Tgorasone salt and application thereof

Abstract

The invention provides tegorazan D-tartrate and tegorazan phosphate and a preparation method thereof, the tegorazan D-tartrate and the tegorazan phosphate provided by the invention have better dissolving property, meanwhile, the impurity content is slowly increased in a long-term stability test, and excellent water solubility is beneficial to dissolution of a medicine from a pharmaceutical composition, so that the tegorazan D-tartrate and the tegorazan phosphate are suitable for clinical application. The medicine effects including improved bioavailability, maximum blood concentration, peak reaching time and the like can be better exerted. According to the preparation method of the tigorasone new salt, provided by the invention, the use of an organic solvent is reduced, and the problem of organic solvent residue is solved.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to the synthesis and application of new salts of tegoprazan. Background Art

[0002] Tegoprazan, also known as Tegorazan, has the chemical name of (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N-dimethyl-1H-benzo[d]imidazole-6-carboxamide, with a molecular weight of 387.38. Its structural formula is shown in Formula (I). It is a novel potassium ion competitive acid inhibitor developed by Pfizer Pharmaceuticals Limited and was approved for the treatment of erosive esophagitis and gastroesophageal reflux disease in South Korea in 2018.

[0003] Formula (I).

[0004] Gastrointestinal diseases related to gastric acid, such as gastroesophageal reflux disease, non-erosive reflux disease, gastric ulcer, and ulcers caused by non-steroidal anti-inflammatory drugs, are the most common diseases in gastrointestinal diseases. Histamine 2 receptor blockers and proton pump inhibitors (PPIs) are used for the treatment of the above symptoms, showing good efficacy and greatly improving the quality of life of patients. However, the satisfaction of existing drugs in the treatment of gastric acid-related gastrointestinal diseases is still not high. For example, the heartburn and esophageal reflux symptoms that occur at night during the use of proton pump inhibitors are still difficult to overcome. In addition, the relevant symptoms cannot be effectively relieved within the first 3 days of taking the medicine. Potassium ion competitive acid blockers (P-CABs) are a new mechanism of H-K-ATPase inhibitors and are reversible proton pump inhibitors.

[0005] Chinese Patent CN109769392A discloses various salts of tegoprazan and their preparation methods, and preferably pyroglutamate and malate. The patent points out that there are partial crystallizations in the prepared salt forms, indicating that there may be mixed crystal phenomena between batches of purity, thus affecting the product quality uniformity. Regarding the stability study, the patent only reported the crystal form stability for one month, and there may be crystal form stability problems in the long term. In addition, the solubility of the compound salt still has room for further improvement. The preparation method of this patent uses a large amount of ethyl acetate, and there is likely to be a problem of solvent residue. Therefore, it is urgent to study a new salt form of tegoprazan with long-term crystal form stability and higher solubility. Summary of the Invention

[0006] In order to solve the problems of the solubility and long-term stability of tegoprazan salts in the prior art, the present invention endeavors to find an acid with a more suitable acidity to form a salt with tegoprazan, in order to improve the solubility of tegoprazan and obtain a new crystal form with long-term stability.

[0007] Tegoprazan compounds have limited salt selection because the compound has very low water solubility (0.02 mg / ml, pH 6.8). Its solubility increases under acidic conditions, but the degradation products also increase under acidic conditions. Studies have shown that for various acid addition salts of tegoprazan, the total impurity increase during a one-month stability test is 0.1% - 0.3%, and the stronger the acidity of the acid, the faster the impurity growth. It can be seen that acidic conditions are a double-edged sword for the solubility and stability of the compound. Therefore, screening out organic or inorganic acids with suitable acidity to improve the compound's solubility while ensuring that the impurity content does not increase is the key to solving the problem in this invention.

[0008] This invention provides tegoprazan D-tartrate and tegoprazan phosphate. Specifically, tegoprazan D-tartrate can be the D-tartrate represented by the following formula (II), and tegoprazan phosphate can be the phosphate represented by the following formula (III).

[0009] Formula (II); Formula (III).

[0010] This invention screened the acid radicals commonly used in injection excipients, and the specific acid radicals are shown in Table 1.

[0011] Table 1 Commonly used acid radicals in injections

[0012] This invention also provides a preparation method for the new salt form of tegoprazan, which specifically includes the following steps: (1) Add a certain amount of organic solvent A to the reaction kettle, then add the tegoprazan raw material drug and acid, stir at a certain temperature, and concentrate under reduced pressure to dryness; (2) Add water and stir to dissolve, filter, and freeze-dry the filtrate to obtain the new salt of tegoprazan.

[0013] In the above preparation method of this invention, the organic solvent A in step 1 is one of methanol, acetonitrile, acetone, ethanol, and isopropanol, preferably methanol or acetonitrile.

[0014] In the above preparation method of this invention, the mass-volume ratio of the tegoprazan raw material drug to the organic solvent A is 1:3 - 10, preferably 1:4 - 6.

[0015] In the above preparation method of this invention, the acid in step (1) is D-tartaric acid or phosphoric acid.

[0016] In the above preparation method of this invention, the molar ratio of the equivalents of the tegoprazan raw material and the acid used is 1:1.

[0017] In the preparation method of the present invention described above, in step 1, the stirring time is 2 - 8 h, preferably 4 - 6 h, and the temperature during stirring is controlled at 20 - 70 °C, preferably 30 - 50 °C.

[0018] In the preparation method of the present invention described above, in step 2, the volume - mass ratio of the amount of water added to the tigolacic raw material is 1 - 13:1, preferably 2 - 5:1.

[0019] In the preparation method of the present invention described above, the specific steps of the freeze - drying in step 2 are shown in the following table:

[0020] The tigolacic salt obtained by the above - mentioned preparation method is a white solid powder, a stable amorphous crystal form, and has good pharmaceutical properties, such as good solubility, long - term stability, and precipitation stability. This preparation method reduces the use of organic solvents, can effectively reduce solvent residues, and reduces the risk of solvent residues.

[0021] The D - tartrate and phosphate of tigolacic provided by the present invention can be used as active ingredients and applied to the preparation of drugs for common gastrointestinal diseases such as gastroesophageal reflux disease, non - erosive reflux disease, and gastric ulcer.

[0022] In summary, the beneficial effects of the present invention are as follows: The new salt form of tigolacic provided by the present invention is different from all the salt forms disclosed in patents and is a new salt form of tigolacic.

[0023] The solubility of the D - tartrate and phosphate of tigolacic provided by the present invention is better than that of the preferred pyroglutamate and malate in the original research patent. The excellent water solubility is conducive to the dissolution of the drug from the pharmaceutical composition and better exerts the drug effect, including improved bioavailability, maximum plasma drug concentration, time to peak concentration, etc.

[0024] The results of the 6 - month crystal form stability test of the D - tartrate and phosphate of tigolacic provided by the present invention show that the impurity content is significantly lower than that of pyroglutamate and malate. On the premise of further improving the solubility, the impurity content of the new salt of tigolacic provided by the present invention is also well controlled.

[0025] The preparation method of the new salt of tigolacic provided by the present invention reduces the use of organic solvents and effectively avoids the problem of organic solvent residues. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic diagram of the 1H NMR result of the D - tartrate of tigolacic prepared by the embodiment of the present invention; Figure 2 It is a schematic diagram of the 1H NMR result of the phosphate of tigolacic prepared by the embodiment of the present invention; Figure 3 Schematic diagram of the stability results of the 0-day crystal form of tigolixostat D-tartrate of the present invention; Figure 4 Schematic diagram of the stability results of the 0-day crystal form of tigolixostat phosphate of the present invention; Figure 5 Schematic diagram of the stability results of the 6-month crystal form of tigolixostat phosphate and tigolixostat D-tartrate of the present invention. Detailed implementation mode

[0027] Next, in combination with the embodiments of the invention, the technical solutions in the embodiments of the invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0028] In the preparation method of the present invention, the freeze-drying step is specifically shown in the following table:

[0029] Example 1 Add 50 ml of methanol and 10 g of tigolixostat to the reaction flask, add 4 g of D-tartaric acid, stir at 20 - 30°C for 5 h. Concentrate under reduced pressure to dryness, add 20 ml of water, stir to dissolve, filter, and freeze-dry the filtrate to obtain 13.9 g of tigolixostat D-tartrate, with a yield of 99.3%. Example 2

[0030] Add 50 ml of methanol and 10 g of tigolixostat to the reaction flask, add 3.3 g of phosphoric acid, stir at 20 - 30°C for 5 h. Concentrate under reduced pressure to dryness, add 20 ml of water, stir to dissolve, filter, and freeze-dry the filtrate to obtain 12 g of tigolixostat phosphate, with a yield of 91.5%. Example 3

[0031] Add 100 ml of acetonitrile and 10 g of tigolixostat to the reaction flask, add 4 g of D-tartaric acid, stir at 30 - 50°C for 5 h. Concentrate under reduced pressure to dryness, add 120 ml of water, stir to dissolve, filter, and freeze-dry the filtrate to obtain 13.9 g of tigolixostat D-tartrate, with a yield of 99.3%. Example 4

[0032] Add 60 ml of acetonitrile and 10 g of tigolixostat to the reaction flask, add 3.3 g of phosphoric acid, stir at 30 - 50°C for 5 h. Concentrate under reduced pressure to dryness, add 100 ml of water, stir to dissolve, filter, and freeze-dry the filtrate to obtain 13.1 g of tigolixostat phosphate, with a yield of 98.5%. Example 5

[0033] Add 50 ml of acetone and 1 ml of water to a reaction flask, add 5 g of tigolacine, add 2 g of D-tartaric acid, and stir at 40 - 50 °C for 5 h. Concentrate under reduced pressure to dryness, add 65 ml of water, stir to dissolve, filter, and lyophilize the filtrate to obtain 6.8 g of tigolacine D-tartrate, with a yield of 97.1%. Example 6

[0034] Add 50 ml of acetone and 1 ml of water to a reaction flask, add 5 g of tigolacine, add 1.7 g of phosphoric acid, heat to 40 - 50 °C, and stir for 5 h. Concentrate under reduced pressure to dryness, add 20 ml of water, stir to dissolve, filter, and lyophilize the filtrate to obtain 6.2 g of tigolacine phosphate, with a yield of 94.5%.

[0035] The tigolacine D-tartrate and tigolacine phosphate prepared by the embodiments of the present invention were respectively structurally identified using 1H NMR spectra. The specific results are shown in Figure 1 and Figure 2 .

[0036] Comparative Example 1 At 25 °C, 100 g of the tigolacine crystalline compound and 34.98 g of L-pyroglutamic acid were completely dissolved in 1000 ml of methanol. Then, the resulting solution was concentrated at 50 °C while stirring under reduced pressure until a solid precipitated. At 25 °C, a co-solvent of acetone and ethyl acetate was added to the concentrate at a ratio of acetone:ethyl acetate = 1:4 (500 ml), and the resulting solution was vigorously stirred for 30 minutes. The solid was filtered out under reduced pressure, washed with 100 ml of ethyl acetate, and dried in vacuo at 40 °C for 16 hours to obtain 119.7 g of tigolacine pyroglutamate, with a yield of 88.7%.

[0037] Comparative Example 2 At 25 °C, 100 g of the tigolacine crystalline compound and 36.33 g of L-malic acid were completely dissolved in 1000 ml of methanol. Then, the resulting solution was concentrated at 50 °C while stirring under reduced pressure until a solid precipitated. At 25 °C, a co-solvent of acetone and ethyl acetate was added to the concentrate at a ratio of acetone:ethyl acetate = 1:4 (500 ml), and the resulting solution was vigorously stirred for 30 minutes. The solid was filtered out under reduced pressure, washed with 100 ml of ethyl acetate, and dried in vacuo at 40 °C for 16 hours to obtain 125.6 g of tigolacine malate, with a yield of 92.1%.

[0038] Experimental Example 1 Determination of the Solubility of New Salts of Tigolacine In the present invention, tigrasen raw material is respectively combined with L-tartaric acid, benzenesulfonic acid, citric acid, fumaric acid, p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid, D-tartaric acid, phosphoric acid, maleic acid, L-pyroglutamic acid, D-pyroglutamic acid, L-malic acid and D-malic acid, and each salt form is prepared according to the methods described in Examples 1-6. The purity of the product is confirmed by HPLC. On the premise of confirming that their purities are consistent, solubility measurement is carried out, and the solubility is measured by the supersaturation method. The water solubility of each salt form is shown in Table 2.

[0039] Table 2 Water Solubility of Tigrasen Salts

[0040] From the solubility results, it can be seen that the solubilities of tigrasen D-tartrate and tigrasen phosphate proposed in the present invention are more soluble than the preferred salt forms of pyroglutamate and malate in the original research patent.

[0041] Experimental Example 2 Stability Investigation According to the relevant guiding principles of ICH Q1A, the stabilities of tigrasen D-tartrate, phosphate, L-pyroglutamate, and L-malate were investigated. The investigation conditions were long-term at 5°C ± 3°C, accelerated at 25°C ± 2°C, 60% ± 5% RH, and accelerated at 30°C ± 2°C, 65% ± 5% RH. Samples were placed for 0 days, 1 month, 2 months, and 6 months. The water content was detected by Karl Fischer (General Principles of the Chinese Pharmacopoeia, 2020 Edition, Volume IV, Method 1 of 0832), and the related substances were detected by HPLC. The specific results are shown in Table 3. Among them, impurity A is (S)-4-((5,7-difluorochroman-4-yl)oxy)-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid, impurity B is 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide, and impurity C is R-5,7-difluorochroman-4-ol. The specific structures are as follows: Impurity A; Impurity B; Impurity C.

[0042] Table 3 Results of Stability Tests

[0043] The results show that under the condition of long-term storage for 6 months, the impurity content of tigrasen D-tartrate and tigrasen phosphate in the present invention is lower than that of tigrasen malate and tigrasen pyroglutamate in the original research, indicating that the new salts of tigrasen in the present invention have good long-term stability.

[0044] Experimental Example 3 Investigation on Crystal Form Stability Regarding the tigecalsen D-tartrate and phosphate, in accordance with the relevant guidelines of ICH Q1A, the crystal form stability of the above two salt forms was investigated. Under the heat-sealing conditions of a medicinal low-density polyethylene bag + an aluminum-plastic composite film bag, samples were taken and tested at 0 day and 6 months respectively under the long-term conditions of 5°C ± 3°C and the accelerated conditions of 25°C ± 2°C, 60% ± 5% RH. The crystal form was detected by powder diffraction (X-ray diffraction method, General Principles of the Fourth Part of Chinese Pharmacopoeia 2020 Edition, 0451). The X-ray diffraction patterns of tigecalsen D-tartrate and tigecalsen phosphate at 0 day are shown in Figure 3 and Figure 4 , and the X-ray diffraction patterns of tigecalsen D-tartrate and tigecalsen phosphate at 6 months are shown in Figure 5 , where the black is the diffraction pattern of phosphate at 5°C; the red is the diffraction pattern of phosphate at 25°C; the blue is the diffraction pattern of tartrate at 5°C; the green is the diffraction pattern of tartrate at 25°C.

[0045] Characterized by powder diffraction, the powder diffraction peak patterns of tigecalsen phosphate and tigecalsen D-tartrate are both diffuse. It shows that the crystals are arranged in a random combination form, proving that the product is not crystalline and is an amorphous crystal form.

[0046] It can be seen from the crystal form stability results that under the heat-sealed storage conditions of a medicinal low-density polyethylene bag + an aluminum-plastic composite film, tigecalsen phosphate and tigecalsen D-tartrate have good stability after being placed at 5°C and 25°C for 6 months, and both are stable amorphous crystal forms.

[0047] Experimental Example 4 Investigation on Precipitation Stability Tigecalsen D-tartrate, phosphate, L-pyroglutamate, and L-malate were completely dissolved in a buffer solution with a pH of 6.8 at a concentration of 20 mg / ml respectively, and stored at 37°C for 24 hours. The states of the solutions of each salt form were observed, and the results are shown in Table 4.

[0048] Table 4 Results of Precipitation Stability Experiment

[0049] It can be seen from the precipitation stability results that the D-tartrate and phosphate proposed in the present invention do not precipitate within 24 hours under high-concentration conditions, ensuring the safety of the injection dosage form.

[0050] Experimental Example 5 Determination of Solvent Residue in the Preparation Method The tigecalsen salt raw materials prepared in Examples 1-6 and Comparative Examples 1-2 of the present invention were taken respectively, and gas chromatography was used to determine the solvent residue in the raw drug. The chromatographic conditions are as follows, and the experimental results are shown in Table 5.

[0051] Gas Chromatographic Conditions:

[0052] Gas chromatograph settings:

[0053] Injection volume: 1 μl; Collection time: 20 minutes; Temperature programming:

[0054] Table 5 Results of solvent residue determination

[0055] The results show that the preparation method of tigolixium salt adopted in the present invention can effectively reduce solvent residues, thereby ensuring the safety, effectiveness and quality controllability of tigolixium D-tartrate and tigolixium phosphate bulk drugs.

[0056] Experimental Example 6 Pharmacokinetic study of tigolixium D-tartrate and tigolixium phosphate Male SD rats aged 7-9 weeks, weighing 200-250 g, 12 rats, were assigned to 3 groups, namely the intravenous administration group of tigolixium D-tartrate, the intravenous administration group of tigolixium phosphate, and the intragastric administration group of tigolixium.

[0057] Route of administration: intravenous injection, and an intragastric administration group of tigolixium was set as a control.

[0058] Dose of administration: single intravenous injection of 5 mg / kg, administration volume of 2 ml / kg, administration concentration of 2.5 mg / ml, prepared with normal saline. Intragastric administration of 5 mg / kg, administration volume of 2 ml / kg, administration concentration of 2.5 mg / ml, prepared with CMC-Na. All the above administration doses are calculated based on the prototype of tigolixium.

[0059] Sample collection and processing: 0.2 ml of blood was taken from the jugular vein before and at 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h after administration, placed in a heparin sodium anticoagulant test tube, and centrifuged at 4°C and 12000 rpm for 3 min within 2 h after collection. After centrifugation, the plasma was collected and temporarily stored in a container containing dry ice.

[0060] Biological sample test results

[0061] Pharmacokinetic results showed that both tigolacine D-tartrate and tigolacine phosphate existed in the form of free tigolacine base in vivo, and the oral bioavailability in rats was approximately 50%.

[0062] Experimental Example 7: Pharmacodynamic Study of Tigolacine D-Tartrate and Tigolacine Phosphate Test method: Sprague-Dawley (SD) rats were selected as the experimental system for the test. Sixty rats that passed the quarantine were divided into a normal control group, a model control group, a tigolacine 5.2 mg / kg control group, a tigolacine D-tartrate 2.6 mg / kg dose group, and a tigolacine phosphate 2.6 mg / kg dose group by the ordinary Latin method according to body weight. There were a total of 5 groups, with 12 animals in each group, half male and half female. The normal control group and the model control group were given 0.9% sodium chloride injection by tail vein injection; the tigolacine control group was given the reference oral preparation by gavage; tigolacine D-tartrate and phosphate were both given the corresponding concentration of the test preparation by tail vein injection. All animals were continuously administered for 7 days, and the administration volume was 10 ml / kg for all animals.

[0063] Modeling method: All animals must be strictly fasted for about 24 hours (water not prohibited) before modeling. After the model control group and the animals of tigolacine D-tartrate and phosphate groups were given the corresponding group preparations, and 1 hour after the tigolacine control group was gavaged, all animals were gavaged with 1.0 ml / animal of absolute ethanol. One hour after the administration of absolute ethanol, all animals were euthanized with CO2. After ligating the cardia and pylorus, the entire stomach was removed. About 3 - 5 ml of 10% formaldehyde solution was injected from the cardia with a syringe, and then the stomach was immersed in 10% formaldehyde. After soaking for 20 minutes, it was cut along the greater curvature of the stomach, and the contents were washed with 0.9% sodium chloride injection. The gastric mucosa was unfolded, and the length and width of the bleeding points or bleeding bands were measured with a vernier caliper under a stereoscopic dissection microscope or with the naked eye. After the observation, the stomach was fixed in 10% formaldehyde solution for histological examination.

[0064] Test results 1) General physical signs observation: During the test period, there were no obvious abnormalities in the general state of the animals in each group after administration.

[0065] 2) Body weight: During the test period, the body weights of the animals in each group increased steadily without obvious abnormalities. The body weights of male and female animals in the model control group, the tigolacine control group, the tigolacine D-tartrate group, and the phosphate group were basically the same as those of the normal control group in the same period (P > 0.05).

[0066] 3) Macroscopic observation and scoring: In the normal control group, the gastric mucosa of the animals was of normal color and luster, the surface was smooth, without bleeding points or bleeding bands, and the incidence of gastric mucosal injury was 0%. In the model control group, the overall color and luster of the gastric mucosa of the animals was normal, bleeding points or strip-shaped bleeding bands could be seen in the glandular area, and the incidence of gastric mucosal injury was 100%. In the tigolacic 5.2 mg / kg control group, the overall color and luster of the gastric mucosa of the animals was normal, bleeding points or strip-shaped bleeding bands could be seen in the glandular area, the incidence of gastric mucosal injury in each group was 100%, the injury inhibition rate was 66.20%, and the injury scores of the tigolacic control group were significantly lower than those of the model control group (P < 0.01). In the tigolacic D-tartrate and phosphate 2.6 mg / kg dose groups, the overall color and luster of the gastric mucosa of the animals was normal, bleeding points or strip-shaped bleeding bands could be seen in the glandular area, the incidence of gastric mucosal injury in each group was 100%, and the injury inhibition rates were 29.42% and 23.34% respectively. The injury scores of the tigolacic D-tartrate group were significantly lower than those of the model control group (P < 0.05).

[0067] 4) Histopathological examination: In the normal control group, the structures of each layer of the stomach were clear, and no congestion, bleeding or epithelial cell lesions were seen. In the model control group, the tigolacic control group and each test article group, different degrees of erosion, lymphocyte infiltration, submucosal edema, unclear structure of mucosal epithelium and gastric glands were seen in the mucosal layer of the gastric tissue. The bleeding scores and total lesion scores of the tigolacic control group were significantly lower than those of the model control group (P < 0.05 or P < 0.01); the bleeding scores of the tigolacic L-pyroglutamate group were significantly lower than those of the model control group (P < 0.05); although there was no significant statistical difference in the total lesion scores of the tigolacic D-tartrate and phosphate groups compared with the model control group (P > 0.05), they all showed a relatively obvious downward trend.

[0068] Summary of pathological scores of animals in each group (Mean±SD)

[0069] Conclusion: Under the conditions of this experiment, tigolacic D-tartrate and phosphate were continuously administered intravenously at a dose of 2.6 mg / kg / day for 7 days, and both had a significant improvement effect on the ethanol-induced gastric mucosal injury model in rats.

[0070] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A new salt of tigolixant, characterized in that, The new tegoprazan salt is the D-tartrate or phosphate of the compound shown by the following formula (I): Formula (I).

2. The novel tegoprazan salt according to claim 1, wherein, The tegoprazan D-tartrate has the structure shown by the following formula (II): Formula (II).

3. The new salt of tigolixant according to claim 1, wherein, The tegoprazan phosphate has the structure shown by the following formula (III): Formula (III).

4. A preparation method of a new salt of tigolacine, characterized in that, Specifically, it includes the following steps: (1) Add a certain amount of organic solvent A to the reaction kettle, then add the tegoprazan raw material and an acid, stir at a certain temperature, and concentrate to dryness under reduced pressure; (2) Add water and stir to dissolve, filter, and lyophilize the filtrate to obtain the new tegoprazan salt; Among them, in step (1), the organic solvent A is selected from one of methanol, acetonitrile, acetone, ethanol, and isopropanol; the acid is D-tartaric acid or phosphoric acid.

5. The preparation method of the new tegoprazan salt according to claim 4, characterized in that, The mass-volume ratio of the tegoprazan raw material to the organic solvent A is 1:3 - 10.

6. The preparation method of the new tegoprazan salt according to claim 4, wherein, The molar ratio of the equivalents of the tegoprazan raw material and the acid used is 1:

1.

7. The preparation method of the new tegoprazan salt according to claim 4, characterized in that, In step (1), the stirring time is 2 - 8 h, and the temperature during stirring is controlled at 20 - 70 °C.

8. The preparation method of the new tegoprazan salt according to claim 4, characterized in that, In step (2), the mass ratio of the amount of water added to the mass of the tegoprazan raw material is 1 - 13:

1.

9. The preparation method of the new tegoprazan salt according to claim 4, characterized in that, The specific steps of lyophilization in step (2) are shown in the following table: 。 10. The application of the new tegoprazan salt according to claim 1 in the preparation of drugs for gastrointestinal diseases.

11. Use of the new salt of tigolixant according to claim 10, characterized in that, The gastrointestinal diseases include gastroesophageal reflux disease, non-erosive reflux disease, and gastric ulcer.

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