. Under high temperature conditions, the appearance changed from a white powder to a yellow cake-like substance, and the related substances increased with time.

[0135] Test Example 3: DSC and TGA tests of the crystal form of the present invention

[0136] X-ray powder diffraction (XRPD):

[0137] The X-ray powder diffractometer used was a Brucker D8 Advance X-ray powder diffractometer. The test conditions were: 4.00°-50.002°, Step 0.020°, Steptime 0.2s, Target material: Cu, Voltage 40kV, Current 40mA.

[0138] Thermogravimetric analysis (TGA):

[0139] The thermogravimetric analyzer is model TA Q500 (TA, US). It uses an open Pt pan and heats from 25°C to 400°C at a rate of 10°C / min, with nitrogen as the carrier gas.

[0140] Differential scanning calorimetry (DSC):

[0141] The differential scanning calorimeter is model TA Q2000(TA, US), with an aluminum disk, unsealed, heating from 25°C to 300°C at a rate of 10°C / min, with nitrogen as the carrier gas.

[0142] The acetate crystal form A described in this invention begins to lose weight at approximately 50–190°C in the TGA spectrum, and continues to lose weight at temperatures above approximately 190°C. The TGA spectrum is shown in Figure 3, where the upper curve represents “weight (%)” and the lower curve represents “micro-weight (%) / °C”.

[0143] The endothermic peak of crystal form A of the acetate described in this invention is at 99±3℃ in the DSC spectrum, as shown in Figure 4.

[0144] As can be seen from the above description, the above embodiments of the present invention achieve the following technical effects: the compounds of the present invention themselves cannot form solids, but not all of their salts can form solids / crystals. For example, the nitrates of the compounds of the present invention in the above embodiments cannot form solids. Through a large number of experiments and screenings, the inventors finally screened out that the acetates of the compounds of the present invention can form crystals. Furthermore, the crystal form A of this application has high purity and excellent stability, making it more suitable for industrial-scale production. It can also be further applied to the preparation of potassium ion competitive acid blockers, as well as to the preparation of drugs for treating erosive esophagitis, gastric ulcers, duodenal ulcers, Helicobacter pylori eradication indications, and related diseases caused by excessive gastric acid.

[0145] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A crystal, characterized in that, The crystal is of crystal form A, and the structural formula of the crystal is shown in formula (I); The XRPD pattern of crystal form A includes six or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, 17.38°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 26.70°±0.2°, and 27.51°±0.2°.

2. The crystal according to claim 1, characterized in that, The XRPD pattern of crystal form A includes three or more 2θ values ​​selected from the following group: 6.60°±0.2°, 7.57°±0.2°, 10.02°±0.2°, 11.36°±0.2°, 13.66°±0.2°, 15.17°±0.2°, 16.07°±0.2°, 16.54°±0.2°, and 17.38°±0.2°. °, 17.78°±0.2°, 18.99°±0.2°, 19.74°±0.2°, 20.11°±0.2°, 21.49°±0.2°, 22.82°±0.2°, 23.78°±0.2°, 24.67°±0.2°, 26.70°±0.2°, 27.51°±0.2° and 28.82°±0.2°.

3. The crystal according to claim 1, characterized in that, The crystal form A has one or more technical features selected from the group consisting of: (i1) The XRPD pattern of the crystal form A is basically characterized by Figure 1; (i2) Crystal form A does not lose weight at 20–190°C; (i3) The DSC endothermic peak of crystal form A is 99±3℃.

4. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (a) a crystal as described in any one of claims 1 to 3, and (b) a pharmaceutically acceptable carrier.

5. A method for preparing a crystal as described in any one of claims 1 to 3, characterized in that, The crystal is of crystal form A; the method includes: (s1) dissolving the compound of formula (II) in an organic solvent and mixing it thoroughly; (s2) After adding acetic acid, the reaction is carried out and dried to obtain the crystal form A.

6. The method according to claim 5, characterized in that, The organic solvent includes one or more of ethyl acetate, isopropyl acetate, ethanol, tetrahydrofuran, methyl tert-butyl ether, acetonitrile, toluene, acetone, dichloromethane, 1,4-dioxane, or 2-methyltetrahydrofuran.

7. The method according to claim 5, characterized in that, The mass ratio of the compound of formula (II) to the organic solvent is 1:1 to 20, and / or the mass ratio of the compound of formula (II) to the acetic acid is 1 to 10:

1.

8. The method according to claim 5, characterized in that, The mass ratio of the compound of formula (II) to the organic solvent is 1:2 to 10, and / or the mass ratio of the compound of formula (II) to the acetic acid is 5 to 7:

1.

9. Use of the crystal according to any one of claims 1 to 3 in the preparation of a medicament or pharmaceutical composition for treating diseases caused by excessive gastric acid.

10. A method for treating diseases related to excessive stomach acid, characterized in that, The method includes administering a therapeutically effective amount of the crystal according to any one of claims 1 to 3 to the subject.

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