Crystalline form of novel salt of imidazo [1,2-a] pyridine compound and method for preparing same

Abstract

The present invention relates to a novel salt of an imidazo [1,2-a] pyridine compound and, more specifically, to a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate and a method for preparing same. The crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate according to the present invention has excellent solubility, bulk density, light / temperature stability, acid / base stability, and the like, and thus can be effectively utilized in pharmaceutical formulation.

Description

Crystalline form of a novel salt of imidazo[1,2-a]pyridine compound and a method for preparing the same

[0001] The present invention relates to a crystalline form of a novel salt of an imidazo[1,2-a]pyridine compound and a method for preparing the same, and more specifically, to a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate and a method for preparing the same.

[0002] Gastrointestinal inflammatory diseases or acid-related diseases, such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), are the most common digestive diseases that affect most people in Korea and around the world.

[0003] To solve the problems of conventional proton pump inhibitors (PPIs), H + / K + -K of ATPase + There is growing interest in and need for potassium-competitive acid blockers (P-CABs, acid pump antagonists), drugs that reversibly bind to the binding site and inhibit acid secretion through potassium-competitive inhibition. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) exhibit rapid onset of action due to their mechanism of action, are easy to take regardless of mealtime, and are expected to be highly effective in alleviating nocturnal symptoms, a problem with irreversible PPIs.

[0004] Meanwhile, to be considered as a candidate for development as a pharmaceutical, a compound must possess not only desirable biological properties but also physical properties that facilitate its use in the manufacture of pharmaceutical compositions. Furthermore, such compounds should preferably possess a solid phase, allowing for easy preparation and stable formulation.

[0005] In this regard, Korean Patent No. 10-1777971 discloses azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone as an imidazo[1,2-a]pyridine derivative and a method for preparing the same, and Korean Patent No. 10-2496869 discloses azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate and a method for preparing the same.

[0006] However, conventional azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt has a very high scattering property in powder form and even a sticky property. Because of these properties, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt is very difficult to handle and difficult to formulate, and in particular, it has a problem that it is poorly soluble and can only be dissolved at low pH, which limits its expansion into formulations such as injections.

[0007] Accordingly, the inventors of the present invention have made extensive research efforts to discover a form of the imidazo[1,2-a]pyridine compound that is stable in various aspects and has improved solubility to enable expansion of formulations in order to use the compound pharmaceutically, and as a result, they have confirmed a novel salt and its crystal form that exhibit a remarkable effect that could not be predicted, thereby completing the present invention.

[0008] [Prior Art Literature]

[0009] [Patent Document]

[0010] (Patent Document 1) Republic of Korea Patent Publication No. 10-1777971

[0011] (Patent Document 2) Republic of Korea Patent Publication No. 10-2496869

[0012] One object of the present invention is to provide a crystalline form of a novel salt of an imidazo[1,2-a]pyridine compound.

[0013] Another object of the present invention is to provide a method for preparing a crystalline form of a novel salt of an imidazo[1,2-a]pyridine compound.

[0014] As used herein, the singular form may include the plural form unless the context clearly indicates otherwise.

[0015] When a part in this specification is said to “include” a certain component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0016] In addition, all numbers and expressions indicating the amounts of components, reaction conditions, etc. described in this specification should be understood to be modified by the term “about” in all cases unless otherwise specified.

[0017] In the present invention, the term "about" means having a value that falls within an acceptable standard error of the mean, as considered by one of ordinary skill in the art. Often, the term "about" means ± 15%, specifically ± 10%, and more specifically ± 5% of the value or range being described. For example, "about 10 wt%" means 10 wt% ± 1.5 wt%, specifically 10 wt% ± 1 wt%, and more specifically 10 wt% ± 0.5 wt%.

[0018]

[0019] Novel salts of imidazo[1,2-a]pyridine compounds

[0020] A novel salt of the imidazo[1,2-a]pyridine compound according to the present invention is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate.

[0021] Hereinafter, in this specification, the terms “chemical formula Ⅰ diphosphate” or “diphosphate” all mean “azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate.”

[0022] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is represented by the following chemical formula Ⅰ.

[0023] [Chemical Formula I]

[0024]

[0025]

[0026] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate of the present invention can be represented by the following chemical formula II.

[0027] [Chemical Formula II]

[0028]

[0029]

[0030] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate according to the present invention is characterized by having particularly excellent solubility, and specifically, the amount of solvent required to dissolve 1 g or 1 mL of the diphosphate may have a solubility of 1 to 30 mL, more specifically 1 to 28 mL, 1 to 24 mL, or 1 to 20 mL. Here, the solvent may be water, specifically purified water, but is not limited thereto.

[0031] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate according to the present invention has the advantage of being easily manufactured through a simple process and being obtained with a high purity and a high yield of 90% or more.

[0032] Furthermore, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt according to the present invention produces various crystal forms due to differences in reaction temperature, reaction speed, etc. even under similar solvent conditions, and these crystal forms have excellent photostability, heat stability, long-term storage stability, etc., and can be usefully utilized in the formulation of pharmaceuticals.

[0033] One aspect of the present invention provides a pharmaceutical composition comprising azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate or a crystalline form thereof as an active ingredient together with a pharmaceutically acceptable carrier.

[0034] The pharmaceutical composition according to the present invention may additionally comprise one or more pharmaceutically acceptable carriers, one or more excipients and / or diluents.

[0035] Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids, such as ethanol, glycerol, water, and the like. The amount of carrier in the therapeutic composition can range from about 5 to about 99 weight percent, based on the total weight of the therapeutic composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and diluents include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, bulking agents, antioxidants, lubricants, flavoring agents, thickening agents, coloring agents, surfactants, emulsifiers, suspending agents, and the like. Such excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and it will be apparent to those skilled in the art that any other pharmaceutically acceptable carrier, excipient and diluent may be used.

[0036] The pharmaceutical composition of the present invention comprises azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate in a therapeutically effective amount.

[0037] The pharmaceutical composition of the present invention can treat or prevent a disease selected from the group consisting of peptic ulcer, gastric / duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, and gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD).

[0038]

[0039] Method for preparing a novel salt of imidazo[1,2-a]pyridine compound

[0040] In the present invention, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be synthesized according to the following reaction scheme 1.

[0041] [Reaction Formula 1]

[0042]

[0043]

[0044] In the above reaction scheme 1, 8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid can be obtained as described in Korean Patent Publication No. 10-1777971, and the specific process of the above reaction scheme 1 can also be performed according to the contents disclosed therein.

[0045]

[0046] One aspect of the present invention provides a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, characterized in that azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is reacted with phosphoric acid.

[0047] In a specific example according to the present invention, the phosphoric acid may be added in a molar ratio of 2.0 to 5.0 equivalents, specifically 2.0 to 3.0 equivalents, relative to 1.0 equivalent of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone.

[0048] In another specific example according to the present invention, a first solution containing the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent and a second solution containing phosphoric acid and a second solvent may be mixed.

[0049] In another specific embodiment according to the present invention, the first solvent and the second solvent may each independently be selected from the group consisting of alcohols having 1 to 4 carbon atoms, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP), purified water, and mixtures thereof, and specifically, the first solvent and the second solvent may each independently be alcohols having 1 to 4 carbon atoms.

[0050] In another specific embodiment according to the present invention, the first solvent may be methanol or a mixed solvent of methanol and one or more organic solvents other than methanol, the second solvent may be methanol, and specifically, the first solvent and the second solvent may both be methanol, and under the first and second solvent conditions, the diphosphate salt according to the present invention may be amorphous.

[0051] In another specific example according to the present invention, the reaction may be carried out by reacting azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with phosphoric acid at about 10°C to about 30°C, specifically about 20°C to about 25°C, then heating and stirring at about 45°C to about 60°C, specifically about 50°C to about 55°C, and then cooling and stirring at about 10°C to about 30°C, specifically about 15°C to about 20°C. Here, phosphoric acid may be slowly added to azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone for 10 minutes or more, specifically for 30 minutes or more.

[0052] In another specific example according to the present invention, the result obtained by reacting the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with phosphoric acid may be concentrated and dried, and the drying may be performed by vacuum drying or nitrogen drying.

[0053]

[0054] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may specifically be a solvate.

[0055] In the case of using a solvate, the method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate according to the present invention may include the steps of (i) producing a solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone; and (ii) reacting the solvate obtained in (i) with phosphoric acid to produce a diphosphate.

[0056] In a specific example according to the present invention, the solvate of step (i) may be prepared by reacting azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with an alcohol having 1 to 4 carbon atoms.

[0057] In another specific embodiment according to the present invention, the alcohol having 1 to 4 carbon atoms may be methanol, ethanol, n-propyl alcohol, isopropyl alcohol or butanol, specifically, isopropyl alcohol, but is not limited thereto.

[0058] In another specific example according to the present invention, the solvate of the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be obtained by vacuum drying at a temperature of about 20°C or higher and about 35°C or lower.

[0059] In another specific example according to the present invention, in step (ii), phosphoric acid may be added in a molar ratio of 2.0 to 5.0 equivalents, specifically 2.0 to 3.0 equivalents, with respect to 1.0 equivalent of the solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone.

[0060]

[0061] In the present invention, the terms “first”, “second”, etc. do not specifically indicate an order, but are simply used to indicate that the meanings of the terms described below are different from each other.

[0062] In another specific embodiment according to the present invention, the reaction of step (ii) may include a step of mixing a first solution comprising a solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent, and a second solution comprising phosphoric acid and a second solvent.

[0063] In another embodiment according to the present invention, the first solution may be first stirred in the reactor and then the second solution may be added, or the second solution may be first stirred in the reactor and then the first solution may be added.

[0064] The first solvent and the second solvent may each independently include a solvent selected from the group consisting of alcohols having 1 to 4 carbon atoms, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP), purified water, and mixtures thereof.

[0065] In another specific embodiment according to the present invention, the first solvent is an organic solvent, the second solvent is an organic solvent, and the first and second solvents may be the same. Specifically, the first solvent and the second solvent may each independently be an alcohol having 1 to 4 carbon atoms.

[0066] In another specific embodiment according to the present invention, the first solvent may be methanol or a mixed solvent comprising methanol and one or more organic solvents other than methanol, and the second solvent may be methanol. More specifically, both the first solvent and the second solvent may be methanol. Under the first and second solvent conditions, the diphosphate salt according to the present invention may be amorphous.

[0067] In another specific embodiment according to the present invention, the reaction of step (ii) may be performed by reacting a solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with phosphoric acid at about 10°C to about 30°C, specifically about 20°C to about 25°C, then heating and stirring at about 45°C to about 60°C, specifically about 50°C to about 55°C, and then cooling and stirring at about 10°C to about 30°C, specifically about 15°C to about 20°C. Here, phosphoric acid can be slowly added to the solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone for 10 minutes or more, specifically, for 30 minutes or more.

[0068] In another specific embodiment according to the present invention, the reaction of step (ii) may be carried out by completely dissolving the solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone at about 45°C to 60°C, specifically at about 50°C to 55°C, and then reacting phosphoric acid at about 30°C to about 50°C, specifically at about 40°C to about 45°C, heating and stirring at about 45°C to about 60°C, specifically at about 50°C to about 55°C, and then cooling and stirring at about 10°C to about 30°C, specifically at about 15°C to about 20°C.

[0069] In another specific embodiment according to the present invention, the resultant product obtained by reacting the solvate of the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with phosphoric acid may be concentrated and dried. The concentration and drying may each be performed by a method performed in conventional salt production. The drying may be performed by vacuum drying, nitrogen drying, or freeze drying.

[0070]

[0071] Another aspect of the present invention provides azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, characterized in that it is manufactured by the above manufacturing method.

[0072]

[0073] Method for preparing crystalline form of imidazo[1,2-a]pyridine compound diphosphate salt

[0074] In the present invention, the crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate is prepared by (i) mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent to prepare a first solution;

[0075] (ii) preparing a second solution by mixing phosphoric acid and a second solvent; and

[0076] (iii) It can be manufactured by mixing and reacting the first solution and the second solution.

[0077]

[0078] In a specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be a solvate.

[0079]

[0080] In another specific embodiment according to the present invention, the first solvent may be selected from the group consisting of acetone, dichloromethane, ethanol, isopropanol, and mixtures thereof. In this case, the second solvent may be selected from the group consisting of acetone, ethanol, and isopropanol. Under the first and second solvent conditions, the diphosphate salt according to the present invention may be in the crystalline form Form I.

[0081] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate may be a crystalline Form I having a powder X-ray diffraction pattern having three or more diffraction peaks selected from the group consisting of 2θ values ​​of 8.984° (±0.2°), 6.626° (±0.2°), 20.914° (±0.2°), 13.843° (±0.2°), 10.525° (±0.2°), 22.809° (±0.2°), 11.750° (±0.2°), 27.214° (±0.2°), and 23.476° (±0.2°).

[0082] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate may be a crystalline Form I that exhibits a powder X-ray diffraction pattern further having at least one diffraction peak selected from the group consisting of 2θ values ​​of 23.057° (±0.2°), 19.929° (±0.2°), 20.166° (±0.2°), 17.998° (±0.2°), 22.228° (±0.2°), and 15.166° (±0.2°).

[0083] In one specific example according to the present invention, the crystalline Form I may have a differential scanning calorimetry (DSC) endothermic peak at 197.28°C (±0.5°C) when the heating rate is 10°C / min.

[0084] The amount of solvent required to dissolve 1 g of the above-mentioned crystalline Form I may have a solubility of 1 to 30 mL, more specifically 1 to 28 mL, 1 to 24 mL, or 1 to 20 mL. Here, the solvent may be water, specifically purified water, but is not limited thereto.

[0085]

[0086] In another specific embodiment according to the present invention, the first solvent may be selected from the group consisting of isopropanol, tetrahydrofuran, and mixtures thereof. In this case, the second solvent may be selected from isopropanol or tetrahydrofuran. Under the first and second solvent conditions, the diphosphate salt according to the present invention may be in the crystalline form Form II.

[0087] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate may be a crystalline Form II having a powder X-ray diffraction pattern having three or more diffraction peaks selected from the group consisting of 2θ values ​​of 4.158° (±0.2°), 16.637° (±0.2°), 24.248° (±0.2°), 22.466° (±0.2°), 10.185° (±0.2°), 12.934° (±0.2°), 13.802° (±0.2°), 14.489° (±0.2°), and 7.223° (±0.2°).

[0088] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate may be a crystalline Form II having a powder X-ray diffraction pattern having at least one diffraction peak further selected from the group consisting of 2θ values ​​of 17.224° (±0.2°), 20.447° (±0.2°), 24.701° (±0.2°), 18.289° (±0.2°), 12.529° (±0.2°), and 21.922° (±0.2°).

[0089] In one specific example according to the present invention, the crystalline Form II may have a differential scanning calorimetry (DSC) endothermic peak at 187.44°C (±0.5°C) when the heating rate is 10°C min.

[0090] The amount of solvent required to dissolve 1 g of the above crystalline Form II may have a solubility of 1 to 30 mL, more specifically 1 to 28 mL, 1 to 24 mL, or 1 to 20 mL. Here, the solvent may be water, specifically purified water, but is not limited thereto.

[0091] In another specific embodiment according to the present invention, the first solvent may be acetonitrile. In this case, the second solvent may also be acetonitrile. Under the first and second solvent conditions, the diphosphate salt according to the present invention may be in the crystalline form Form III.

[0092] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate is a powder having three or more diffraction peaks selected from the group consisting of 3.807° (±0.2°), 8.381° (±0.2°), 11.128° (±0.2°), 8.999° (±0.2°), 22.384° (±0.2°), 15.178° (±0.2°), 13.139° (±0.2°), 16.750° (±0.2°), 18.782° (±0.2°), and 14.388° (±0.2°) in the 2θ value of the X-ray powder diffraction pattern. It may be a crystalline FormⅢ that exhibits an X-ray diffraction pattern.

[0093] In one specific example according to the present invention, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate has 2θ values ​​of an X-ray powder diffraction pattern of 20.163° (±0.2°), 29.629° (±0.2°), 25.191° (±0.2°), 25.401° (±0.2°), 23.030° (±0.2°), 21.786° (±0.2°), 19.385° (±0.2°), 18.988° (±0.2°), 19.714° (±0.2°), 20.843° (±0.2°), and 21.304° It may be a crystalline FormⅢ that exhibits a powder X-ray diffraction pattern having at least one diffraction peak further selected from the group consisting of (±0.2°).

[0094] In one specific example according to the present invention, the crystalline Form III may have differential scanning calorimetry (DSC) endothermic peaks at 129.08°C, 170.91°C, and 191.88°C (±0.5°C) when the heating rate is 10°C / min.

[0095] The amount of solvent required to dissolve 1 g of the above-mentioned crystalline Form III may have a solubility of 1 to 30 mL, more specifically 1 to 28 mL, 1 to 24 mL, or 1 to 20 mL. Here, the solvent may be water, specifically purified water, but is not limited thereto.

[0096]

[0097] In another specific embodiment according to the present invention, the reaction of step (iii) may be performed by reacting the first solution and the second solution at about 10°C to about 30°C, specifically about 20°C to about 25°C, then heating and stirring at about 45°C to about 60°C, specifically about 50°C to about 55°C, and then cooling and stirring at about 10°C to about 30°C, specifically about 15°C to about 20°C. Here, the second solution may be slowly added to the first solution for 10 minutes or more, specifically about 30 minutes or more.

[0098] In another specific embodiment according to the present invention, the reaction of step (iii) may be carried out by completely dissolving azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone at about 45°C to 60°C, specifically at about 50°C to 55°C, then reacting phosphoric acid at about 30°C to about 50°C, specifically at about 40°C to about 45°C, heating and stirring at about 45°C to about 60°C, specifically at about 50°C to about 55°C, and then cooling and stirring at about 10°C to about 30°C, specifically at about 15°C to about 20°C.

[0099]

[0100] In another specific embodiment according to the present invention, the step of preparing the diphosphate crystalline form may be a step of concentrating and drying the product produced by the reaction of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and phosphoric acid. The concentration and drying may each be performed by a method performed in the production of a conventional salt. The drying may be performed by vacuum drying, nitrogen drying, or freeze drying.

[0101] In another specific embodiment according to the present invention, the step of preparing the diphosphate crystalline form may further include the steps of filtering the product formed by the reaction of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and phosphoric acid, i.e., the diphosphate; washing the product; and drying the product. The filtering step and the washing step may each be performed by a method performed in a typical salt preparation. The drying step may be performed at about 35°C to about 50°C, specifically, at about 35°C to about 45°C, and may be performed by vacuum drying or nitrogen drying.

[0102]

[0103] In another specific embodiment according to the present invention, the diphosphate crystalline form Form I can be prepared from crystalline Form II or Form III. Specifically, it can be prepared by a method including the step of stirring azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate of crystalline Form II or Form III and a solvent at about 45°C to about 60°C, specifically about 50°C to 55°C, and cooling to about 10°C to about 30°C, specifically about 15°C to about 20°C and stirring. The solvent may be a solvent selected from the group consisting of an alcohol having 1 to 4 carbon atoms, acetone, ethyl acetate, dichloromethane, and mixtures thereof, and may be specifically, but is not limited to, acetone.

[0104] In another specific embodiment according to the present invention, the production of the diphosphate crystal form may further include the steps of filtering the produced product; washing; and drying. The filtering and washing steps may each be performed using a method commonly used in the production of salts. The drying step may be performed at a temperature of about 35°C to about 50°C, specifically about 35°C to about 45°C, and may be performed by vacuum drying or nitrogen drying.

[0105]

[0106] Another aspect of the present invention provides a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, characterized in that it is manufactured by the above manufacturing method.

[0107] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate and its crystalline form according to the present invention have the advantage of being easily manufactured by a simple process and being obtained with a high purity and a high yield of 90% or more.

[0108] Furthermore, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate and its crystalline form according to the present invention have excellent solubility, bulk density, light / temperature stability, and acid / base stability, and thus can be usefully utilized in the formulation of pharmaceuticals.

[0109] In particular, it has excellent solubility in water, making it easy to clean and maintain equipment during commercial production.

[0110] FIG. 1 shows an X-ray powder diffraction (XRD) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate prepared according to Example 1 of the present invention.

[0111] Figure 2 shows an X-ray powder diffraction (XRD) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I prepared according to Example 2 (2-1 to 2-7) of the present invention.

[0112] Figure 3 shows a differential scanning calorimetry (DSC) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I prepared according to Example 2 (2-1 to 2-7) of the present invention.

[0113] FIG. 4 shows an X-ray powder diffraction (XRD) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form II prepared according to Example 3 (3-1 to 3-3) of the present invention.

[0114] FIG. 5 shows a differential scanning calorimetry (DSC) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form II prepared according to Example 3 (3-1 to 3-3) of the present invention.

[0115] FIG. 6 shows an X-ray powder diffraction (XRD) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form III prepared according to Example 4 of the present invention.

[0116] Figure 7 shows a differential scanning calorimetry (DSC) analysis diagram of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form III prepared according to Example 4 of the present invention.

[0117] FIG. 8 shows a photograph comparing the bulk density of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate prepared according to Example 1 of the present invention and azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate prepared according to Comparative Example 1.

[0118] FIG. 9 shows photographs comparing the bulk densities of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline forms I to III prepared according to Examples 2 to 4 of the present invention and azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate prepared according to Comparative Example 1.

[0119] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning within the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0120] Additionally, the experimental procedures specified in this specification are identical to those commonly performed in the art unless specifically described otherwise.

[0121] Hereinafter, the present invention will be described in detail.

[0122]

[0123] <Measurement method>

[0124] The following measurement method is commonly applied to each of the embodiments according to the present invention.

[0125] 1. NMR analysis

[0126] Nuclear magnetic resonance (NMR) analysis was performed using Bruker 400.

[0127] 2. Thermal analysis (DSC)

[0128] Differential scanning calorimetry (DSC) was performed using a DSC 8000 (PerkinElmer). Samples were evaluated using a linear heating ramp at 10°C / min over the range of 30°C to 300°C.

[0129] 3. X-ray powder diffraction (XPRD)

[0130] X-ray powder diffraction patterns were obtained using a solid-state detector with a D8 Focus (Bruker ASX) over the range of diffraction angles (2θ) from 2° to 40° with a step size of 0.02°.

[0131] 4. HPLC purity analysis

[0132] Purity analysis was performed on the obtained samples using the Agilent 1260 series.

[0133] 5. pH measurement

[0134] The pH of the obtained sample was measured using a 913 pH meter from Metrohm.

[0135]

[0136] Manufacturing Example 1: Synthesis of Compound I

[0137]

[0138] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was synthesized in the same manner as the preparation method of compound Example 6 of Korean Patent Publication No. 10-1777971.

[0139] 1 H NMR (400 MHz, CDCl3); δ7.63(d,J=1.2 Hz, 1H), 7.13(dd,J=8.4, 6.8 Hz, 1H), 7.06-7.04(m, 2H), 6.42(d,J=1.2 Hz, 1H), 4.86-4.84(m, 1H), 4.41-4.28(m, 4H), 4.37(d,J=4.4 Hz, 2H), 3.75-3.69(m, 1H), 2.43-2.34(m, 13H)

[0140]

[0141] Manufacturing Example 2: Preparation of solvate of compound Ⅰ

[0142] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained in the above Preparation Example 1 was crystallized in an alcohol solvent (isopropyl alcohol, IPA) and vacuum dried at about 30°C to 35°C to obtain a solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone.

[0143]

[0144] Example 1-1: Preparation of diphosphate salt of compound Ⅰ

[0145]

[0146] 11.77 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 250 mL of methanol were added to a reactor and stirred at 20 to 25 °C for 10 minutes. Thereafter, 6.68 g of 85% phosphoric acid was dissolved in 50 mL of methanol and added dropwise over 1 hour, stirred at the same temperature for 1 hour, heated to 50 to 55 °C and stirred for 2 hours, then cooled to 15 to 20 °C and stirred for an additional hour. The obtained product was concentrated and vacuum-dried to prepare 15.1 g (98%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0147] The compound obtained by the above manufacturing method was confirmed to be amorphous.

[0148]

[0149] Example 1-2: Preparation of diphosphate salt of compound Ⅰ

[0150] 10 g each of the diphosphate salts of compound Ⅰ obtained in the above Example 1-1 and Examples 2-1 to 4 below were added to a reactor together with 100 mL of purified water, and stirred at 20°C to 25°C for 10 minutes. Thereafter, the mixture was cooled and freeze-dried to produce 9.8 g (98%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0151] The compound obtained by the above manufacturing method was confirmed to be amorphous.

[0152]

[0153] Analysis 1: XRD measurement of diphosphate of compound Ⅰ

[0154] The results of measuring the X-ray powder diffraction pattern of the amorphous diphosphate compound I according to the present invention are shown in Fig. 1. As a result of the XRD pattern of the compound obtained in Example 1, the compound obtained by the above manufacturing method was confirmed to be amorphous (Fig. 1).

[0155]

[0156] Example 2-1: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0157] 10 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 167.8 g of acetone were added to a reactor and stirred at 20°C to 25°C for 10 minutes. Thereafter, a solution of 33.6 g of acetone dissolved in 5.72 g of 85% phosphoric acid was slowly added dropwise over 60 minutes, stirred at 20°C to 25°C for 1 hour, heated to 50°C to 55°C and stirred for 1 hour, then cooled to 15°C to 20°C and stirred for an additional hour. After this, the produced solid was filtered, washed with 20.1 g of acetone, and then vacuum dried at 40°C to produce 13.06 g (99%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate.

[0158] The compound obtained by the above manufacturing method was confirmed to be a FormⅠ crystal form.

[0159] - 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d,J=1.2 Hz, 1H), 7.12-7.16 (m, 1H), 7.06-7.08 (m, 2H), 6.39 (s, 1H), 5.13 (t,J=5.0 Hz, 1H), 4.37 (d,J=4.8 Hz 4H), 4.05 (s, 2H), 2.36 (s, 3H), 2.34 (s, 6H), 2.25-2.31 (m, 2H), 2.24 (s, 3H)

[0160]

[0161] Example 2-2: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0162] 11.77 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 70 mL of ethanol were added to a reactor, and stirred at 20 to 25°C for 10 minutes. Thereafter, 6.68 g of 85% phosphoric acid was dissolved in 30 mL of ethanol, added dropwise over 1 hour, stirred at the same temperature for 1 hour, heated to 50 to 55°C, stirred for 2 hours, cooled to 15 to 20°C, and stirred for an additional hour. The resulting solid was filtered, washed with 30 mL of ethanol, and dried under vacuum at 40°C to prepare 14.8 g (96%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0163] The compound obtained by the above manufacturing method was confirmed to be a Form I crystal form.

[0164]

[0165] Example 2-3: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0166] 5.88 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2, 75 mL of dichloromethane, and 50 mL of acetone were added to a reactor, and stirred at 20 to 25°C for 10 minutes. Thereafter, 3.34 g of 85% phosphoric acid dissolved in 25 mL of acetone was added, stirred at the same temperature for 1 hour, heated to 50 to 55°C, stirred for 1 hour, cooled to 15 to 20°C, and stirred for an additional hour. The resulting solid was filtered, washed with 15 mL of acetone, and dried under vacuum at 40°C to prepare 7.46 g (97%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0167] The compound obtained by the above manufacturing method was confirmed to be a FormⅠ crystal form.

[0168]

[0169] Example 2-4: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0170] 11.77 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 250 mL of isopropanol were added to a reactor, stirred at 50°C to 55°C until completely dissolved, and then cooled to 40°C to 45°C. Thereafter, 6.68 g of 85% phosphoric acid was dissolved in 50 mL of isopropanol and added dropwise over 1 hour, heated to 50°C to 55°C and stirred for 2 hours, then cooled to 15°C to 20°C and stirred for an additional hour. The resulting solid was filtered, washed with 30 mL of isopropanol, and then vacuum dried at 40°C to produce 14.52 g (94%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0171] The compound obtained by the above manufacturing method was confirmed to be a FormⅠ crystal form.

[0172]

[0173] Example 2-5: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0174] 11.77 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 250 mL of acetone were added to a reactor, stirred at 50 to 55°C until completely dissolved, and then cooled to 40 to 45°C. Thereafter, 6.68 g of 85% phosphoric acid was dissolved in 50 mL of acetone, added dropwise over 1 hour, heated to 50 to 55°C, stirred for 2 hours, cooled to 15 to 20°C, and stirred for an additional hour. The resulting solid was filtered, washed with 30 mL of acetone, and then vacuum-dried at 40°C to prepare 15.4 g (100%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0175] The compound obtained by the above manufacturing method was confirmed to be a FormⅠ crystal form.

[0176]

[0177] Example 2-6: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0178] 5 g of Form II crystalline azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt and 150 mL of acetone were added to a reactor and stirred at 50°C to 55°C for more than 2 hours. After cooling to 15°C to 20°C and stirring for an additional hour, the resulting solid was filtered, washed with 30 mL of acetone, and dried under vacuum at 40°C to obtain 4.95 g (99%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0179] The compound obtained by the above manufacturing method was confirmed to be a FormⅠ crystal form.

[0180]

[0181] Example 2-7: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅰ

[0182] 5.6 g of Form Ⅲ crystalline azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt and 84 mL of acetone were added to a reactor and stirred at 50°C to 55°C for more than 2 hours. After cooling to 15°C to 20°C and stirring for an additional hour, the resulting solid was filtered, washed with 18 mL of acetone, and dried under vacuum at 40°C to obtain 5.16 g (92%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0183] The compound obtained by the above manufacturing method was confirmed to be a FormⅠ crystal form.

[0184]

[0185] Analysis 2: XRD and DSC measurements of crystalline Form I

[0186] The results of measuring X-ray powder diffraction of the Form I crystal form of the diphosphate of compound I according to the present invention are shown in Fig. 2. The XRD pattern of the Form I crystal form according to the present invention has diffraction peaks having 2θ values ​​(unit: °) of 8.984°, 6.626°, 20.914°, 13.843°, 10.525°, 22.809°, 11.750°, 27.214°, and 23.476°. In addition, it further has at least one diffraction peak selected from the group consisting of 23.057°, 19.929°, 20.166°, 17.998°, 22.228°, and 15.166°.

[0187] Differential scanning calorimetry (DSC) of the Form I crystalline form of the diphosphate of compound I according to the present invention was performed using a DSC 8000 (PerkinElmer). The sample was evaluated using a linear heating ramp at 10°C / min over a range of 30°C to 300°C. The results are shown in Figure 3, and the endothermic peak of the DSC appeared at 197.28°C.

[0188]

[0189] Example 3-1: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅱ

[0190] 5.88 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 125 mL of isopropyl alcohol were added to a reactor and stirred at 20 to 25°C for 10 minutes. Thereafter, 3.34 g of 85% phosphoric acid dissolved in 25 mL of isopropyl alcohol was added, stirred at the same temperature for 1 hour, heated to 50 to 55°C and stirred for 1 hour, then cooled to 15 to 20°C and stirred for an additional 1 hour. The resulting solid was filtered, washed with 15 mL of isopropyl alcohol, and then vacuum-dried at 40°C to prepare 7.56 g (98%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0191] The compound obtained by the above manufacturing method was confirmed to be a FormⅡ crystal form.

[0192]

[0193] Example 3-2: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅱ

[0194] 5.88 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 125 mL of tetrahydrofuran were added to a reactor, and stirred at 20 to 25 °C for 10 minutes. Thereafter, 3.34 g of 85% phosphoric acid dissolved in 25 mL of tetrahydrofuran was added, stirred at the same temperature for 1 hour, heated to 50 to 55 °C, stirred for 1 hour, cooled to 15 to 20 °C, and stirred for an additional 1 hour. The resulting solid was filtered, washed with 15 mL of tetrahydrofuran, and dried under vacuum at 40 °C to prepare 7.7 g (100%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0195] The compound obtained by the above manufacturing method was confirmed to be a FormⅡ crystal form.

[0196]

[0197] Example 3-3: Preparation of diphosphate of compound Ⅰ - crystalline Form Ⅱ

[0198] 11.77 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 250 mL of isopropanol were added to a reactor and stirred at 20 to 25°C for 10 minutes. Thereafter, 6.68 g of 85% phosphoric acid was dissolved in 50 mL of isopropanol and added dropwise over 1 hour, stirred at the same temperature for 1 hour, heated to 50 to 55°C and stirred for 2 hours, then cooled to 15 to 20°C and stirred for an additional hour. The resulting solid was filtered, washed with 30 mL of isopropanol, and then vacuum-dried at 40°C to prepare 14.52 g (94%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0199] The compound obtained by the above manufacturing method was confirmed to be a FormⅡ crystal form.

[0200]

[0201] Analysis 3: XRD and DSC measurements of crystalline Form II

[0202] The results of measuring X-ray powder diffraction of the Form II crystal form of the diphosphate of compound I according to the present invention are shown in Fig. 4. The XRD pattern of the Form II crystal form according to the present invention has diffraction peaks having 2θ values ​​(unit: °) of 4.158°, 16.637°, 24.248°, 22.466°, 10.185°, 12.934°, 13.802°, 14.489°, and 7.223°. In addition, it further has at least one diffraction peak selected from the group consisting of 17.224°, 20.447°, 24.701°, 18.289°, 12.529°, and 21.922°.

[0203] Differential scanning calorimetry (DSC) of the Form II crystal form of the diphosphate of compound I according to the present invention was performed using DSC 8000 (PerkinElmer). The results are shown in Fig. 5, and the endothermic peak of DSC appeared at 187.44°C.

[0204]

[0205] Example 4: Preparation of diphosphate salt of compound Ⅰ - crystalline Form Ⅲ

[0206] 11.77 g of the IPA solvate of compound Ⅰ obtained in the above Preparation Example 2 and 250 mL of acetonitrile were added to a reactor and stirred at 20°C to 25°C for 10 minutes. Thereafter, 6.68 g of 85% phosphoric acid was dissolved in 50 mL of acetonitrile and added dropwise over 1 hour, stirred at the same temperature for 1 hour, heated to 50°C to 55°C and stirred for 2 hours, then cooled to 15°C to 20°C and stirred for an additional hour. The resulting solid was filtered, washed with 30 mL of acetonitrile, and then vacuum dried at 40°C to produce 14.2 g (92%) of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

[0207] The compound obtained by the above manufacturing method was confirmed to be a FormⅢ crystal form.

[0208]

[0209] Analysis 4: XRD and DSC measurements of crystalline FormⅢ

[0210] The results of measuring X-ray powder diffraction of the Form III crystal form of the diphosphate of compound I according to the present invention are shown in Fig. 6. The XRD pattern of the Form III crystal form according to the present invention has diffraction peaks with 2θ values ​​(unit: °) of 3.807°, 8.381°, 11.128°, 8.999°, 22.384°, 15.178°, 13.139°, 16.750°, 18.782°, and 14.388°. Additionally, it further has at least one diffraction peak selected from the group consisting of 20.163°, 29.629°, 25.191°, 25.401°, 23.030°, 21.786°, 19.385°, 18.988°, 19.714°, 20.843°, and 21.304°.

[0211] Differential scanning calorimetry (DSC) of the Form III crystal form of the diphosphate of compound I according to the present invention was performed using DSC 8000 (PerkinElmer). The results are shown in Fig. 7, and the endothermic peaks of DSC appeared at 129.08°C, 170.91°C, and 191.88°C.

[0212]

[0213] Comparative Example 1: Preparation of citric acid salt of compound Ⅰ

[0214] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained in the above Preparation Example 1 was mixed with an alcohol solvent (isopropyl alcohol, IPA), stirred, and then vacuum-dried at about 30°C to 35°C to obtain a dried product. About 10 g of the dried product was taken and stirred with about 167 g of acetone. A solution of citric acid (about 5 g) dissolved in acetone (about 33 g) was slowly added dropwise over 60 minutes and stirred at the same temperature for 1 hour. The mixture was cooled to about 20°C to 25°C and stirred for an additional hour. The resulting solid was filtered, washed with acetone, and then vacuum-dried to produce 11.76 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0215] - 1 H NMR (400 MHz, MeOD); δ7.90(s, 1H), 7.06-7.15(m, 3H), 6.77(s, 1H), 4.50(t,J=7.2Hz, 2H), 4.45(s, 2H), 4.24(t,J=7.2Hz, 2H), 2.80(d,J=15.6Hz, 2H), 2.70(d,J=12.0, 2H), 2.39-2.44(m, 11H), 2.35(s, 3H).

[0216]

[0217] Experimental Example 1: Physical Properties of Compound I Diphosphate

[0218] pH

[0219] After dissolving 10 mg of the diphosphate according to Example 1 in 100 ml of water, the pH was measured using a 913 pH meter from Metrohm, and the result was pH 3.78.

[0220] molecular weight

[0221] As a result of measuring the molecular weight of the diphosphate according to Example 1, the molecular weight was found to be 558.46.

[0222]

[0223] Experimental Example 2: Solubility Evaluation

[0224] The solubility was measured for the diphosphate salt according to Example 1 of the present invention and the citric acid salt according to Comparative Example 1. Specifically, 1 g of each sample was added to purified water, purified water at pH 1.2, purified water at pH 4.0, and purified water at pH 6.8, respectively, and the amount of solvent required to dissolve 1 g of the solute was measured and evaluated according to the solubility standards of the Korean Pharmacopoeia (Table 1), and the results are shown in Table 2 below.

[0225] [Table 1]

[0226] Korean Pharmacopoeia solubility standards

[0227]

[0228]

[0229] [Table 2]

[0230]

[0231]

[0232] As a result, the diphosphate salts and their crystal forms according to Examples 1 to 4 had significantly superior solubility compared to the citrate salt of Comparative Example 1. In particular, among the crystal forms, Form I showed the best solubility. This means that when the diphosphate salt crystal form of the present invention is developed into a drug, significant improvements in absorption, dissolution, and bioavailability are possible.

[0233]

[0234] Experimental Example 3: Bulk Density Evaluation

[0235] The bulk density (1 g each) of the diphosphate salts and their crystal forms (Forms I to III) according to Examples 1 to 4 of the present invention and the citric acid salt according to Comparative Example 1 was compared and evaluated. The results are shown in Figures 8 and 9.

[0236] As a result, it was confirmed that the diphosphate salts and their crystal forms according to Examples 1 to 4 of the present invention had significantly higher bulk densities, with a volume of approximately 1 / 2 to 1 / 3 that of the citric acid salt according to Comparative Example 1. In particular, among the crystal forms, the crystal form Form I was found to have the best bulk density. This means that the diphosphate salts of the present invention can be more easily manufactured into products in the sieving or mixing process when formulating a formulation using them as a raw material.

[0237]

[0238] Experimental Example 4: Evaluation of Light and Temperature Stability

[0239] For the diphosphate crystal forms according to Examples 2 to 4 of the present invention, each sample was spread thinly on a petri dish and then irradiated using a photostability chamber (CARON 6542-2) at 25°C and 60% humidity with a visible light intensity of 35 k lux, so that the total irradiation amount was 1200 k lux. After spreading the sample thinly on a petri dish, using a photostability chamber (CARON 6542-2) at 25°C and 60% humidity, UV with a light intensity of 35 W, so that the total irradiation amount was 200 watt, and then discoloration was observed with the naked eye, and HPLC was performed to measure purity.

[0240] In addition, the color and purity of the diphosphate crystals according to Examples 2 to 4 were measured, and then the crystals were left at 60°C for one week, after which the color and purity were measured. Discoloration was observed with the naked eye, and purity was measured using HPLC.

[0241] The measurement results are shown in Table 3 below.

[0242] [Table 3]

[0243]

[0244]

[0245] As a result, it was confirmed that the diphosphate salt according to the present invention possesses excellent light and temperature stability. In particular, the crystalline Form I showed the best light and temperature stability. This excellent light and temperature stability means that the diphosphate salt of the present invention can be very advantageous in handling and storage when commercializing products.

[0246]

[0247] Experimental Example 5: Acid and Base Stability Evaluation

[0248] The stability of the diphosphate salts and their crystal forms (Forms I to III) according to Examples 1 to 4 of the present invention and the citric acid salt according to Comparative Example 1 under acid and base conditions was evaluated using HPLC.

[0249] At this time, for the acidic condition experiment, a sample was taken after leaving it in a 1N HCl aqueous solution for 1 day, diluted in an analysis solvent, and analyzed for purity using HPLC.

[0250] Additionally, for the experiment under basic conditions, a sample was taken after leaving it in a 1N NaOH aqueous solution for 1 day, diluted in an analytical solvent, and analyzed for purity using HPLC.

[0251] As a result, it was confirmed that the diphosphate and its crystal form according to the present invention have acid and base stability that is equally or better than that of the citrate salt.

[0252]

[0253] Although the present invention has been described above with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various modifications and changes may be made to the present invention without departing from the spirit and scope of the present invention as set forth in the claims below.

Claims

1. A crystalline FormⅠ of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt having at least three diffraction peaks selected from the group consisting of 2θ values ​​of 8.984° (±0.2°), 6.626° (±0.2°), 20.914° (±0.2°), 13.843° (±0.2°), 10.525° (±0.2°), 22.809° (±0.2°), 11.750° (±0.2°), 27.214° (±0.2°), and 23.476° (±0.2°) in a powder X-ray diffraction pattern.

2. In the first paragraph, a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt, characterized in that it further has at least one diffraction peak selected from the group consisting of 2θ values ​​of 23.057° (±0.2°), 19.929° (±0.2°), 20.166° (±0.2°), 17.998° (±0.2°), 22.228° (±0.2°), and 15.166° (±0.2°).

3. In the first paragraph, a crystalline Form I of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, characterized in that it has a differential scanning calorimetry (DSC) endothermic peak at 197.28°C (±0.5°C) when the heating rate is 10°C / min.

4. A crystalline form FormⅡ of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt having at least three diffraction peaks selected from the group consisting of 2θ values ​​of 4.158° (±0.2°), 16.637° (±0.2°), 24.248° (±0.2°), 22.466° (±0.2°), 10.185° (±0.2°), 12.934° (±0.2°), 13.802° (±0.2°), 14.489° (±0.2°), and 7.223° (±0.2°) in a powder X-ray diffraction pattern.

5. In the fourth paragraph, a crystalline form Form II of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt, characterized in that the powder X-ray diffraction pattern further has at least one diffraction peak selected from the group consisting of 2θ values ​​of 17.224° (±0.2°), 20.447° (±0.2°), 24.701° (±0.2°), 18.289° (±0.2°), 12.529° (±0.2°), and 21.922° (±0.2°).

6. In the fourth paragraph, a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, characterized in that it has a differential scanning calorimetry (DSC) endothermic peak at 187.44°C (±0.5°C) when the heating rate is 10°C / min. Form II.

7. A crystalline form FormⅢ of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt having at least three diffraction peaks selected from the group consisting of 2θ values ​​of 3.807° (±0.2°), 8.381° (±0.2°), 11.128° (±0.2°), 8.999° (±0.2°), 22.384° (±0.2°), 15.178° (±0.2°), 13.139° (±0.2°), 16.750° (±0.2°), 18.782° (±0.2°), and 14.388° (±0.2°) in a powder X-ray diffraction pattern.

8. In the 7th paragraph, the powder X-ray diffraction pattern is characterized in that it further has at least one diffraction peak selected from the group consisting of 2θ values ​​of 20.163° (±0.2°), 29.629° (±0.2°), 25.191° (±0.2°), 25.401° (±0.2°), 23.030° (±0.2°), 21.786° (±0.2°), 19.385° (±0.2°), 18.988° (±0.2°), 19.714° (±0.2°), 20.843° (±0.2°), and 21.304° (±0.2°). Crystalline Form III of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate salt.

9. In the 7th paragraph, a crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, characterized in that it has differential scanning calorimetry (DSC) endothermic peaks at 129.08°C, 170.91°C, and 191.88°C (±0.5°C) when the heating rate is 10°C / min. FormⅢ. 10.(i) A first solution is prepared by mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent selected from the group consisting of acetone, dichloromethane, ethanol, isopropanol, and mixtures thereof; (ii) preparing a second solution by mixing phosphoric acid and a second solvent selected from the group consisting of acetone, ethanol, isopropanol and mixtures thereof; and (iii) A method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I, comprising mixing and reacting the first solution and the second solution.

11. In the 10th paragraph, the reaction of step (iii) is characterized in that the second solution is slowly added to the first solution for 30 minutes or more, a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I.

12. In the 10th paragraph, the reaction of step (iii) is characterized in that the first solution and the second solution are reacted at 10°C to 30°C, heated, stirred at 45°C to 60°C, and cooled to 10°C to 30°C and stirred, a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I.

13. A method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline form Form Ⅰ, comprising reacting azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline form of crystalline Form Ⅱ or Form Ⅲ with a solvent selected from the group consisting of alcohols having 1 to 4 carbon atoms, acetone, ethyl acetate, dichloromethane and mixtures thereof.

14. A method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I, characterized in that the solvent is acetone in the 13th paragraph.

15. A method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form I, characterized in that in the 13th paragraph, the reaction is stirred at 45°C to 60°C and stirred while cooling to 10°C to 30°C.

16. Crystalline Form I of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, manufactured by the manufacturing method of any one of items 10 to 15. 17.(i) A first solution is prepared by mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent selected from the group consisting of isopropanol, tetrahydrofuran, and mixtures thereof; (ii) preparing a second solution by mixing phosphoric acid and a second solvent selected from the group consisting of isopropanol, tetrahydrofuran and mixtures thereof; and (iii) A method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form II, comprising mixing and reacting the first solution and the second solution.

18. In the 17th paragraph, the reaction of step (iii) is characterized in that the second solution is slowly added to the first solution for 30 minutes or more, a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form II.

19. In the 17th paragraph, the reaction of step (iii) is characterized in that the first solution and the second solution are reacted at 10°C to 30°C, heated, stirred at 45°C to 60°C, and cooled to 10°C to 30°C and stirred, a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline Form II.

20. Crystalline Form II of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, prepared by the preparation method of any one of items 17 to 19. 21.(i) A first solution is prepared by mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent, which is acetonitrile; (ii) preparing a second solution by mixing phosphoric acid and a second solvent, which is acetonitrile; and (iii) A method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline FormⅢ, comprising mixing and reacting the first solution and the second solution.

22. In the 21st paragraph, the reaction of step (iii) is characterized in that the second solution is slowly added to the first solution for 30 minutes or more, a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline FormⅢ.

23. In the 21st paragraph, the reaction of step (iii) is characterized in that the first solution and the second solution are reacted at 10°C to 30°C, heated, stirred at 45°C to 60°C, and cooled to 10°C to 30°C and stirred, a method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate crystalline FormⅢ.

24. Crystalline Form III of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate, manufactured by the manufacturing method of any one of items 21 to 23.

25. A pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of peptic ulcer, gastroduodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, and gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD), comprising the crystalline form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone diphosphate of any one of claims 1 to 9 as an active ingredient, together with a pharmaceutically acceptable carrier.

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