Method for producing vonoprazan fumarate

Abstract

The present invention provides a method for producing vonoprazan fumarate with a purity of 99.9% or higher in high yield. Specifically, the present invention relates to a method for producing vonoprazan fumarate with a purity of 99.9% or higher in high yield by forming vonoprazan hydrochloride using a specific amount of hydrochloric acid, and then converting it into a fumarate form to form vonoprazan fumarate. Furthermore, the present invention provides a specific crystalline form of vonoprazan hydrochloride that can be usefully used in the above production method.

Description

Technical Field

[0001] The present invention relates to a method for producing high-purity vonoprazan fumarate of 99.9% or more in a high yield. The production method of the present invention includes forming vonoprazan hydrochloride using a specific amount of hydrochloric acid and then converting it into the form of fumarate. The present invention also relates to a specific crystal form of vonoprazan hydrochloride that can be usefully used in the above production method.

Background Art

[0002] Vonoprazan fumarate having the chemical structure of Chemical Formula 1 below is used for the treatment of peptic ulcer, reflux esophagitis, hyperacidity, etc. by competitively blocking the binding of potassium ions to proton pumps that promote gastric acid secretion. [[ID=

[13] ] <Chemical Formula 1> JPEG2026525299000002.jpg3452

[0003] Korean Patent Registration No. 10-1115857 discloses a method of producing vonoprazan using an aldehyde intermediate with methylamine and a reducing agent and then converting it into the form of fumarate as shown in Reaction Scheme 1 below. <Reaction Scheme 1> JPEG2026525299000003.jpg32160

[0004] However, since the above production method involves the use of a reducing agent, various impurities will be generated. Therefore, the production method disclosed in Korean Patent Registration No. 10-1115857 has to be purified using silica gel column chromatography, which is not suitable for industrial mass production, for impurity removal, and the extraction and washing steps using aqueous ammonia have to be performed a total of 4 times, so the purification process is complicated. In addition, the yield of obtaining vonoprazan in the form of fumarate is 64.6% to 72.1%, which is unsatisfactory.

[0005] On the other hand, Chinese Patent Publication No. CN107778286A discloses a manufacturing method that includes producing crude vonoprazan in the form of vonoprazan hydrochloride by reacting an aldehyde intermediate with methylamine and a reducing agent, and then converting it to vonoprazan fumarate. Specifically, the manufacturing method disclosed in Chinese Patent Publication No. CN107778286A includes reacting an aldehyde intermediate with methylamine and a reducing agent, then (i) producing vonoprazan hydrochloride by adjusting the pH of the reaction mixture to 1-4 without isolating crude vonoprazan, and then treating the isolated vonoprazan fumarate with a base and fumaric acid to convert it to vonoprazan fumarate, or (ii) isolating crude vonoprazan in the form of an extract through a washing and extraction step, adjusting the pH of the extract to 1-4 to produce vonoprazan hydrochloride, and then treating the isolated vonoprazan hydrochloride with a base and fumaric acid to convert it to vonoprazan fumarate. However, the manufacturing method disclosed in Chinese Patent Publication No. CN107778286A shows a large variation in yield, ranging from 55.22% to 71.60%, and still exhibits an unsatisfactory yield. Furthermore, the manufacturing method disclosed in Chinese Patent Publication No. CN107778286A shows a large variation in HPLC purity, and even to obtain the highest HPLC purity of 99.85%, a complex washing and extraction process is required, resulting in a yield of only 58.78% (Example 6 of Chinese Patent Publication No. CN107778286A). Moreover, without the complex washing and extraction process, the yield can be increased to 71.60%, but this is still unsatisfactory, and the HPLC purity drops to a low 99.70% (Example 5 of Chinese Patent Publication No. CN107778286A).

[0006] Therefore, there is a need in the industry to develop a method for producing vonoprazan fumarate in high purity and high yield through a simple manufacturing process, without involving complex washing, extraction, or filtration steps. [Overview of the project] [Problems that the invention aims to solve]

[0007] The inventors conducted various studies to develop a method for producing vonoprazan fumarate in high purity and high yield through a simple manufacturing process. In particular, they conducted various studies to improve conventional manufacturing methods (for example, the manufacturing method disclosed in Chinese Patent Publication No. CN107778286A). As a result, the inventors found that in conventional manufacturing methods, vonoprazan hydrochloride obtained by adjusting the pH to 1-4 can be obtained in the form of dihydrochloride or a complex form containing dihydrochloride, and that the use of such intermediate forms has a significant impact on the purity and yield of vonoprazan fumarate. The inventors found that by adjusting the pH to pH 6 or higher using a specific amount of hydrochloric acid, an intermediate in the form of vonoprazan monohydrochloride can be produced through a simple manufacturing process without complex washing, extraction, filtration, etc. In particular, the inventors have found that when vonoprazan monohydrochloride is converted to vonoprazan fumarate, high-purity vonoprazan fumarate with a purity of 99.9% or higher can be produced in high yield.

[0008] Therefore, the present invention aims to provide a manufacturing method that can produce vonoprazan fumarate in high purity and high yield.

[0009] Furthermore, the present invention provides a specific crystalline form of vonoprazan hydrochloride that can be usefully used in the above-described manufacturing method. [Means for solving the problem]

[0010] One embodiment of the present invention provides a method for producing vonoprazan fumarate, comprising the steps of: (a) reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent; (b) adding 0.9 to 1.5 equivalents of hydrochloric acid per 1 equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde to the reaction mixture obtained in step (a), and then concentrating the mixture to form vonoprazan hydrochloride in solid form; and (c) adding a first organic solvent and a base to the vonoprazan hydrochloride obtained in step (b) to form vonoprazan free base, and then adding a second organic solvent and fumaric acid to form vonoprazan fumarate.

[0011] In another aspect of the present invention, a method for producing vonoprazan fumarate is provided, comprising the steps of: (a) reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent; (b') adding 0.9 to 1.5 equivalents of hydrochloric acid per 1 equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde to the reaction mixture obtained in step (a), then concentrating the mixture to form vonoprazan hydrochloride in solid form, and then converting the vonoprazan hydrochloride to a crystalline form of vonoprazan hydrochloride; and (c') adding a first organic solvent and a base to the crystalline form of vonoprazan hydrochloride obtained in step (b') to form vonoprazan free base, and then adding a second organic solvent and fumaric acid to form vonoprazan fumarate.

[0012] In yet another aspect of the present invention, a specific crystalline form of vonoprazan hydrochloride is provided, which can be usefully used in the above-described manufacturing method, namely crystalline form A of vonoprazan hydrochloride having characteristic peaks at diffraction angle 2θ values ​​of 9.7, 10.6, 15.1, 17.8, and 24.8°±0.2°. [Effects of the Invention]

[0013] The manufacturing method according to the present invention allows for the production of vonoprazan fumarate with a purity of 99.9% or higher in high yield by first forming vonoprazan hydrochloride using a specific amount of hydrochloric acid, and then converting it to a fumarate form to form vonoprazan fumarate. Furthermore, since the manufacturing method according to the present invention allows for the production of vonoprazan fumarate with high purity and high yield through a simple manufacturing process without complex washing, extraction, or filtration steps, it is suitable for large-scale industrial production. Moreover, crystalline form A of vonoprazan hydrochloride obtained by the present invention can be usefully used to produce vonoprazan fumarate with high purity and high yield. [Brief explanation of the drawing]

[0014] [Figure 1] The X-ray powder diffraction (XRPD) pattern of crystalline form A of vonoprazan hydrochloride obtained according to the present invention is shown. [Figure 2] The differential scanning calorimetry (DSC) thermogram of crystalline form A of vonoprazan hydrochloride obtained according to the present invention is shown. [Figure 3] The X-ray powder diffraction (XRPD) pattern of crystalline form B of vonoprazan hydrochloride obtained according to the present invention is shown. [Figure 4] The X-ray powder diffraction (XRPD) pattern of crystalline form C of vonoprazan hydrochloride obtained according to the present invention is shown. [Figure 5] The X-ray powder diffraction (XRPD) pattern of crystalline form D of vonoprazan hydrochloride obtained according to the present invention is shown. [Modes for carrying out the invention]

[0015] The present invention provides a method for producing vonoprazan fumarate, comprising the steps of: (a) reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent; (b) adding 0.9 to 1.5 equivalents of hydrochloric acid per equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde to the reaction mixture obtained in step (a), and then concentrating the mixture to form vonoprazan hydrochloride in solid form; and (c) adding a first organic solvent and a base to the vonoprazan hydrochloride obtained in step (b) to form vonoprazan free base, and then adding a second organic solvent and fumaric acid to form vonoprazan fumarate.

[0016] Furthermore, the present invention provides a method for producing vonoprazan fumarate, comprising the steps of: (a) reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent; (b') adding 0.9 to 1.5 equivalents of hydrochloric acid per equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde to the reaction mixture obtained in step (a), then concentrating the mixture to form vonoprazan hydrochloride in solid form, and then converting the vonoprazan hydrochloride into a crystalline form; and (c') adding a first organic solvent and a base to the crystalline form of vonoprazan hydrochloride obtained in step (b') to form vonoprazan free base, and then adding a second organic solvent and fumaric acid to form vonoprazan fumarate.

[0017] In the manufacturing method of the present invention, step (a) is a step of forming crude vonoprazan free base. Therefore, step (a) can be carried out by reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent, according to the method disclosed in Korean Patent Registration No. 10-1115857. For example, step (a) can be carried out by dissolving 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde in an organic solvent and reacting it with a 40% aqueous solution of methylamine and sodium borohydride, which is a reducing agent. The reaction may be carried out at a temperature of about 5°C, and organic solvents such as methanol, dimethyl sulfoxide, and tetrahydrofuran may be used as the solvent, and methanol is preferably used.

[0018] The manufacturing method of the present invention avoids washing and extraction steps by using the reaction mixture from step (a) directly in step (b) or step (b') without isolating the reaction product (i.e., crude vonoprazan free base) from step (a). Therefore, it is preferable to use the reaction mixture obtained in step (a) directly in step (b) or step (b') without isolating the reaction product from step (a).

[0019] In the production method of the present invention, step (b) or step (b') includes a step of adding a specific amount of hydrochloric acid to the reaction mixture obtained in step (a), and then concentrating to form bonoprazan hydrochloride in solid form. That is, the production method of the present invention includes forming bonoprazan hydrochloride in the form of monohydrochloride as a solid by adding 0.9 to 1.5 equivalents of hydrochloric acid per equivalent of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde. As described above, when a specific amount of hydrochloric acid is used, the pH of the reaction mixture is adjusted to pH 6.0 or higher, for example, pH 6.0 to pH 9.0, preferably about pH 8.5. Therefore, in step (b) or step (b'), the formation of the bonoprazan hydrochloride can be carried out by adding 0.9 to 1.5 equivalents of hydrochloric acid to the reaction mixture obtained in step (a) per equivalent of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde and adjusting the pH of the reaction mixture to pH 6.0 or higher, for example, pH 6.0 to pH 9.0, preferably about pH 8.5.

[0020] In the production method of the present invention, in step (b) or step (b'), bonoprazan hydrochloride can be obtained in solid form by concentrating (for example, concentrating under reduced pressure) according to a normal method. That is, the concentrate obtained in solid form can be used in the next reaction without performing operations such as filtration and washing. Also, in step (b'), the crystal form of bonoprazan hydrochloride can also be obtained by adding a solvent to bonoprazan hydrochloride, stirring for a certain period of time, and filtering. Therefore, step (c) or step (c') can be carried out in the reactor in which step (b) or step (b') has been carried out. Therefore, the production method of the present invention can preferably be carried out by a one-pot reaction of step (a), step (b), and step (c) or step (a), step (b'), and step (c').

[0021] Steps (c) and (c') are steps of adding a base to bonoprazan hydrochloride or a specific crystalline form of bonoprazan hydrochloride to form the free base of bonoprazan and then converting it to bonoprazan fumarate. The solvent used in the step of forming the free base of bonoprazan (i.e., the first organic solvent) may be selected from one or more of the group consisting of dichloromethane, ethyl acetate, and methanol, and preferably may be dichloromethane. Also, the base may be an inorganic base selected from one or more of the group consisting of sodium bicarbonate, sodium hydroxide, and potassium hydroxide, and preferably may be sodium bicarbonate. The amount of the base used is not particularly limited, and for example, it may be used in the range of 1.0 to 1.5 equivalents, preferably 1.1 equivalents, relative to 1 equivalent of bonoprazan hydrochloride or the crystalline form of bonoprazan hydrochloride. The solvent used in the step of converting to bonoprazan fumarate (i.e., the second organic solvent) may be selected from one or more of the group consisting of ethyl acetate, methanol, dimethyl sulfoxide, and water, and preferably may be ethyl acetate.

[0022] According to the present invention, it has been clarified that bonoprazan hydrochloride in the monohydrochloride form can be produced in various crystalline forms, namely, forms of crystalline forms A, B, C, and D. When producing bonoprazan fumarate via these, it has been clarified that high-purity bonoprazan fumarate of 99.90% or more can be produced. In particular, according to the present invention, when producing bonoprazan fumarate via crystalline form A of bonoprazan hydrochloride, it has been clarified that high-purity bonoprazan fumarate can be produced in a high yield.

[0023] Therefore, in the manufacturing method of the present invention, the crystalline form of vonoprazan hydrochloride in step (b') is preferably crystalline form A of vonoprazan hydrochloride, i.e., crystalline form A of vonoprazan hydrochloride having characteristic peaks at diffraction angle 2θ values ​​of 9.7, 10.6, 15.1, 17.8, and 24.8°±0.2°, for example, the X-ray powder diffraction (XRPD) pattern shown in Figure 1. The crystalline form A of vonoprazan hydrochloride may have a differential scanning calorimetry (DSC) thermogram showing a melt endothermic peak at 170.1°C, for example, the differential scanning calorimetry (DSC) thermogram shown in Figure 2.

[0024] The present invention also provides a specific crystalline form of vonoprazan hydrochloride that can be usefully used in the above-described manufacturing method, namely crystalline form A of vonoprazan hydrochloride having characteristic peaks at diffraction angle 2θ values ​​of 9.7, 10.6, 15.1, 17.8, and 24.8°±0.2°, for example, having an X-ray powder diffraction (XRPD) pattern as shown in Figure 1. The crystalline form A of vonoprazan hydrochloride may have a differential scanning calorimetry (DSC) thermogram showing a melt endothermic peak at 170.1°C, for example, the differential scanning calorimetry (DSC) thermogram as shown in Figure 2.

[0025] The crystalline form A of vonoprazan hydrochloride obtained by the present invention avoids the difficulties associated with handling oily vonoprazan free base and improves the stability problem of vonoprazan free base, which degrades in purity during long-term storage. Furthermore, crystalline form A of vonoprazan hydrochloride does not change its crystalline form even under harsh conditions and has excellent stability, making it useful for long-term storage. The results of the characterization analysis of crystalline form A of vonoprazan hydrochloride are shown in Table 1 below.

[0026] [Table 1]

[0027] The present invention will be described in more detail below with reference to examples. However, these examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0028] In the following examples, HPLC purity was measured using high-performance liquid chromatography (HPLC) according to the conditions disclosed in Chinese Patent Publication No. CN107778286A.

[0029] X-ray powder diffraction (XRPD) analysis was performed using the Aeris X-ray powder diffractometer from Malvern PANalytical, operated at 15 mA and 40 kV. α1 Line (λ α1 Using (=1.54060Å), the 2θ values ​​between 3 and 40° were measured at a scan rate of 3° per second.

[0030] Differential scanning calorimeter (DSC) analysis was performed using a Mettller Toledo DSC3 differential scanning calorimeter, under the following conditions: starting temperature -10°C, ending temperature 250°C, heating rate 10°C / min, and nitrogen gas supply rate 50 mL / min.

[0031] Example 1: Production of vonoprazan fumarate 500 ml of methanol was cooled to approximately 5°C, then 20.0 g of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde was added, followed by 6.8 ml of 40% aqueous methylamine solution. The reaction mixture was stirred for 30 minutes while maintaining the temperature at approximately 5°C to form a clear solution. 41.2 g of NaBH was added to the resulting solution, and the mixture was stirred at approximately 5°C for 2 hours. 6.5 ml of 38% aqueous hydrochloric acid was added to the reaction mixture to adjust the pH to approximately pH 8.5, and the mixture was concentrated under reduced pressure to obtain vonoprazan hydrochloride in solid form. 100 ml of dichloromethane was added to the obtained vonoprazan hydrochloride, followed by 200 ml of 8% aqueous sodium bicarbonate solution, and the mixture was stirred for 5 minutes. The organic layer was separated, dehydrated and decolorized with magnesium sulfate and activated carbon, respectively, and then filtered. The resulting filtrate was concentrated under reduced pressure. After adding 80 ml of dimethyl sulfoxide to the residue, the mixture was heated to 40°C, and then 10.5 g of fumaric acid was added and stirred for 5 minutes. 400 ml of ethyl acetate was added to the reaction mixture and stirred at room temperature for 2 hours, after which it was filtered. The resulting filtrate was vacuum-dried at 70°C to obtain 22.7 g of vonoprazan fumarate. Yield: 81.2% mp 199±3℃ HPLC purity: 99.90%

[0032] Example 2: Production of vonoprazan fumarate via crystalline form A of vonoprazan hydrochloride Step 1: Production of vonoprazan hydrochloride crystalline form A 500 ml of methanol was cooled to approximately 5°C, then 20.0 g of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde was added, followed by 6.8 ml of 40% aqueous methylamine solution. The reaction mixture was stirred for 30 minutes while maintaining it at approximately 5°C to form a clear solution. 41.2 g of NaBH was added to the resulting solution, and the mixture was stirred at approximately 5°C for 2 hours. 6.5 ml of 38% aqueous hydrochloric acid was added to the reaction mixture to adjust the pH to approximately pH 8.5, and the mixture was concentrated under reduced pressure to obtain vonoprazan hydrochloride in solid form. 600 ml of ethyl acetate was added to the obtained vonoprazan hydrochloride, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred at approximately 5°C for 1 hour, and then filtered. The resulting solid was vacuum-dried at approximately 70°C to obtain 21.2 g of crystalline form A of vonoprazan hydrochloride (yield: 91.7%, HPLC purity: 99.70%).

[0033] The XRD diffraction pattern of crystalline form A of vonoprazan hydrochloride obtained above is shown in Figure 1. As can be seen from the results in Figure 1, crystalline form A of vonoprazan hydrochloride has characteristic peaks at diffraction angle 2θ values ​​of 9.7, 10.6, 15.1, 17.8, and 24.8°±0.2°.

[0034] Furthermore, the differential scanning colorimetry (DSC) thermogram of crystalline form A of vonoprazan hydrochloride is shown in Figure 2. As can be seen from the results in Figure 2, crystalline form A of vonoprazan hydrochloride has a differential scanning colorimetry (DSC) thermogram showing a melt endothermic peak at 170.1°C.

[0035] Step 2: Manufacturing of vonoprazan fumarate 100 ml of dichloromethane was added to 21.2 g of crystalline form A of vonoprazan hydrochloride obtained in Step 1, and 200 ml of 8% sodium bicarbonate aqueous solution was added, and the mixture was stirred for 5 minutes. The organic layer was separated, dehydrated and decolorized with magnesium sulfate and activated carbon, respectively, and then filtered. The obtained filtrate was concentrated under reduced pressure. 80 ml of dimethyl sulfoxide was added to the residue, and after heating to 40°C, 10.5 g of fumaric acid was added and the mixture was stirred for 5 minutes. 400 ml of ethyl acetate was added to the reaction mixture, and after stirring at room temperature for 2 hours, the mixture was filtered. The obtained filtrate was vacuum dried at 70°C to obtain 20.6 g of vonoprazan fumarate. Yield: 73.7% mp 199±3℃ HPLC purity: 99.92%

[0036] Example 3: Production of vonoprazan fumarate via crystalline form B of vonoprazan hydrochloride Step 1: Preparation of vonoprazan hydrochloride crystalline form B Vonoprazan hydrochloride was obtained in solid form by the same method as in Step 1 of Example 2. 1000 ml of dichloromethane was added to the obtained vonoprazan hydrochloride and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred at approximately 5°C for 1 hour and then filtered. The obtained solid was vacuum-dried at approximately 70°C to obtain 28.0 g of crystalline form B of vonoprazan hydrochloride (yield: 80.7%, HPLC purity: 99.26%).

[0037] The XRD diffraction pattern of crystalline form B of vonoprazan hydrochloride obtained above is shown in Figure 3. As can be seen from the results in Figure 3, crystalline form B of vonoprazan hydrochloride has characteristic peaks at diffraction angle 2θ values ​​of 5.2, 10.2, 15.3, 20.4, and 26.6°±0.2°.

[0038] Step 2: Manufacturing of vonoprazan fumarate 17.2 g of vonoprazan fumarate was obtained in the same manner as in Step 2 of Example 2, except that crystalline form B of vonoprazan hydrochloride obtained in Step 1 was used. Yield: 61.6% mp 199±3℃ HPLC purity: 99.91%

[0039] Example 4: Production of vonoprazan fumarate via crystalline form C of vonoprazan hydrochloride Step 1: Production of crystalline form C of vonoprazan hydrochloride Vonoprazan hydrochloride was obtained in solid form by the same method as in Step 1 of Example 2. 600 ml of toluene was added to the obtained vonoprazan hydrochloride and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred at approximately 5°C for 1 hour and then filtered. The obtained solid was vacuum-dried at approximately 70°C to obtain 28.2 g of crystalline vonoprazan hydrochloride (yield: 81.3%, HPLC purity: 98.69%).

[0040] The XRD diffraction pattern of crystalline form C of vonoprazan hydrochloride obtained above is shown in Figure 4. As can be seen from the results in Figure 4, crystalline form C of vonoprazan hydrochloride has characteristic peaks at diffraction angle 2θ values ​​of 12.9, 13.7, 14.6, 15.5, 18.4, and 23.5°±0.2°.

[0041] Step 2: Manufacturing of vonoprazan fumarate 17.8 g of vonoprazan fumarate was obtained in the same manner as in Step 2 of Example 2, except that crystalline form C of vonoprazan hydrochloride obtained in Step 1 was used. Yield: 63.7% mp 199±3℃ HPLC purity: 99.89%

[0042] Example 5: Production of vonoprazan fumarate via crystalline form D of vonoprazan hydrochloride Step 1: Preparation of crystalline form D of vonoprazan hydrochloride Vonoprazan hydrochloride was obtained in solid form by the same method as in Step 1 of Example 2. 10 ml of methanol was added to the obtained vonoprazan hydrochloride, and the mixture was stirred at room temperature for 5 minutes, followed by filtration at room temperature. The resulting solid was vacuum-dried at approximately 70°C to obtain 7.8 g of crystalline form D of vonoprazan hydrochloride (yield: 22.5%, HPLC purity: 99.01%).

[0043] The XRD diffraction pattern of crystalline form D of vonoprazan hydrochloride obtained above is shown in Figure 5. As can be seen from the results in Figure 5, crystalline form D of vonoprazan hydrochloride has characteristic peaks at diffraction angle 2θ values ​​of 11.0, 12.6, 13.4, 14.3, 16.6, and 31.6°±0.2°.

[0044] Step 2: Manufacturing of vonoprazan fumarate 15.6 g of vonoprazan fumarate was obtained in the same manner as in Step 2 of Example 2, except that crystalline form D of vonoprazan hydrochloride obtained in Step 1 was used. Yield: 55.8% mp 199±3℃ HPLC purity: 99.92%

Claims

1. (a) A step of reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent; (b) Adding 0.9 to 1.5 equivalents of hydrochloric acid per 1 equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde to the reaction mixture obtained in step (a), and then concentrating it to form vonoprazan hydrochloride in solid form; and (c) A step in which the vonoprazan hydrochloride obtained in step (b) is combined with a first organic solvent and a base to form vonoprazan free base, and then the second organic solvent and fumaric acid are added to form vonoprazan fumarate. A method for producing vonoprazan fumarate, including the method described above.

2. (a) A step of reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde with methylamine and a reducing agent; (b') A step in which the reaction mixture obtained in step (a) is to be concentrated with 0.9 to 1.5 equivalents of hydrochloric acid per equivalent of 1 equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde, and then the mixture is concentrated to form vonoprazan hydrochloride in solid form, and then the vonoprazan hydrochloride is converted into the crystalline form of vonoprazan hydrochloride; (c') A step in which the crystalline form of vonoprazan hydrochloride obtained in step (b') is combined with a first organic solvent and a base to form vonoprazan free base, and then a second organic solvent and fumaric acid are added to form vonoprazan fumarate. A method for producing vonoprazan fumarate, including the method described above.

3. The manufacturing method according to claim 1 or 2, wherein the reaction product of step (a) is not isolated, and the reaction mixture obtained in step (a) is used directly in step (b) or step (b').

4. The manufacturing method according to claim 1 or 2, wherein in step (b) or step (b'), the formation of the vonoprazan hydrochloride is carried out by adding 0.9 to 1.5 equivalents of hydrochloric acid per equivalent of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxyaldehyde to the reaction mixture obtained in step (a) to adjust the pH of the reaction mixture to pH 6.0 or higher.

5. The manufacturing method according to claim 1 or 2, wherein in step (c) or step (c'), the first organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, and methanol.

6. The manufacturing method according to claim 1 or 2, wherein in step (c) or step (c'), the base is an inorganic base selected from the group consisting of sodium bicarbonate, sodium hydroxide, and potassium hydroxide.

7. The method for producing a product according to claim 1 or 2, wherein in step (c) or step (c'), the second organic solvent is selected from the group consisting of ethyl acetate, methanol, dimethyl sulfoxide, and water.

8. The manufacturing method according to claim 1 or 2, wherein steps (a), (b), and (c) or steps (a), (b'), and (c') are carried out by a single-container reaction.

9. The manufacturing method according to claim 2, wherein the crystalline form of vonoprazan hydrochloride is crystalline form A of vonoprazan hydrochloride having characteristic peaks at diffraction angle 2θ values ​​of 9.7, 10.6, 15.1, 17.8, and 24.8°±0.2°.

10. The manufacturing method according to claim 9, wherein the crystalline form A of the vonoprazan hydrochloride has a differential scanning calorimeter (DSC) thermogram showing a melt endothermic peak at 170.1°C.

11. Crystalline form A of vonoprazan hydrochloride, exhibiting characteristic peaks at diffraction angle 2θ values ​​of 9.7, 10.6, 15.1, 17.8, and 24.8°±0.2°.

12. Crystalline form A of vonoprazan hydrochloride according to claim 11, having a differential scanning calorimeter (DSC) thermogram showing a melting endothermic peak at 170.1°C.

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