A kind of vonoprazan intermediate and its preparation method and application

Abstract

The present invention provides a kind of vonoprazan intermediate compound 5, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine and its preparation method; the method uses the compound of formula 2 as the starting material, and compound 5 can be obtained through hydrolysis reaction, amidation reaction and reduction reaction; the method has high efficiency, green and environmental protection, high yield and high purity, and provides high-quality intermediate compounds for preparing vonoprazan. The present invention also provides a method for preparing vonoprazan by compound 5, and compared with the technical scheme disclosed in the prior art, the technical scheme provided by the present invention avoids the more dangerous hydrogenation reaction, and the reaction route is simple and efficient, safe and environmentally friendly, and the product purity is high, which is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a vonoprazan fumarate intermediate and a preparation method thereof, and a method for using the intermediate to prepare vonoprazan fumarate. Background Art

[0002] Vonoprazan fumarate, with the chemical formula of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine fumarate, is a potassium ion (K + ) Competitive acid pump inhibitor (P-CAB), with strong and lasting inhibitory effect on gastric acid secretion. The metabolism of vonoprazan fumarate is less related to the liver drug enzyme CYP2C19. At the same time, the inhibitory effect of vonoprazan fumarate on the proton pump does not require acid activation. The drug is absorbed at high concentrations in the target organ stomach, and can produce nearly maximal efficacy on the first day of administration, and this effect can last for 24 hours. The structure of vonoprazan fumarate is shown below:

[0003]

[0004] At present, although the literature reports a variety of preparation methods of vonoprazan fumarate, there are areas that need to be improved, and no technical route suitable for industrial production has been reported. Patent WO2007026916 first reported the synthesis route of vonoprazan, but this method has a long synthesis step, and also uses complex and dangerous process steps such as reduction hydrogenation; at the same time, the reaction also involves ester reduction, aldehyde reduction, amination reduction and other reactions, the corresponding operation process is cumbersome, the conversion efficiency is not high, and it is not suitable for industrial large-scale production. The specific synthesis route is as follows:

[0005]

[0006]

[0007] Chinese patent CN200680040789 discloses a method for obtaining vonoprazan using 1H-pyrrole-3-carboxylic acid ethyl ester as a starting material through bromination, sulfonylation, ester reduction, amination reduction and other reactions. However, the synthesis steps are relatively complicated, and other impurities will be generated during the reduction process when the nitrogen methyl group is introduced into the reaction.

[0008]

[0009] Another Chinese patent CN102421753 provides an improved synthetic route, which avoids the reduction of esters by adopting the reaction of reducing cyano groups to aldehydes, but still does not avoid the process steps of hydrogenation reduction reaction and amination reaction, which should be avoided as much as possible in industrial production. In addition, the reaction operation of this route is relatively complicated, and this step may introduce aldehyde groups with genotoxic warning structures, affecting the product quality of the final product.

[0010]

[0011] Chinese patent CN104860923 reports a technical solution of directly reducing cyano groups to amine groups and then reacting with paraformaldehyde and sodium borohydride. Although the reaction route has fewer steps, the reduction step is still used. At the same time, paraformaldehyde with high toxicity is used, and a cumbersome post-treatment process is required to avoid the residue of paraformaldehyde, which is not suitable for industrial production.

[0012]

[0013] In addition, patent CN107778286A mentioned that the synthesis process of the prior art requires a final reduction reaction to obtain N-methyl-1-(3-pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-methylamine, and a series of key impurities are generated as follows:

[0014]

[0015] This is because the reductive amination step of introducing the methyl group is highly active and easily generates multi-substituted impurities. At the same time, the reduction of other functional groups will be caused during the reduction of the imine. In addition, methylamine is highly volatile, which easily leads to the formation of impurities.

[0016] In summary, although the existing literature has disclosed a variety of preparation methods of vonoprazan, there are still problems such as long reaction routes, complicated reaction operation processes, and being unsuitable for industrial production. In addition, the introduction of genotoxic substances such as halogenated alkyls and paraformaldehyde during the reaction process increases the difficulty of post-processing and also brings certain safety hazards to the quality of the product. Therefore, it is still very important to develop a relatively green, economical, and environmentally friendly synthetic route. It is necessary to provide a new synthetic method that is suitable for industrial production and can effectively avoid the residue of toxic impurities. Summary of the invention

[0017] In view of the problems of complicated operation process and residual toxic impurities in the current preparation process of vonoprazan, the present invention aims to provide a preparation method of the intermediate compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, which can simplify the synthesis steps of vonoprazan, change the synthesis idea of ​​introducing nitrogen methyl group and reduce the residual toxic impurities; the present invention also provides a technical method suitable for the industrial production of vonoprazan with relatively simple operation, efficient reaction and environmentally friendly reaction.

[0018] The specific technical contents of the present invention are as follows:

[0019] First, the present invention provides a vonoprazan intermediate N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, which has a structure shown in Formula 5:

[0020]

[0021] Secondly, the present invention provides a method for preparing a vonoprazan intermediate N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine (Compound 5), and the specific preparation steps include:

[0022]

[0023] Step 1: hydrolyzing the compound of formula 2 in a solvent to obtain the compound of formula 3, 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid;

[0024] Step 2: The compound of formula 3 is subjected to amidation reaction to obtain the compound of formula 4, N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide;

[0025] Step 3: The compound of formula 4 is subjected to reduction reaction to obtain the compound of formula 5, N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine.

[0026] Preferably, the solvent in step 1 is methanol-water, ethanol-water or a combination thereof; preferably ethanol-water.

[0027] Preferably, the mass fraction of alcohol in the solvent in step 1 is 60% to 90%.

[0028] Preferably, in step 1, the mass volume ratio of compound 2 to solvent is 1:5 to 20; preferably 1:10 to 15; the mass is in g and the volume is in mL.

[0029] Preferably, the acid used in the hydrolysis reaction in step 1 is one or more of hydrochloric acid, sulfuric acid, and acetic acid; preferably concentrated sulfuric acid.

[0030] Further preferably, the molar ratio of compound 2 to acid in the hydrolysis reaction in step 1 is 1:1-2.

[0031] Preferably, the reaction time of the hydrolysis in step 1 is 5 to 10 hours; preferably 7 to 8 hours.

[0032] Preferably, the reaction temperature in step 1 is 30-60°C; preferably 40-50°C.

[0033] Preferably, after the reaction in step 1 is completed, a purification step can be performed to obtain a product with higher purity, specifically comprising:

[0034] After the reaction is completed, purified water is added, and the mixture is extracted three times with ethyl acetate. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and the filtrate is dried under reduced pressure to obtain the compound of formula 3, 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid.

[0035] Preferably, the acylating agent for the amidation reaction in step 2 is oxalyl chloride.

[0036] Preferably, the solvent for the reaction in step 2 is one or more of acetonitrile, tetrahydrofuran, and dichloromethane; preferably acetonitrile.

[0037] Further preferably, the mass volume ratio of compound 3 to solvent in step 2 is 1:5-10.

[0038] Further preferably, the molar ratio of compound 3 to oxalyl chloride in step 2 is 1:1 to 1.5; preferably 1:1.2.

[0039] Preferably, the catalyst for the amidation reaction in step 2 is DMF; wherein the mass volume ratio of compound 3 to DMF is 1:0.001-0.005; the mass is g, and the volume is mL.

[0040] Preferably, the methylamine reagent for the amidation reaction in step 2 is one or more of methylamine hydrochloride, methylamine alcohol solution, and methylamine aqueous solution; preferably methylamine hydrochloride.

[0041] Further preferably, in step 2, the molar ratio of compound 3 to methylamine reagent is 1:1.0-1.1.

[0042] Preferably, the reaction temperature in step 2 is 30-50° C., preferably 40° C.; the reaction time is 1-4 h; preferably 2 h.

[0043] Preferably, the acid binding agent for the amidation reaction in step 2 is one or more of diethylamine, triethylamine, and DIEA; preferably diethylamine.

[0044] Further preferably, in step 2, the molar ratio of the compound 3 to the acid binding agent is 1:1 to 1.2.

[0045] Preferably, after the reaction in step 2 is completed, a product with higher purity can be obtained through a purification step, which specifically includes:

[0046] After the reaction is completed, one volume (calculated based on the reaction solution) of purified water is added dropwise, and the mixture is stirred at 5°C and filtered to obtain an off-white solid compound 4, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide.

[0047] Preferably, the reducing agent for the reduction reaction in step 3 is a sodium borohydride / boron trifluoride reduction system.

[0048] Preferably, the solvent for the reaction in step 3 is tetrahydrofuran, diethyl ether or dimethyl sulfoxide.

[0049] Further preferably, the mass-to-volume ratio of the compound 4 described in step 3 to the solvent is 1:1-5; the mass is in g and the volume is in mL.

[0050] Preferably, the molar ratio of the reduction reaction compound 4 to sodium borohydride in step 3 is 1:1-3.

[0051] Further preferably, the molar ratio of the reduction reaction compound 4 to boron trifluoride in step 3 is 1:0.3-1.8.

[0052] Preferably, the reaction temperature of the reaction in step 3 is 30-70° C., preferably 50° C.; the reaction time is 1-4 h, preferably 2 h.

[0053] Preferably, after the reaction in step 3 is completed, a product with higher purity can be obtained through a purification step, which specifically includes:

[0054] After the reaction, 1 mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH to 4-5, and the solvent was removed by distillation under reduced pressure to obtain an off-white solid compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine.

[0055] In addition, the present invention also provides a method for preparing vonoprazan fumarate, the specific steps comprising:

[0056]

[0057] Step a: Compound 5 and compound 6 are subjected to coupling reaction to obtain compound 7 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine;

[0058] Step b: The compound of formula 7 is salified with fumaric acid and purified to obtain the compound of formula 1, namely, vonoprazan fumarate.

[0059] Preferably, the base used in the coupling reaction in step a is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, and potassium phosphate; preferably sodium carbonate or potassium carbonate.

[0060] Further preferably, in step a, the molar ratio of the compound of coupling reaction formula 5 to the base is 1:1-2.

[0061] Preferably, the solvent used for the coupling reaction in step a is one or more of tetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0062] Further preferably, the mass-to-volume ratio of the compound of the coupling reaction formula 5 to the solvent in step a is 1:5-10, the mass is g, and the volume is mL.

[0063] Preferably, the catalyst used in the coupling reaction described in step a is one of PD(PPH3)4, PD(PPH3)2Cl2 or a combination thereof.

[0064] Further preferably, the amount of the catalyst used in the coupling reaction in step a is 1% to 10% by mass of Formula 5.

[0065] Preferably, in step a, the molar ratio of the compound of formula 5 to the compound of formula 6 is 1:1.05-1.2.

[0066] Preferably, the coupling reaction time in step a is 18 to 30 hours; preferably 22 to 26 hours.

[0067] Preferably, the temperature of the coupling reaction in step a is 60-120°C.

[0068] Preferably, after the coupling reaction described in step a is completed, a purification step can be performed to obtain a product with higher purity, specifically comprising:

[0069] After the reaction is completed, cool down, add one volume (calculated based on the reaction liquid) of purified water, keep warm and stir for 1 to 2 hours, filter with suction, dissolve the filter cake in ethyl acetate, add NaOH aqueous solution, adjust pH to 8 to 9, extract and separate the phases, wash the organic phase three times with saturated brine, then add petroleum ether, keep warm and stir after the addition is complete, filter with suction, and dry the filter cake in vacuo to obtain a white solid.

[0070] Compared with the prior art, the technical effects achieved by the present invention are:

[0071] The present invention provides a vonoprazan intermediate compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine (compound 5) and a preparation method thereof; the method has high reaction efficiency, is green and environmentally friendly, has high yield and high purity, and provides a high-quality intermediate compound for preparing vonoprazan. The present invention also provides a method for preparing vonoprazan using compound 5, which can avoid the generation of impurities A, E and F, and impurities B and C can be effectively removed. Compared with the technical solutions disclosed in the prior art, the technical solution provided by the present invention avoids the more dangerous hydrogenation reaction, and the reaction route is simple and efficient, safe and environmentally friendly, and the product purity is high, which is suitable for industrial production. DETAILED DESCRIPTION

[0072] The present invention is further described below by examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed in the present invention. The solvents or reagents used in the present invention can be purchased from commercial products or prepared by conventional techniques in the field from commercial products.

[0073] Example 1 Preparation of Compound 5

[0074] 31.2 g of 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carbonitrile was dissolved in 320 mL of ethanol aqueous solution (80%), 5.4 mL of concentrated sulfuric acid solution was added, the temperature was raised to 45°C, and the reaction was kept warm for 8 hours. After the reaction was completed, 500 mL of purified water was added, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain an oily compound 3, namely 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid, with a yield of 90.1%. ESI-MS (m / z): 332.25 [M+H] + .

[0075] 29.82g of oily compound 3 was dissolved in 170mL of acetonitrile solution, and then 6.08g of methylamine hydrochloride solid was added, 9.7mL of diethylamine was added, 0.1mL of DMF was added, the temperature was cooled to 5°C with stirring, 9mL of oxalyl chloride solution was added dropwise, and the temperature was raised to 40°C and stirred for 2h after the addition was completed. After the reaction was completed, 170mL of purified water was added dropwise, and the temperature was kept at 5°C and stirred for 2h after the addition was completed. The mixture was filtered to obtain an off-white solid compound 4, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide, with a yield of 93.6%, ESI-MS (m / z): 345.13 [M+H] + .

[0076] 29.00gN-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide was added to 50mL tetrahydrofuran, and the temperature was lowered to 0-10°C. 3.33g sodium borohydride solid was added in batches. After the addition was completed, 4mL of boron trifluoride (2.22g) tetrahydrofuran solution was added dropwise. After the addition was completed, the temperature was raised to 50°C and stirred for 2h. After the reaction was completed, 1mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH to 4-5. The solvent was removed by distillation under reduced pressure to obtain an off-white solid compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine with a yield of 90.3% and HPLC: 99.46%.

[0077] Structural confirmation: ESI-MS (m / z): 331.23 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δ: 8.82~8.84 (d, J=2.8Hz, 1H), 8.55 (d, J=0.8Hz, 1H), 7.89~7.90 (d,J=5.6Hz,1H),7.11~7.16(m,1H),6.72(s,2H),6.46(s,1H),4.12(s,2H),2.70(s,3H). 13 CNMR (100MHz, DMSO-d6) δ: 161.5, 154.0, 148.1, 135.1, 134.6, 133.5, 118.8~118.9, 117.0, 115.3~115.5, 85.2, 35.8.

[0078] Purity detection: [HPLC area normalization method: chromatographic column Waters Symmetry-C 18 Column (4.6mm×250mm, 5μm); mobile phase A: phosphate buffer (weigh 3.86g K2HPO4·3H2O and 1.44g sodium pentane sulfonate, add 1000mL water to dissolve, and adjust the pH to 5.0 with phosphoric acid) B: acetonitrile; gradient elution 0-45minA(90%):B(10%); 45-70minA(35%):B(65%), detection wavelength: 220nm; column temperature 30℃; flow rate 1.0mL / min].

[0079] Example 2 Preparation of Compound 5

[0080] 31.2 g of 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carbonitrile was dissolved in 460 mL of ethanol aqueous solution (60%), 10 mL of concentrated sulfuric acid solution was added, the temperature was raised to 45°C, and the reaction was kept warm for 8 hours. After the reaction was completed, 500 mL of purified water was added, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain an oily compound 3, namely 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid, with a yield of 87.1%. ESI-MS (m / z): 332.25 [M+H] + .

[0081] 28.92 g of oily compound 3 was dissolved in 150 mL of acetonitrile solution, and then 6.48 g of methylamine hydrochloride solid was added, 9.1 mL of diethylamine was added, 0.2 mL of DMF was added, the temperature was cooled to 5°C with stirring, 7.5 mL of oxalyl chloride solution was added dropwise, and the temperature was raised to 40°C and stirred for 2 h after the addition was completed. After the reaction was completed, 170 mL of purified water was added dropwise, and the temperature was kept at 5°C and stirred for 2 h. The mixture was filtered to obtain an off-white solid compound 4, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide, with a yield of 92.3%. ESI-MS (m / z): 345.12 [M+H] + .

[0082] 27.71g N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide was added to 100mL tetrahydrofuran, cooled to 0-10°C, 4.57g sodium borohydride solid was added in batches, and after the addition was completed, 6mL boron trifluoride (5.42g) tetrahydrofuran solution was added dropwise. After the addition was completed, the temperature was raised to 50°C and stirred for 2h. After the reaction was completed, 1mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH to 4-5, and the solvent was removed by distillation under reduced pressure to obtain an off-white solid compound 5N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, with a yield of 89.3%, HPLC: 99.31%. ESI-MS (m / z): 331.24 [M+H] + .

[0083] Example 3 Preparation of Compound 5

[0084] 31.2 g of 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carbonitrile was dissolved in 160 mL of ethanol aqueous solution (90%), 8 mL of concentrated sulfuric acid solution was added, the temperature was raised to 60°C, and the reaction was kept warm for 7 hours. After the reaction was completed, 500 mL of purified water was added, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain an oily compound 3, namely 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid, with a yield of 87%. ESI-MS (m / z): 332.26 [M+H] + .

[0085] 28.89 g of oily compound 3 was dissolved in 290 mL of acetonitrile solution, and then 6.15 g of methylamine hydrochloride solid was added, 11 mL of diethylamine was added, 0.1 mL of DMF was added, the temperature was cooled to 5°C with stirring, 11 mL of oxalyl chloride solution was added dropwise, the temperature was raised to 40°C and stirred for 2 h after the addition was complete, 170 mL of purified water was added dropwise after the addition was complete, the temperature was kept at 5°C and stirred for 2 h, and suction was filtered to obtain an off-white solid compound 4, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide, with a yield of 91.2%, ESI-MS (m / z): 345.14 [M+H] + .

[0086] 27.38g of N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide was added to 150mL of tetrahydrofuran, and the temperature was lowered to 0-10°C. 9.36g of sodium borohydride solid was added in batches. After the addition was completed, 8mL of boron trifluoride (6.51g) tetrahydrofuran solution was added dropwise. After the addition was completed, the temperature was raised to 50°C and stirred for 2h. After the reaction was completed, 1mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH to 4-5. The solvent was removed by distillation under reduced pressure to obtain an off-white solid compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, with a yield of 88.6%, HPLC: 99.28%. ESI-MS (m / z): 331.23 [M+H] + .

[0087] Example 4 Preparation of Compound 5

[0088] 31.2 g (0.1 mol) of 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carbonitrile was dissolved in 320 mL (10 q) of methanol aqueous solution (80%), and 5.4 mL (0.1 mol, 1 q) of concentrated sulfuric acid solution was added, and the temperature was raised to 45°C. The mixture was kept warm for 10 h. After the reaction was completed, 500 mL of purified water was added, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain an oily compound 3, namely 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid, with a yield of 88.2%. ESI-MS (m / z): 332.26 [M+H] + .

[0089] The obtained 29.30g oily compound 3 was dissolved in 170mL tetrahydrofuran solution, and then 6.83g methylamine aqueous solution (methylamine content 40%) was added, 12.8mL triethylamine was added, 0.1mL DMF was added, the temperature was cooled to 5°C with stirring, 9mL oxalyl chloride solution was added dropwise, and the temperature was raised to 50°C and stirred for 2h after the addition was completed. After the reaction was completed, 170mL purified water was added dropwise, and the temperature was kept at 5°C and stirred for 2h after the addition was completed. The mixture was filtered to obtain an off-white solid compound 4, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide 2, with a yield of 91.2%, ESI-MS (m / z): 345.13 [M+H] + .

[0090] 27.70g N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide was added to 50mL ether, cooled to 0-10°C, 3.12g sodium borohydride solid was added in batches, and after the addition was completed, 4mL boron trifluoride (2.22g) tetrahydrofuran solution was added dropwise. After the addition was completed, the temperature was raised to 30°C and stirred for 2h. After the reaction was completed, 1mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH to 4-5, and the solvent was removed by distillation under reduced pressure to obtain an off-white solid compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, with a yield of 90.3%, HPLC: 99.39%. ESI-MS (m / z): 331.24 [M+H] + .

[0091] Example 5 Preparation of Compound 5

[0092] 31.2 g of 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carbonitrile was dissolved in 320 mL of ethanol aqueous solution (80%), 13.5 mL of concentrated sulfuric acid solution was added, the temperature was raised to 70°C, and the reaction was kept warm for 12 h. After the reaction was completed, 500 mL of purified water was added, and the mixture was extracted three times with 500 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain an oily compound 3, namely 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid, with a yield of 78.2%. ESI-MS (m / z): 332.13 [M+H] + .

[0093] The obtained 26.00g oily compound 3 was dissolved in 170mL acetonitrile solution, and then 6.75g methylamine hydrochloride solid was added, 12.2mL diethylamine was added, 0.1mL DMF was added, the temperature was cooled to 5°C with stirring, 15mL oxalyl chloride solution was added dropwise, and the temperature was raised to 60°C and stirred for 2h after the addition was completed. After the reaction was completed, 170mL purified water was added dropwise, and the temperature was kept at 5°C and stirred for 2h after the addition was completed. The mixture was filtered to obtain an off-white solid compound 4, namely N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide, with a yield of 81.3%, ESI-MS (m / z): 345.14 [M+H] + .

[0094] 21.89g N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide was added to 50mL tetrahydrofuran, cooled to 0-10°C, and 2.27g sodium borohydride solid was added in batches. After the addition was completed, 2mL boron trifluoride (0.89g) tetrahydrofuran solution was added dropwise. After the addition was completed, the temperature was raised to 50°C and stirred for 2h. After the reaction was completed, 1mol / L hydrochloric acid aqueous solution was added dropwise to adjust the pH to 4-5. The solvent was removed by distillation under reduced pressure to obtain an off-white solid compound N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, with a yield of 82.6%, HPLC: 98.26%. ESI-MS (m / z): 331.22 [M+H] + .

[0095] Example 6 Preparation of Vonoprazan Fumarate

[0096] 33.10gN-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine was dissolved in 150mL tetrahydrofuran solution, and then 1.11g of PD(PPH3)4, 24.43g of compound 6, and 14g of potassium carbonate were added, heated to 60°C, and stirred for 24h; after the reaction was completed, the temperature was lowered to 5°C, 120mL of purified water was added dropwise, and the mixture was stirred for 1h. The mixture was filtered with suction, and the filter cake was dissolved in 40mL of ethyl acetate. A 20% NaOH aqueous solution was added dropwise to adjust the pH to 8-9, and the mixture was extracted and separated. The organic phase was washed three times with saturated brine, and then 80mL of petroleum ether was added dropwise. After the addition was completed, the mixture was stirred for 2h at 10°C, filtered with suction, and the filter cake was dried in vacuo at 20-30°C to obtain a white solid with a yield of 92.1%.

[0097] The obtained 31.81g solid was added to 70% methanol aqueous solution, heated to 60-65°C for complete dissolution, then 10g fumaric acid was added, stirred at this temperature for 0.5h, then cooled to 0-10°C, stirred at this temperature for 1.0h, filtered, and the filter cake was vacuum dried to obtain fumaric acid vonoprazan solid, with a yield of 93.6%. HPLC: 99.91%, impurities A, C, E, and F were not detected, impurity B 0.01%, impurity D 0.01%; ESI-MS (m / z): 461.43 [M+H] + .

[0098] Purity test: [HPLC area normalization method: chromatographic column UltimateXB-C 18 Column (4.6 mm × 250 mm, 5 μm); mobile phase: 0.04 mol / L sodium dihydrogen phosphate buffer (phosphoric acid adjusted to pH 6.0): acetonitrile (3:7); detection wavelength: 254 nm; column temperature: 30°C; flow rate: 1.0 mL / min].

[0099] Example 7 Preparation of Vonoprazan Fumarate

[0100] 33.10g of N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine was dissolved in 150mL of N,N-dimethylformamide solution, and then 1.66g of PD(PPH3)4, 23.32g of compound 6, and 15.90g of sodium carbonate were added, heated to 100°C, and stirred for 26h; after the reaction was completed, the temperature was lowered to 5°C, 120mL of purified water was added dropwise, and the mixture was stirred for 1h. The filter cake was dissolved in 40mL of ethyl acetate, and 20% NaOH aqueous solution was added dropwise to adjust the pH to 8-9, and the phases were extracted and separated. The organic phase was washed three times with saturated brine, and then 80mL of petroleum ether was added dropwise. After the addition was completed, the mixture was stirred for 2h at 10°C, filtered, and the filter cake was dried in vacuo at 20-30°C to obtain a white solid with a yield of 91.7%.

[0101] The obtained 31.67g solid was added to 70% methanol aqueous solution, heated to 60-65°C for complete dissolution, then 10g fumaric acid was added, stirred at this temperature for 0.5h, then cooled to 0-10°C, stirred at this temperature for 1.0h, filtered, and the filter cake was vacuum dried to obtain fumarate vonoprazan solid, with a yield of 93.4%. HPLC: 99.89%, impurities A, C, E, and F were not detected, impurity B 0.01%, impurity D 0.01%; ESI-MS (m / z): 461.43 [M+H] + .

Claims

1. A vonoprazan intermediate N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, characterized in that: It has the structure shown in Formula 5: 。 2. A method for preparing a vonoprazan intermediate N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine, characterized in that: The specific preparation steps include: ； Step 1: hydrolyzing the compound of formula 2 in a solvent to obtain the compound of formula 3, 1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxylic acid; Step 2: Amidation of the compound of formula 3 to obtain the compound of formula 4, N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-carboxamide; Step 3: The compound of formula 4 is subjected to reduction reaction to obtain the compound of formula 5, N-methyl-1-(3-pyridylsulfonyl)-2-bromo-1H-pyrrole-3-methylamine.

3. The preparation method according to claim 2, characterized in that: The solvent described in step 1 is one of methanol-water and ethanol-water or a combination thereof.

4. The preparation method according to claim 3, characterized in that: The mass fraction of alcohol in the solvent is 60% to 90%.

5. The preparation method according to claim 2, characterized in that: The acid used in the hydrolysis reaction in step 1 is one or more of hydrochloric acid, sulfuric acid and acetic acid.

6. The preparation method according to claim 2, characterized in that: The temperature of the reaction in step 1 is 30-60°C.

7. The preparation method according to claim 2, characterized in that: The acylating agent for the amidation reaction in step 2 is oxalyl chloride.

8. The preparation method according to claim 2, characterized in that: The methylamine reagent for the amidation reaction in step 2 is one or more of methylamine hydrochloride, methylamine alcohol solution, and methylamine aqueous solution.

9. The preparation method according to claim 8, characterized in that: In step 2, the molar equivalent ratio of compound 3 to methylamine reagent is 1:1.0 to 1.

1.

10. The preparation method according to claim 2, characterized in that: The reducing agent for the reduction reaction in step 3 is a sodium borohydride / boron trifluoride reduction system.

11. A method for preparing vonoprazan fumarate, comprising the following specific steps: ； Step a: Compound 5 and compound 6 are subjected to coupling reaction to obtain compound 7 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine; Step b: The compound of formula 7 is salified with fumaric acid and purified to obtain the compound of formula 1, namely, vonoprazan fumarate.

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