A method for preparing low-impurity vonerogefumate

Abstract

The application provides a preparation method of low-impurity vonerogefumate. The application provides a method for removing impurities A-E in the preparation of vonerogefumate, wherein vonerogefumate is reacted with hydrobromic acid to obtain vonerogefumate hydrobromide, and the method specifically comprises the following steps: (1) dissolving vonerogefumate and hydrobromic acid in a solvent; (2) cooling or directly precipitating a solid; and (3) separating to obtain vonerogefumate hydrobromide. The method can remove impurities A-E which are difficult to remove by a recrystallization refining method, and the method has good selectivity for impurities A-E. The application provides an impurity D, a preparation method thereof and application of the impurity D as an impurity control sample of vonerogefumate.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201910898185.5, filed on September 23, 2019, entitled "Preparation Method of Low-impurity Vonoprazan Fumarate". TECHNICAL FIELD

[0002] The present application relates to the technical field of medicine, in particular to a preparation method of low-impurity vonoprazan fumarate. BACKGROUND

[0003] Vonoprazan fumarate is developed by Takeda Pharmaceutical Company Limited, Japan, and is mainly used for treating gastric ulcer, duodenal ulcer, reflux esophagitis, and inhibiting recurrence of gastric ulcer or duodenal ulcer. Vonoprazan fumarate is a novel potassium ion (K + ) competitive acid blocker (P-CAB), which can terminate the secretion of gastric acid in the last step of gastric wall cell gastric acid secretion by inhibiting the combination of K + with H + -K + -ATPase (proton pump), and has a strong and lasting inhibitory effect on gastric acid secretion.

[0004] Chinese Patent Application No. CN102421753A discloses that 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is used as a raw material to react with pyridine-3-sulfonyl chloride to obtain an intermediate 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde, then the intermediate is reacted with methylamine to form a Schiff base, and sodium borohydride is used for reduction to obtain vonoprazan, and finally the vonoprazan is salified with fumaric acid to obtain the final product vonoprazan fumarate. According to the prior art analysis, the process is the best route for realizing industrial large-scale production at present. However, in the process, the vonoprazan is obtained by reduction in the last step, and a large amount of impurities is generated in the reduction process, which is very difficult to separate and purify, and is difficult to remove by refining and purification, greatly affecting the purity and quality control of vonoprazan. The impurity E generated in the step is similar in structure and polarity to vonoprazan, and is difficult to remove by conventional methods. Overall, the vonoprazan obtained by using the process has many types of impurities with high content, poor purity, and is difficult to directly prepare high-purity vonoprazan fumarate, especially 99.9% of the pharmaceutical grade of raw material drug. In other prior arts, although column chromatography purification can remove multiple impurities, it is not suitable for industrial production. In another prior art, multiple refining processes are used, which affects the yield of the final product and increases the production cost.

[0005] Chinese Patent Application No. CN101300229A also discloses the above preparation route. In the experiment, 15-crown-5 is added, and silica gel column chromatography is used for purification in the post-treatment, which is not suitable for industrial production.

[0006] Chinese patent application CN107778286A, which is prepared by the above synthetic route, has a purity of more than 99.7% after four times of purification, and has a relatively low yield. In addition, the patent discloses that 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-formaldehyde forms a Schiff base with methylamine, sodium borohydride is used for reduction, and then the pH is adjusted by dropwise adding dilute hydrochloric acid to obtain vorolanib hydrochloride, and the vorolanib free base is obtained by alkaline hydrolysis, and then the final product fumaric acid vorolanib is obtained by salifying with fumaric acid. In examples 1-6 of the patent, the weight of methylamine is calculated and added, but methylamine itself is a gas, and it is not practical to accurately weigh the amount of methylamine to be added, so the methylamine alcohol solution commonly used in the prior art is used to repeat experiments 1-6. It is difficult to obtain vorolanib hydrochloride by adjusting the pH by dropwise adding dilute hydrochloric acid to precipitate a solid. SUMMARY

[0007] The present application provides a method for preparing high-purity vorolanib and its salts. Specifically, it is surprisingly found that by preparing vorolanib obtained by a reduction reaction into a hydrobromide salt, a large amount of impurities generated in the reaction process, especially impurities A-E which are difficult to remove in the prior art, can be effectively removed. The method is suitable for industrial mass production, simple operation, greatly reduces production cost, and does not introduce new impurities.

[0008] The specific technical solutions of the present application are as follows:

[0009] The vorolanib obtained by the reduction reaction is reacted with hydrobromic acid to obtain vorolanib hydrobromide.

[0010] Further, the method specifically comprises the following steps:

[0011] (1) dissolving vorolanib and hydrobromic acid in a solvent;

[0012] (2) cooling or directly precipitating a solid;

[0013] (3) separating to obtain vorolanib hydrobromide.

[0014] In step (1) of the above preparation method, the mass percentage of hydrogen bromide in the hydrobromic acid is generally 10% to 48%, and preferably 48%.

[0015] In step (1) of the above preparation method, the hydrobromic acid is directly added or dissolved in ethanol and then added.

[0016] In step (1) of the above preparation method, the molar ratio of hydrogen bromide to vorolanib in the hydrobromic acid is 0.5:1 to 2:1, preferably 0.8:1 to 1.5:1, and more preferably 1:1.

[0017] Further, the voneranat is obtained by reacting 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde with methylamine or a salt thereof in the presence of a reducing agent.

[0018] In the step (1) of the above preparation method, the solvent is selected from one or two or more of methanol, ethanol, isopropanol, n-butanol, isobutanol, acetone, butanone, 2-pentanone, 3-pentanone, cyclopentanone, methyl isopropyl ketone, diethyl ether, tetrahydrofuran, tert-butyl methyl ether, dichloromethane, ethyl acetate, acetonitrile, toluene, preferably one or two or more of ethyl acetate, isopropanol, ethanol, acetone, tetrahydrofuran, more preferably one or two or more of ethanol, isopropanol, acetone.

[0019] In the step (1) of the above preparation method, the dissolution temperature is room temperature to the boiling point of the crystallization system, preferably room temperature to 60°C, more preferably room temperature.

[0020] In the step (2) of the above preparation method, the cooling temperature is 0-40°C lower than the dissolution temperature, and when the dissolution temperature is room temperature, the solid is directly precipitated at room temperature.

[0021] In the step (2) of the above preparation method, the precipitated solid can be a static precipitated solid or a stirred precipitated solid; preferably a stirred precipitated solid.

[0022] In the step (3) of the above preparation method, the separation can be performed by filtration or centrifugation, and the separated solid can be eluted with the solvent used in the crystallization system.

[0023] Further, after step (3), the voneranat free base is obtained by reacting in the presence of an inorganic base.

[0024] Further, the voneranat free base can be reacted with other organic acids or inorganic acids to obtain a voneranat salt.

[0025] Further, the purpose of the present application is to provide a preparation method of high-purity fumaric acid voneranat.

[0026] Specifically comprising the following steps:

[0027] (1) 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde is reacted with methylamine or a salt thereof in the presence of a reducing agent to obtain voneranat;

[0028] (2) Voneranat is reacted with hydrobromic acid to obtain voneranat hydrobromide;

[0029] (3) Voneranat hydrobromide is reacted in the presence of an inorganic base to obtain voneranat free base;

[0030] (4) reacting the vonoprazan free base with fumaric acid to obtain a fumaric acid vonoprazan product.

[0031] The fumaric acid vonoprazan product has a purity of 99.5% or more, and further has a purity of 99.7% or more.

[0032] Further, the fumaric acid vonoprazan product can be dissolved in a solvent and recrystallized to obtain a fumaric acid vonoprazan refined product having a higher purity. The fumaric acid vonoprazan refined product has a purity of 99.8% or more, and even 99.9% or more.

[0033] Further, after the fumaric acid vonoprazan is dissolved in a solvent, activated carbon is added, and then filtered while hot.

[0034] Further, the activated carbon is not eluted after the filtration while hot or eluted with a heated solvent; and the temperature of the solvent after further heating is equivalent to the temperature of the crystallization system before the filtration.

[0035] In the step (1) of the above production method, 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde is reacted with methylamine or a salt thereof, and then reduced to obtain vonoprazan; alternatively, 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde is reacted with methylamine or a salt thereof in the presence of a reducing agent without isolating the imine formed.

[0036] The reaction can be performed according to conventional reaction conditions known as reductive amination reaction. For example, the reaction can be performed according to the method described in Jikken Kagaku Koza (Courses in Experimental Chemistry), Vol. 14-III, pp. 1380-1385 (Maruzen Co., Ltd.).

[0037] The reducing agent is selected from a metal hydride or a boron reagent; the boron reagent is selected from one or two or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium cyanoborohydride; preferably one or two or more of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride; and more preferably sodium borohydride.

[0038] The reaction solvent is selected from one or two or more of an alcohol, an aromatic hydrocarbon, an aliphatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, and water; further, the reaction solvent is selected from one or two or more of methanol, ethanol, isopropanol, n-butanol, isobutanol, benzene, toluene, xylene, chlorobenzene, hexane, heptane, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and water; and preferably methanol, N,N-dimethylacetamide, or a combination thereof.

[0039] The reaction temperature is -50°C to 100°C, preferably -25°C to 50°C, and more preferably -15°C to 35°C.

[0040] Further, the reduction can also be carried out by catalytic hydrogenation.

[0041] The method for preparing the voneranib hydrobromide in step (2) of the above preparation method is the same as the method described above in the present application.

[0042] In step (3) of the above preparation method, the inorganic base is selected from one or two or more of sodium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and aqueous ammonia; and preferably one or two or more of sodium hydroxide, sodium carbonate, and aqueous ammonia.

[0043] The reaction solvent is selected from one or two or more of ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, dichloroethane, and water; and preferably a mixed solvent of tetrahydrofuran and water, or a mixed solvent of ethyl acetate and water; and when the inorganic base is aqueous ammonia, water can not be added additionally.

[0044] The reaction temperature is -10°C to 50°C, preferably 0°C to 30°C, and more preferably room temperature.

[0045] In step (4) of the above preparation method, the molar ratio of voneranib to fumaric acid is 1:0.8 to 1:1.5, preferably 1:1 to 1:1.2, and more preferably 1:1.

[0046] The fumaric acid can be added directly or after being dissolved in a solution.

[0047] The reaction solvent is selected from one or two or more of methanol, ethanol, isopropanol, n-butanol, isobutanol, acetone, ethyl acetate, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide; and preferably a mixed solvent of ethyl acetate and N,N-dimethylacetamide.

[0048] The dissolution temperature is 30°C to the boiling point of the solution system, preferably 45°C to 55°C, and more preferably 50°C.

[0049] The crystallization temperature is 0°C to 40°C lower than the dissolution temperature, and the crystallization temperature is preferably -10°C to 30°C, and more preferably 0°C to 25°C.

[0050] In step (5) of the above preparation method,

[0051] The crystallization solvent is selected from one or two or more of methanol, ethanol, isopropanol, n-butanol, isobutanol, and water, and preferably a mixed solvent of methanol and water.

[0052] The mass ratio of fumaric acid voneranib: methanol: water is 1:6.25:5 to 1:8.75:3.

[0053] The dissolution temperature is 40℃ to the boiling point of the crystallization system, preferably 50℃ to 70℃, more preferably 60℃ to 65℃.

[0054] The crystallization temperature is -10℃ to 40℃, preferably -5℃ to 25℃, more preferably 0℃ to 10℃.

[0055] The present application also aims to provide a kind of impurity D and preparation method thereof.

[0056]

[0057] Specifically comprising the following steps: voneranib or its salt is reacted in the presence of reducing agent to obtain impurity D.

[0058] The reducing agent is selected from metal hydride or boron reagent;The boron reagent is selected from one or two or more of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride;Preferably one or two or more of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride;More preferably sodium borohydride.

[0059] The reaction solvent is selected from one or two or more of alcohol, aromatic hydrocarbon, aliphatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide;The alcohol is selected from one or two or more of methanol, ethanol, isopropanol, n-butanol, isobutanol;The aromatic hydrocarbon is selected from one or two or more of toluene, xylene, chlorobenzene;The aliphatic hydrocarbon is selected from heptane or a combination thereof;The halogenated hydrocarbon is selected from chloroform, dichloromethane or a combination thereof;The ether is selected from one or two or more of diethyl ether, tetrahydrofuran, 1,4-dioxane;The ester is selected from ethyl acetate;The amide is selected from N,N-dimethylformamide, N,N-dimethylacetamide or a combination thereof;Preferably the reaction solvent is selected from one or two or more of methanol, N,N-dimethylformamide, N,N-dimethylacetamide;Preferably methanol, N,N-dimethylacetamide or a combination thereof.

[0060] The reaction temperature is -50℃ to 100℃, preferably -25℃ to 50℃, more preferably -15℃ to 35℃.

[0061] The inventors found in the research that the content of impurity B sometimes increases instead of decreasing in the removal process, the change is irregular, and the recrystallization refining has limited effect on the removal, which brings great challenge to the quality control of the synthesis process. The inventors surprisingly found that impurity D is not the main content impurity in the final product, but it is converted into impurity B in the process, the high content of impurity D will not only affect the control of impurity D, but also affect the quality control of impurity B, further increasing the difficulty of quality control of Vonoprazan, so it is necessary to control impurities B and D in the middle link and as a whole to improve the quality of the final product. The impurity D of the present application can be used as a control for controlling the quality of Vonoprazan free base or a pharmaceutically acceptable salt thereof. Therefore, another object of the present application is to provide the application of impurity D as a control for controlling the quality of Vonoprazan fumarate.

[0062] The present application has the following beneficial effects:

[0063] 1. Direct recrystallization of Vonoprazan for refining has limited effect on the removal of reducing impurities A-D, which is difficult to purify, affects the purity of the final product, and multiple purifications not only affect the overall yield, but also prolong the process cycle. In addition, repeated purification and temperature rising and falling operations may introduce new impurities; the inventors surprisingly found that the reaction of Vonoprazan with hydrobromic acid to prepare Vonoprazan hydrobromide has high selectivity for removing impurities A-D, which is beneficial to obtaining high-purity final product in the later stage; the inventors tried other salt purification and no solid was precipitated, which is difficult to remove impurities, and more not to selectively remove impurities A-D.

[0064] 2. In the present application, Vonoprazan hydrobromide is prepared by using a single solvent system, which reduces the introduction of organic solvents and is easier to operate, saving energy.

[0065] 3. Impurity E is similar in structure, property and polarity to Vonoprazan, which is very difficult to purify. Although the preparation of Vonoprazan hydrobromide from Vonoprazan and hydrobromic acid has limited effect on the purification of impurity E, the inventors surprisingly found that the content of impurity E in the fumaric acid Vonoprazan obtained by the reaction of Vonoprazan free base obtained by the salt of Vonoprazan hydrobromide with fumaric acid is significantly lower than that in the fumaric acid Vonoprazan obtained by the reaction of Vonoprazan without forming Vonoprazan hydrobromide with fumaric acid, i.e. the content of impurity E in the former is 0.01%, while the content of impurity E in the latter is as high as more than 0.1% (0.15%), which does not meet the quality requirements of a single impurity for pharmaceuticals, and the subsequent refining and purification has not obvious effect on the removal. The present application effectively removes impurity E and effectively controls the content of impurity E in the final product.

[0066] 4. In the recrystallization purification process, the step of washing with crystallization solvent after activated carbon filtration is omitted or the washing with heated solvent is used, which reduces the generation of degradation impurities, improves the yield of final product and improves the safety of drugs.

[0067] 5. The preparation method of impurity D in the application can obtain reference substances of other three impurities, impurity A, impurity B and impurity C, at the same time, which saves time and resources, is conducive to the control of quality standards and improves efficiency.

[0068] Impurities A-E are shown in the following formula:

[0069] BRIEF DESCRIPTION OF DRAWINGS

[0070] Figure 1 Mass spectrum of impurity D

[0071] Figure 2 Hydrogen spectrum of impurity D

[0072] Figure 3 Carbon spectrum of impurity D

[0073] DETAILED DESCRIPTION

[0074] The specific process steps of the application are illustrated by the following examples, but are not limited by the examples, and do not limit the scope of the application in any way.

[0075] In the application, the terms used have the meanings generally understood by those of ordinary skill in the art, unless otherwise specified.

[0076] The mass spectrum was collected by Aglient Technologies 6120 Quadrupole LC / MS type liquid chromatograph-mass spectrometer, and the hydrogen spectrum and carbon spectrum were collected by BRUCKER AVANCE 400 nuclear magnetic resonance instrument.

[0077] Refer to examples 1-6 in Chinese patent application CN107778286A for repetition, and the specific conditions are as follows:

[0078] Comparative example 1

[0079] Into a reaction flask was placed 10.00 g of 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde (0.0303 mol) and methanol 50 mL, stirred to add 6.0 g of methylamine alcohol solution (0.05258 mol), 5℃ stirring reaction 1 hour, cooling to 0℃, add 0.77 g of sodium borohydride (0.02026 mol), add 20 mL of water to quench the reaction, stirring for 0.5 hours, remove methanol under reduced pressure, add 100 ml of ethyl acetate and 10 ml of water to the residue, separate, wash the organic phase with water, add dilute hydrochloric acid to the organic phase until the pH is 1, stir at room temperature for 0.5 hours, add 5% sodium chloride solution, stir, and finally no solid precipitates.

[0080] Comparative Examples 2-6 respectively repeat the addition of dilute hydrochloric acid to pH 4, 2, 3, 3, 3, and no solid precipitates.

[0081] Conclusion:

[0082] Comparative Examples 1-6 repeat the experiments according to Examples 1-6 in the patent CN107778286A, no solid precipitates, the experiment cannot be reproduced, it is difficult to achieve the purpose of preparing high purity voneranib by voneranib hydrochloride.

[0083] Comparative Example 7

[0084] Into a clean 50L reaction kettle was placed 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde 2.5 kg, 4-dimethylaminopyridine 0.323 kg, triethylamine 1.60 kg and acetonitrile 7.31 kg, stirred to add pyridine-3-sulfonyl chloride in acetonitrile solution (2.82 kg of pyridine-3-sulfonyl chloride was added to acetonitrile 2.0 kg), after the addition was completed, the temperature was raised to 50℃, and the reaction was carried out, TLC was used to monitor the reaction progress (developing agent: PE: EA = 2:1), after the reaction was completed, the temperature was lowered to 25℃, 7.5 kg of purified water was added dropwise, 0.5 mol / L hydrochloric acid was added to adjust the pH of the system to 4, then 15.0 kg of purified water was added, stirred at 25℃ for 0.5 h, cooled to 10℃, stirred for 1 h, filtered, the filter cake was rinsed with a mixture of acetonitrile 1.0 kg and purified water 2.5 kg, and purified water 7.5 kg, and dried to obtain 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde 3.75 kg, the yield was 86.0%.

[0085] Into a clean 100 L reactor, 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3- carboxaldehyde 3.00 kg, methanol 12.0 kg, 27% methanolic solution 1.35 kg was added drop wise under stirring, after completion of addition, the reaction mass was stirred at 25 °C for 0.5 h, cooled to -10 °C, sodium borohydride in N,N-dimethylacetamide (sodium borohydride 0.15 kg dissolved in 5.1 kg of N,N-dimethylacetamide) was added drop wise, during the addition, the temperature of the system was maintained below 0 °C, after completion of addition, the reaction mass was maintained at -5 °C for 1.0 h, then 1 mol / L hydrochloric acid 18.0 kg was added drop wise, during the addition, the temperature of the system was maintained below 20 °C, after completion of addition, the reaction mass was stirred at 15 °C for 0.5 h, then 25% ammonia solution 6.0 kg, ethyl acetate 27.0 kg and purified water 15.0 kg was added, the organic layer was separated, the aqueous layer was extracted with purified water 12.0 kg and ethyl acetate 16.35 kg, the organic layers were combined and washed with 5% sodium chloride solution 18.0 kg x 2, then concentrated under reduced pressure till no liquid drops.

[0086] Into a clean 100 L reactor, 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3- carboxaldehyde 3.00 kg, methanol 12.0 kg, 27% methanolic solution 1.35 kg was added drop wise under stirring, after completion of addition, the reaction mass was stirred at 25 °C for 0.5 h, cooled to -10 °C, sodium borohydride in N,N-dimethylacetamide (sodium borohydride 0.15 kg dissolved in 5.1 kg of N,N-dimethylacetamide) was added drop wise, during the addition, the temperature of the system was maintained below 0 °C, after completion of addition, the reaction mass was maintained at -5 °C for 1.0 h, then 1 mol / L hydrochloric acid 18.0 kg was added drop wise, during the addition, the temperature of the system was maintained below 20 °C, after completion of addition, the reaction mass was stirred at 15 °C for 0.5 h, then 25% ammonia solution 6.0 kg, ethyl acetate 27.0 kg and purified water 15.0 kg was added, the organic layer was separated, the aqueous layer was extracted with purified water 12.0 kg and ethyl acetate 16.35 kg, the organic layers were combined and washed with 5% sodium chloride solution 18.0 kg x 2, then concentrated under reduced pressure till no liquid drops.

[0087] Into a clean 100 L reactor, 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3- carboxaldehyde 3.00 kg, methanol 12.0 kg, 27% methanolic solution 1.35 kg was added drop wise under stirring, after completion of addition, the reaction mass was stirred at 25 °C for 0.5 h, cooled to -10 °C, sodium borohydride in N,N-dimethylacetamide (sodium borohydride 0.15 kg dissolved in 5.1 kg of N,N-dimethylacetamide) was added drop wise, during the addition, the temperature of the system was maintained below 0 °C, after completion of addition, the reaction mass was maintained at -5 °C for 1.0 h, then 1 mol / L hydrochloric acid 18.0 kg was added drop wise, during the addition, the temperature of the system was maintained below 20 °C, after completion of addition, the reaction mass was stirred at 15 °C for 0.5 h, then 25% ammonia solution 6.0 kg, ethyl acetate 27.0 kg and purified water 15.0 kg was added, the organic layer was separated, the aqueous layer was extracted with purified water 12.0 kg and ethyl acetate 16.35 kg, the organic layers were combined and washed with 5% sodium chloride solution 18.0 kg x 2, then concentrated under reduced pressure till no liquid drops.

[0088] The second refining was carried out according to the above process, the yield was 80.1%, the HPLC purity was 99.75%, the impurity content was: impurity A was not detected, impurity B was 0.03%, impurity C was 0.06%, impurity D was not detected, and impurity E was 0.05%.

[0089] Example 1

[0090] Vonoprazan was prepared according to Comparative Example 7, the HPLC purity was 94.45%, the impurity content was: the total of impurity A and impurity C was 0.71%, impurity B was not detected, impurity D was 0.31%, and impurity E was 0.14%. Ethanol 15.0 kg was added to the residue, 1.53 kg of 48% hydrobromic acid was added dropwise at room temperature, after the dropwise addition was completed, stirring was carried out at room temperature for 1 h, filtration was carried out, the filter cake was rinsed with 9.0 kg of ethanol, and the filter cake was dried to obtain vonoprazan hydrobromide 2.95 kg, the yield was 76.22%. The HPLC purity was 98.38%, the impurity content was: impurity A was 0.03%, impurity B was 0.01%, impurity C was 0.01%, impurity D was 0.01%, and impurity E was 0.13%.

[0091] In a 50 L reaction kettle, ethyl acetate 12.5 kg, ammonia water 1.65 kg, purified water 12.5 kg, and vonoprazan hydrobromide 2.5 kg were added, stirring was carried out until there was no solid in the system, then stirring was continued for 15 min, phase separation was carried out, the water phase was added with 6.25 kg of ethyl acetate for extraction, the organic phases were combined and washed with saturated sodium chloride solution 6.25 kg x 2, and then concentrated under reduced pressure until there were basically no drops, the residue was added with ethyl acetate 8.0 kg and N,N-dimethylacetamide 17.8 kg, and then warmed to 50°C. Fumaric acid 0.683 kg was added, and stirring was carried out at 50°C for 0.5 h to form a salt. The temperature was lowered to 25°C, and crystallization was carried out at 25°C for 1.0 h. Filtration was carried out, the filter cake was rinsed with a mixture of ethyl acetate 1.13 kg and N,N-dimethylacetamide 2.35 kg and ethyl acetate 4.5 kg in sequence, and then dried to obtain fumaric acid vonoprazan product 2.35 kg, the yield was 86.71%. The HPLC purity was 99.81%, the impurity content was: impurity A was 0.02%, impurity B was 0.01%, impurity C was 0.01%, impurity D was not detected, and impurity E was 0.01%.

[0092] Into a clean 50L reactor, methanol 14.26kg and purified water 7.8kg were added, heated to 62°C, fumaric acid voneranib product 2.0kg was added, after stirring and dissolving, 0.10kg of activated carbon was added to decolorize, stirred for 15min, filtered hot, the filtrate was added to a clean 50L reactor, cooled to 5°C, and crystallized for 1.0h, filtered, the filter cake was rinsed with 1.6kg of methanol and 2.0kg of purified water mixed solvent, and dried to obtain 1.65kg of fumaric acid voneranib refined product, with a yield of 82.50%. The purity was 99.93%, and the impurity content was: impurity A was not detected, impurity B was not detected, impurity C was not detected, impurity D was not detected, and impurity E was 0.01%.

[0093] Example 2

[0094] Voneranib was prepared according to Comparative Example 7, with an HPLC purity of 94.54%, and an impurity content of: the sum of impurity A and impurity C was 0.61%, impurity B was not detected, impurity D was 0.22%, and impurity E was 0.12%. Ethanol 15.0kg was added to the residue, and 1.53kg of 48% hydrobromic acid was added dropwise at room temperature. After the dropwise addition was completed, stirring was carried out at room temperature for 1h, filtration was carried out, the filter cake was rinsed with 9.0kg of ethanol, and the filter cake was dried to obtain 2.98kg of voneranib hydrobromide, with a yield of 76.99%. The HPLC purity was 98.03%, and the impurity content was: impurity A was 0.11%, impurity B was not detected, impurity C was not detected, impurity D was not detected, and impurity E was 0.06%.

[0095] Into a 50L reactor, ethyl acetate 12.5kg, ammonia water 1.65kg, purified water 12.5kg, and voneranib hydrobromide 2.5kg were added, stirring was carried out until there were no solids in the system, and then stirring was continued for 15min, phase separation was carried out, the aqueous phase was added to 6.25kg of ethyl acetate for extraction, the organic phases were combined, the organic phase was washed with saturated sodium chloride solution 6.25kgx2, and was concentrated under reduced pressure until there were basically no drops, the residue was added to ethyl acetate 8.0kg and N,N-dimethylacetamide 17.8kg, and was heated to 55°C. Fumaric acid 0.683kg was added, and salt formation was carried out at 55°C for 0.5h. The temperature was lowered to 25°C, and crystallization was carried out for 1.0h. Filtration was carried out, the filter cake was rinsed with a mixed solution of ethyl acetate 1.13kg and N,N-dimethylacetamide 2.35kg, and then with ethyl acetate 4.5kg, and was dried to obtain 2.36kg of fumaric acid voneranib product, with a yield of 87.08%. The HPLC purity was 99.75%, and the impurity content was: impurity A was 0.09%, impurity B was not detected, impurity C was not detected, impurity D was not detected, and impurity E was 0.01%.

[0096] Into a clean 50L reactor, add methanol 14.26kg and purified water 7.8kg, heat to 65℃, add fumaric acid voneranib product 2.0kg, after stirring and dissolving, add activated carbon 0.10kg for decolorization, stir for 15min, filter while hot, add the filtrate into a clean 50L reactor, cool to 10℃, keep the temperature for 1.0h, filter, rinse the filter cake with a mixed solvent of methanol 1.6kg and purified water 2.0kg, dry to obtain fumaric acid voneranib refined product 1.65kg, yield 82.50%, purity 99.92%, impurity content: impurity A not detected, impurity B not detected, impurity C not detected, impurity D not detected, impurity E not detected.

[0097] The purity and yield of voneranib hydrobromide, fumaric acid voneranib product and fumaric acid voneranib refined product in the above examples 1, 2 and 3 are compared in the following table:

[0098]

[0099] Conclusion: As can be seen, examples 1-2 prove that by removing impurities through voneranib hydrobromide, the purity of fumaric acid voneranib product can reach more than 99.7%, and only one refining can control the purity of fumaric acid voneranib refined product to more than 99.9%, which meets the standard of pharmaceutical grade API. While effectively improving the purity, it can also further effectively improve the product yield.

[0100] The content of impurity A, impurity B, impurity C, impurity D and impurity E in the fumaric acid voneranib product and fumaric acid voneranib refined product in comparative example 7 and the above examples 1-2 are compared in the following table:

[0101]

[0102]

[0103] Conclusion: The content of impurity B, impurity C and impurity E in the fumaric acid vonomrazan product in comparative example 7 is high, which is 0.12%, 0.15% and 0.15% respectively, and the removal effect is limited by the recrystallization refining method in the prior art; after one refining, the content of impurity C is as high as 0.11%, which causes the product of one refining to fail to meet the pharmaceutical standard (0.1%), in addition, the content of impurity B and impurity E is still as high as 0.08% and 0.09% respectively, in addition to the normal fluctuation between batches causing the exceeding standard (0.1%), with the increase of the feeding amount, the impurity content increases, which will inevitably cause the impurity of the whole batch product to exceed the standard, and there is a great risk, which causes great economic loss; after two refinings, the content of the above impurities is still relatively high. In examples 1-2, the impurity B and impurity C are controlled at 0.01% or not detected by preparing vonomrazan hydrobromide, and the impurity E is removed in the salt splitting process of vonomrazan hydrobromide; the content of impurity B, impurity C and impurity E in the fumaric acid vonomrazan product prepared from vonomrazan hydrobromide is greatly reduced, which is 0.01% or not detected; after refining, the above impurities are basically not detected or have very low content, which effectively controls the content of impurity B, impurity C and impurity E in fumaric acid vonomrazan, and improves the purity of the final product.

[0104] Example 3 Preparation of impurity D

[0105] Vonomrazan 15.0 g was dissolved in methanol 50 mL, and sodium borohydride 15.0 g in 100 mL N,N-dimethylacetamide solution was added dropwise under stirring, after the dropwise addition was completed, the reaction was stirred at room temperature for 12 h, 1 mL of the reaction solution was added into purified water 5 ml and ethyl acetate 1 mL, shaken, and then allowed to stand, the organic phase was taken, and HPLC detection showed that four large over-reduction impurity peaks appeared in the organic phase, which were impurity B (relative retention time RTT = 0.28), impurity C (RTT = 0.52), impurity A (RTT = 0.54), and impurity D (RTT = 0.73) in turn. Purified water 500 mL and ethyl acetate 250 mL were added to the reaction system, stirred, allowed to stand to separate the phases, and the organic phase was concentrated under reduced pressure to obtain an oily substance, and 0.90 g of impurity D was separated by preparation. Purity 95.06%, MS (ESI) m / z (M+H) + : 347.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.43 (dd, J = 1.0 Hz, 6.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.19 (m, 2H), 7.13 (m, 1H), 6.26 (s, 1H), 6.22 (d, J = 5.6 Hz, 1H), 5.87 (m, 1H), 4.57 (t, J = 4.0 Hz, 1H), 3.74 (s, 2H), 2.71 (s, 2H), 2.27 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 162.11 159.66 139.13 133.50 131.17 131.09 127.30 125.20 124.92 123.73 123.70 121.96 120.38 120.23 116.42 115.52 115.30 101.52 100.25 47.83 36.09 21.29.

Claims

1. A method for removing impurities A-E in the manufacture of vonoprazan, characterized by, The reaction of vorolanib with hydrobromic acid to obtain vorolanib hydrobromide, comprising the following steps: ， (1) dissolving vorolanib and hydrobromic acid in a solvent; (2) cooling or directly precipitating a solid; (3) separating to obtain vorolanib hydrobromide, In step (1), the solvent is ethanol, and the dissolving temperature is room temperature, And after step (3), the reaction of vorolanib free base in the presence of an inorganic base.

2. The method of claim 1, wherein the molar ratio of hydrogen bromide to vorolanib in the hydrobromic acid is 0.8:1 to 1.5:

1.

3. The method of claim 1, wherein, The vorolanib is obtained by the reaction of 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde with methylamine or a salt thereof in the presence of a reducing agent.

4. The method of claim 1, wherein, In step (2), the solid is directly precipitated at room temperature.

5. The method of claim 4, wherein, In step (2), the solid is precipitated under stirring.

6. The method of claim 1, wherein, The reaction of the obtained vorolanib free base with an organic acid or an inorganic acid to obtain a vorolanib salt.

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