A process for the preparation of an intermediate for the preparation of vonomaci x fumarate

Abstract

The application belongs to the technical field of preparation of pharmaceutical compounds, and particularly relates to a preparation method of an intermediate for preparing vonomacarbazone fumarate, wherein compound S1 and compound S2 are used as raw materials to synthesize compound S3, and then the intermediate S4 is synthesized from the compound S3, wherein the structural formulae of the compounds S1 and S2 are as follows: S1: S2: S3: The above technical scheme of the application fundamentally changes the construction strategy of the key pyrrole ring skeleton of vonomacarbazone fumarate, and two open-chain molecules S1 and S2 with simple structures, which are commercially available or easy to prepare, are used to efficiently and selectively construct the target pyrrole ring structure (S4) on site through a simple addition-electrophilic cyclization reaction. The method not only greatly reduces the cost of raw materials, but also avoids the dependence on unstable intermediates, and simplifies the synthesis path from the source.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compound preparation technology, specifically relating to a method for preparing an intermediate for vonoprazan fumarate. Background Technology

[0002] vonoprazan fumarate (TAK-438), chemically named 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-3-methylaminomethyl-1H-pyrrole fumarate, belongs to the potassium ion (K) group. + A new class of inhibitors of competitive acid blockers, which inhibit K... + With H + -K + The binding action of ATPase (proton pump) prematurely terminates gastric acid secretion, resulting in a strong and long-lasting inhibitory effect on gastric acid secretion in the human body. Clinically, it has shown good efficacy in treating erosive esophagitis, gastric ulcers, duodenal ulcers, and Helicobacter pylori eradication indications.

[0003] The main publicly reported synthetic routes for vonoprazan fumarate are as follows:

[0004] Method 1: The synthesis of vonoprazan in Takeda's patent JP2006317408 begins with 2-fluoroacetophenone as the starting material. First, it is brominated with copper bromide, then condensed with ethyl cyanoacetate to obtain the intermediate ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutyrate. This intermediate is cyclized in a 4 M hydrogen chloride solution in ethyl acetate and then dechlorinated by Pd / C catalytic hydrogenation to generate a pyrrole skeleton. Subsequently, the ester group is reduced to a hydroxyl group by diisobutylaluminum hydride (DIBAL), and further oxidized to an aldehyde group using a tetrapropylperruthenium perruthenium (TPAP) / N-methylmorpholine-N-oxide (NMO) oxidation system, thus yielding the key intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde. The aldehyde compound undergoes sulfonation with pyridine-3-sulfonyl chloride in the presence of sodium hydride (NaH) and 15-crown ether-5, followed by methylation and salt formation with fumaric acid to give the target product, vonorazan fumarate. The reaction is shown below:

[0005]

[0006] In this route, the yield is low during palladium reduction on carbon, and the oxidation of hydroxyl groups to aldehydes requires an expensive metal catalyst—tetrapropylammonium perruthenate (TPAP). Furthermore, the post-processing of several steps in this route relies on column chromatography for separation and purification, making the operation cumbersome and time-consuming.

[0007] Method 2: The synthetic route of vonorazan, as described in patent CN101300229A, uses methyl 1H-pyrrole-3-carboxylate as the starting material. First, it undergoes bromination with N-bromosuccinimide (NBS); then, sulfonation is performed to introduce a sulfonyl group; next, a Suzuki coupling reaction is used to construct the key aromatic ring structure; subsequently, the ester group is reduced to a hydroxyl group, and the hydroxyl group is converted to an aldehyde group using a tetrapropylperruthenium perruthenate (TPAP) / N-methylmorpholine-N-oxide (NMO) oxidation system. Finally, methylamination is performed, followed by salt formation with fumaric acid to obtain the target product, vonorazan fumarate. The reaction is shown below:

[0008]

[0009] The starting material for this synthetic route, methyl 1H-pyrrole-3-carboxylate, is not readily available. The subsequent Suzuki coupling reaction and the oxidation of the hydroxyl group to the aldehyde group require the use of noble metal catalysts, palladium and tetrapropylperruthenium (TPAP).

[0010] Method 3: Patent CN104860923A uses 5-(2-fluorophenyl)-1H-pyrrole-3-carboxynitrile as the starting material. First, a pyridine-3-sulfonyl group is added to the nitrogen atom of the pyrrole ring; then, the cyano group is reduced to an amino group; the resulting amino group undergoes a methylamination reaction, and finally forms a salt with fumaric acid to obtain the target product, vonorazan fumarate. The reaction is shown below:

[0011]

[0012] The starting material for this reaction route, 5-(2-fluorophenyl)-1H-pyrrole-3-carboxynitrile, is not readily available, and the reaction of reducing the cyano group to the amino group requires a noble metal catalyst such as palladium, platinum, or tungsten.

[0013] Method 4: Patent CN105085484A uses 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde as the starting material. First, it reacts with methylamine to generate an imine intermediate, which is then reduced to a secondary amine intermediate by a borohydride (such as NaBH4). Subsequently, the secondary amine group is protected with a tert-butoxycarbonyl (Boc) group, followed by sulfonylation with pyridine-3-sulfonyl chloride. After removing the Boc protecting group, it forms a salt with fumaric acid to yield the product vonorazan fumarate. The specific reaction flow is shown below:

[0014]

[0015] The starting material 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is not readily available for this route. Subsequently, a tert-butyloxycarbonyl (Boc) group needs to be introduced for amino protection, and then removed again after the reaction is complete.

[0016] Method 5: In 2017, Yu Qianying reported a method using ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate as a starting material. The product was first hydrolyzed to a carboxylic acid, then amination was performed, followed by sulfonation with pyridine-3-sulfonyl chloride to reduce the carbonyl group, and finally salt formation with fumaric acid to yield vonorazan fumarate. The specific reaction procedure is shown below:

[0017]

[0018] The starting material for this route, ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate, is relatively expensive, and the sulfonation reaction requires n-butyllithium, making the reaction difficult to control. Summary of the Invention

[0019] The purpose of this invention is to provide a method for preparing an intermediate for vonoprazan fumarate, using readily available raw materials, through a simple process and mild conditions, and without using a precious metal catalyst in the synthesis process.

[0020] In a first aspect, the present invention provides a method for preparing an intermediate for vonoprazan fumarate, wherein compound S3 is synthesized from compounds S1 and S2 as raw materials, and intermediate S4 is then synthesized from compound S3, wherein the structural formulas of compounds S1 and S2 are as follows:

[0021] S1: S2: S3: ,

[0022] Among them, R 1 Selected from any one of p-toluenesulfonyl (Ts), tert-butyl (tBu), benzyl (Bn), N-(dimethylamine)sulfonyl, tert-butylsulfinyl, N-diphenylphosphine, hydroxy, methoxy, ethoxy, methanesulfonyloxy, p-toluenesulfonyloxy, tert-butoxycarbonyloxy (BocO), benzyloxycarbonyloxy (CbzO), allyloxycarbonyl (AllocO), acetoxy (AcO), R 2 It is selected from any one of methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, and isoamyl ester.

[0023] The reaction route is as follows:

[0024] .

[0025] In existing technologies, pyrrole ring derivatives (such as 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde or its esters / nitriles) are often used as starting materials. These starting materials are difficult to synthesize and expensive, and some routes involve unstable aldehyde intermediates or require expensive noble metal catalysts (such as Pd or Ru). The technical solution of this invention fundamentally changes the construction strategy of the key pyrrole ring skeleton of vonoprazan fumarate. It uses two simple, commercially available, or easily prepared open-chain molecules—o-fluorophenylimine derivative (S1) and allyl bromide ester (S2)—to efficiently and selectively construct the target pyrrole ring structure (S4) in situ through a simple addition-electrophilic cyclization reaction. This method not only significantly reduces the cost of starting materials but also avoids dependence on unstable intermediates, simplifying the synthetic route from the outset.

[0026] The overall process conditions are mild, easy to operate, and environmentally friendly. No precious metal catalysts (such as Pd, Pt, Ru) or highly active, hazardous reagents (such as tert-butyllithium, sodium hydride / crown ether systems, etc.) are used throughout the process. All key transformations are completed in conventional organic solvents at a mild temperature range of 0–100°C. More importantly, each intermediate can be obtained in high purity through simple extraction, concentration, and recrystallization, completely avoiding time-consuming, material-intensive, and difficult-to-scale column chromatography separation operations, significantly improving the robustness and industrial feasibility of the process.

[0027] The preparation method of the above intermediate includes the following steps:

[0028] (1) Mix S1 and S2 in organic solvent A, add saturated ammonium chloride aqueous solution, add zinc powder, quench the reaction with acid aqueous solution after the reaction is completed, extract with ethyl acetate, remove the solvent, recrystallize to obtain product methyl 2-fluoro-α-methylene-β-[[(4-methylphenyl)sulfonyl]amino]phenylcarboxylate S3.

[0029] (2) Mix S3 in organic solvent B, add an electrophilic reagent, add a base, extract with ethyl acetate after the reaction is complete, remove the solvent, and recrystallize to obtain methyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid S4.

[0030] Preferably, in step (1), the organic solvent A is any one of tetrahydrofuran, acetonitrile, methanol, and ethanol, with tetrahydrofuran being more preferred.

[0031] Preferably, the ratio of organic solvent A to saturated ammonium chloride aqueous solution in step (1) is 1:(1-4), and more preferably 1:4.

[0032] Preferably, in step (1), the molar ratio of S1 to S2 to zinc powder is 1:(1.5-3):(1.5-3), and more preferably 1:2:2.

[0033] Preferably, the reaction temperature in step (1) is 0℃-50℃, and more preferably 25℃.

[0034] Preferably, the reaction time of step (1) is 1h-6h, and more preferably 2h.

[0035] Preferably, the organic solvent B in step (2) is any one of dichloromethane, acetonitrile, ethanol, ethyl acetate, tetrahydrofuran, DMF, DMA, and 1,4-dioxane, with acetonitrile being a more preferred choice.

[0036] Preferably, the electrophilic reagent in step (2) is any one of bromine, iodine, NBS, NIS, NCS, dichlorohydantoin, and dibromohydantoin, with NBS being more preferred.

[0037] Preferably, the alkali in step (2) is any one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, DBU, triethylamine, DABCO, DIEPA, DBN, MTBD, TBD, and TMG, with DBU being more preferred.

[0038] Preferably, the molar ratio of S3, electrophilic reagent and base in step (2) is 1:3:(3-4), and more preferably 1:3:3.5.

[0039] Preferably, the reaction temperature in step (2) is 0℃-50℃, and more preferably 25℃.

[0040] Preferably, the reaction time of step (2) is 4h-10h, and more preferably 6h.

[0041] A second aspect of the present invention provides a method for preparing vonoprazan fumarate, comprising the following steps:

[0042] (1) Mix S1 and S2 in organic solvent A, add saturated ammonium chloride aqueous solution, add zinc powder, quench the reaction with acid aqueous solution after the reaction is completed, extract with ethyl acetate, remove the solvent, recrystallize to obtain product methyl 2-fluoro-α-methylene-β-[[(4-methylphenyl)sulfonyl]amino]phenylcarboxylate S3.

[0043] (2) Mix S3 in organic solvent B, add an electrophilic reagent, add a base, extract with ethyl acetate after the reaction is complete, remove the solvent, and recrystallize to obtain methyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylic acid S4.

[0044] (3) Mix S4 in organic solvent C, add base A, acidify after the reaction is complete, extract with ethyl acetate, dry by rotary evaporation, add organic solvent D, add base B, dehydrating agent and methylamine hydrochloride, add water after the reaction is complete, extract with ethyl acetate, remove solvent, recrystallize to obtain product 5-(2-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxamide S5.

[0045] (4) Mix S5 in organic solvent E, add pyridine-3-sulfonyl chloride, add base, add DMAP, after the reaction is complete, add water and extract with ethyl acetate, remove the solvent, recrystallize to obtain product 5-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxamide S6.

[0046] (5) Mix S6 in organic solvent F, add reducing agent, react under nitrogen protection, extract with ethyl acetate after the reaction, dry and filter. Then add fumaric acid, stir and filter, recrystallize the filter cake to obtain product 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-3-methylaminomethyl-1H-pyrrole fumarate S7, i.e. vonoprazan fumarate.

[0047] The synthetic route for preparing vonoprazan fumarate provided by this invention is as follows:

[0048] .

[0049] Preferably, the organic solvent C in step (3) is any one of acetonitrile, ethanol, tetrahydrofuran, methanol, DMF, DMA, and 1,4-dioxane, with ethanol being preferred.

[0050] Further preferably, in step (3), alkali A is any one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and sodium hydride, with sodium hydroxide being preferred.

[0051] Further preferred, in step (3), the molar ratio of S4 to base A is 1:(1-5), preferably 1:2.

[0052] Further preferably, the reaction temperature in step (3) is 50℃-100℃, preferably 70℃.

[0053] Further preferred, the reaction time in step (3) is 0.5h-4h, preferably 2h.

[0054] Further preferably, in step (3), the organic solvent D is any one of acetonitrile, tetrahydrofuran, methanol, ethanol, and 1,4-dioxane, with tetrahydrofuran being preferred.

[0055] Further preferably, in step (3), base B is any one of trimethylamine, triethylamine, DABCO, DIEPA, DBU, DBN, MTBD, TBD, and TMG, with triethylamine being preferred.

[0056] Further preferably, the dehydrating agent in step (3) is any one of EDCI, DCC, DIC, and boron trifluoride ether, with EDCI being preferred.

[0057] Further preferably, in step (3), the molar ratio of S4 to base B to methylamine hydrochloride is 1:(1-3):(1-3), preferably 1:1.5:1.5.

[0058] Further preferably, the reaction temperature in step (3) is 0℃-50℃, preferably 25℃.

[0059] Further preferred, the reaction time of step (3) is 1h-6h, preferably 3h.

[0060] Preferably, the organic solvent E in step (4) is any one of acetonitrile, ethanol, tetrahydrofuran, and dichloromethane, with dichloromethane being the most preferred.

[0061] Further preferably, the base in step (4) is any one of triethylamine, DABCO, DIEPA, DBU, DBN, MTBD, TBD, and TMG, with triethylamine being preferred.

[0062] Further preferably, in step (4), the molar ratio of S5 to alkali is 1:(1-3), preferably 1:2.

[0063] Further preferably, the molar ratio of S5 to DMAP in step (4) is 1:(0.1-1), preferably 1:0.5.

[0064] Further preferably, the reaction temperature in step (4) is -20℃ to 25℃, preferably 0℃.

[0065] Further preferred, the reaction time in step (4) is 2h-4h, preferably 2h.

[0066] Preferably, the organic solvent F in step (5) is any one of acetonitrile, ethanol, tetrahydrofuran, and dichloromethane, with tetrahydrofuran being the most preferred.

[0067] Further preferably, the reducing agent in step (5) is any one of LiAlH4, NaBH4, DIBAL-H, and BH3, with LiAlH4 being preferred.

[0068] Further preferably, the molar ratio of S6 to reducing agent in step (5) is 1:(1-1.3), preferably 1:1.1.

[0069] Further preferably, the reaction temperature in step (5) is -20℃ to 25℃, preferably 0℃.

[0070] Further preferred, the reaction time of step (5) is 3h-6h, preferably 5h.

[0071] By implementing the above technical solution, compared with the prior art, the present invention has the following beneficial effects:

[0072] This invention first provides a method for preparing an intermediate for the synthesis of vonoprazan fumarate. The raw materials used in this method are readily available, the process is simple, the entire synthetic route is easy to operate, and the reaction conditions are mild.

[0073] This invention also provides a method for preparing vonoprazan fumarate based on this intermediate, avoiding the dependence on unstable aldehyde intermediates (such as 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde) and the use of expensive noble metal catalysts (such as Pd, Ru, etc.) in the prior art. The entire synthetic route is simple to operate, the reaction conditions are mild, and the products of each step can be purified by recrystallization without column chromatography, which significantly improves the scalability and production efficiency of the process, while reducing costs and environmental pollution, and has outstanding industrial application value. Attached Figure Description

[0074] Figure 1 The compound S3 obtained in Example 1 1 H spectrum;

[0075] Figure 2 Compound S4 obtained in Example 6 1 H spectrum;

[0076] Figure 3 For compound S5 1 H spectrum;

[0077] Figure 4 For compound S6 1 H spectrum;

[0078] Figure 5 For compound S7 1 H spectrum;

[0079] Figure 6 For compound S7 13 C-spectrum. Detailed Implementation

[0080] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0081] The following examples only use R 1 p-Toluenesulfonyl (Ts), R 2 The present invention will be described using methyl ester as an example, but the scope of protection of the present invention is not limited thereto; other R... 1 and R 2 The same applies to combinations.

[0082] Example 1: Preparation of compound S3

[0083] Add compound S1 (R) to a round-bottom flask 1 =Ts, 2.77g, 10mmol), compound S2 (R 2 =methyl ester, 3.58 g, 20 mmol), saturated ammonium chloride (40 ml), tetrahydrofuran (10 ml), zinc powder (1.3 g, 20 mmol), the mixture was stirred at 20 °C, the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:4), the reaction was stopped after 2 h, dilute hydrochloric acid (10 ml) was added to quench the reaction, ethyl acetate was added to extract 2-3 times, the organic matter was combined and dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, recrystallized to give a white solid (3.09 g), the reaction yield was 85%.

[0084] S3 1 H-spectrum: 1 HNMR(500MHz, CDCl3) δ 2.36 (s, 3H), 2.64 (dd, J1 = 5.75Hz, J2 = 14.05 Hz, 1H), 2.74 (dd, J1 = 8.75 Hz, J2 = 14.1 Hz, 1H), 3.71 (s,3H), 4.72-4.77 (m, 1H), 5.52 (s, 1H), 5.61 (d, J = 7.85 Hz, 1H), 6.10 (d, J =1.05 Hz, 1H), 6.85-6.89 (m, 1H), 6.95-6.98 (m, 1H), 7.11-7.17 (m, 4H), 7.57(d, J = 8.15 Hz, 2H).

[0085] Example 2: Preparation of compound S3

[0086] Add compound S1 (R) to a round-bottom flask 1 =Ts, 2.77g, 10mmol), compound S2 (R 2 =Ethyl acetate, 3.86 g, 20 mmol), saturated ammonium chloride (40 ml), tetrahydrofuran (10 ml), zinc powder (1.3 g, 20 mmol), the mixture was stirred at 20 °C, the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:4), the reaction was stopped after 2 h, the reaction was quenched by adding dilute hydrochloric acid (10 ml), the mixture was extracted 2-3 times with ethyl acetate, the organic matter was combined and dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, recrystallized to give a white solid (3.06 g), the reaction yield was 81%.

[0087] Example 3: Preparation of compound S3

[0088] Add compound S1 (R) to a round-bottom flask 1 = tBu, 1.79g, 10mmol), compound S2 (R 2 =Methyl ester, 3.58 g, 20 mmol), saturated ammonium chloride (40 ml), tetrahydrofuran (10 ml), zinc powder (1.3 g, 20 mmol), the mixture was stirred at 20 °C, the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:4), the reaction was stopped after 2 h, the reaction was quenched by adding dilute hydrochloric acid (10 ml), the mixture was extracted 2-3 times with ethyl acetate, the organic matter was combined and dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, recrystallized to give a white solid (2.1 g), the reaction yield was 75%.

[0089] Example 4: Preparation of compound S3

[0090] Add compound S1 (R) to a round-bottom flask 1 =Ts, 2.77g, 10mmol), compound S2 (R 2 =tert-butyl ester, 4.42 g, 20 mmol), saturated ammonium chloride (40 ml), tetrahydrofuran (10 ml), zinc powder (1.3 g, 20 mmol), the mixture was stirred at 20 °C, the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:4), the reaction was stopped after 2 h, the reaction was quenched by adding dilute hydrochloric acid (10 ml), the mixture was extracted 2-3 times with ethyl acetate, the organic matter was combined and dried with anhydrous magnesium sulfate, filtered, evaporated to dryness, recrystallized to give a white solid (3.37 g), the reaction yield was 83%.

[0091] Example 5: Preparation of compound S3

[0092] Add compound S1 (R) to a round-bottom flask 1=Bn, 1.99g, 10mmol), compound S2 (R 2 =tert-butyl ester, 4.42 g, 20 mmol), saturated ammonium chloride (40 ml), tetrahydrofuran (10 ml), zinc powder (1.3 g, 20 mmol), the mixture was stirred at 20 °C, the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:4), the reaction was stopped after 2 h, the reaction was quenched by adding dilute hydrochloric acid (10 ml), the mixture was extracted 2-3 times with ethyl acetate, the organic matter was combined and dried with anhydrous magnesium sulfate, filtered, evaporated to dryness, recrystallized to give a white solid (2.57 g), the reaction yield was 79%.

[0093] Example 6: Preparation of compound S4

[0094] Compound S3 (3.6 g, 10 mmol), NBS (5.34 g, 30 mmol), DBU (5.33 g, 35 mmol), and acetonitrile (30 ml) obtained in Example 1 were added to a round-bottom flask. The mixture was stirred at 25 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:2). The reaction was stopped after 6 h. Water was added, and the mixture was extracted 2-3 times with ethyl acetate. The organic compounds were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and recrystallized to give a white solid (1.47 g), with a yield of 76%.

[0095] S4 1 H-spectrum: 1 HNMR (500MHz, CDCl3) δ 3.86 (s, 3H), 7.05-7.06 (m, 1H), 7.11-7.25 (m, 3H), 7.52-7.53 (m, 1H), 7.62-7.65 (m, 1H), 9.33 (brs, 1H).

[0096] Example 7: Preparation of compound S4

[0097] Compound S3 (3.6 g, 10 mmol), NBS (5.34 g, 30 mmol), DBN (5.33 g, 35 mmol), and acetonitrile (30 ml) obtained in Example 2 were added to a round-bottom flask. The mixture was stirred at 25 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:2). The reaction was stopped after 6 h. Water was added, and the mixture was extracted 2-3 times with ethyl acetate. The organic compounds were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and recrystallized to give a white solid (1.67 g), with a yield of 63%.

[0098] Example 8: Preparation of compound S4

[0099] Compound S3 (3.6 g, 10 mmol), NCS (4.01 g, 30 mmol), DBU (5.33 g, 35 mmol), and acetonitrile (30 ml) obtained in Example 3 were added to a round-bottom flask. The mixture was stirred at 25 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:2). The reaction was stopped after 6 h. Water was added, and the mixture was extracted 2-3 times with ethyl acetate. The organic compounds were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and recrystallized to give a white solid (1.23 g), with a yield of 56%.

[0100] Example 9: Preparation of compound S4

[0101] Compound S3 (3.6 g, 10 mmol), Br2 (4.79 g, 30 mmol), DBU (5.33 g, 35 mmol), and acetonitrile (30 ml) obtained in Example 4 were added to a round-bottom flask. The mixture was stirred at 25 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:2). The reaction was stopped after 6 h. Water was added, and the mixture was extracted 2-3 times with ethyl acetate. The organic compounds were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and recrystallized to give a white solid (1.34 g), with a yield of 61%.

[0102] Example 10: Preparation of compound S5

[0103] Compound S4 (1.1 g, 5 mmol), sodium hydroxide (0.4 g, 10 mmol), and ethanol (20 ml) obtained in Example 6 were added to a round-bottom flask. The mixture was stirred at 70 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:2). After 2 h, the reaction was stopped, acidified, and extracted 2-3 times with ethyl acetate. The mixture was washed 2-3 times with saturated brine. The organic compounds were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness with solvent. THF (20 ml), triethylamine (0.76 g, 7.5 mmol), EDCI (1.15 g, 6 mmol), and methylamine hydrochloride (0.51 g, 7.5 mmol) were added. The mixture was stirred at 25 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:1). After 3 h, the reaction was stopped, water was added, and the mixture was extracted 2-3 times with ethyl acetate. The organic compounds were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness with solvent. Recrystallization gave a grayish-white solid (0.93 g), with a reaction yield of 85%.

[0104] S5 1 H-spectrum: 1H NMR(500MHz, DMSO-d6) δ 2.73 (d, J = 4.45 Hz, 3H), 6.94-6.96 (m, 1H), 7.22-7.30 (m, 3H), 7.43-7.44 (m, 1H), 7.70-7.74 (m, 1H), 7.86-7.89 (m, 1H), 11.63 (s, 1H).

[0105] Example 11: Preparation of compound S6

[0106] Compound S5 (1.1 g, 5 mmol), pyridine-3-sulfonyl chloride (1.07 g, 6 mmol), triethylamine (1.01 g, 10 mmol), DMAP (0.31 g, 2.5 mmol), and dichloromethane (20 mL) were added to a round-bottom flask. The mixture was stirred at 0 °C, and the reaction progress was monitored by TLC (ethyl acetate: petroleum ether = 1:1). The reaction was stopped after 2 h. Water was added, and the mixture was extracted 2-3 times with ethyl acetate and washed 2-3 times with saturated brine. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Recrystallization gave a yellow solid (1.36 g), with a reaction yield of 76%.

[0107] S6 1 H-spectrum: 1 HNMR(500MHz, DMSO-d6) δ 2.74 (d, J = 4.55 Hz, 3H), 6.69(d, J = 1.85 Hz, 1H), 7.14-7.17 (m, 1H), 7.22-7.25 (m, 2H), 7.53-7.57 (m,1H), 7.64 (dd, J1 = 4.75 Hz, J2 = 8.15 Hz, 1H), 7.92-7.94 (m, 1H), 8.14(d, J =2.05 Hz, 1H), 8.26 (q, J = 4.65 Hz, 1H), 8.58 (d, J = 2.35 Hz, 1H), 8.91 (dd,J1 = 1.8 Hz, J2 = 4.8 Hz, 1H).

[0108] Example 12: Preparation of compound S7

[0109] Compound S6 (1.08 g, 3 mol), LiAlH4 (0.13 g, 3.3 mmol), and tetrahydrofuran (10 mL) were added to a round-bottom flask. The mixture was stirred at 0 °C for 5 h. After the reaction was completed, ice water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. Fumaric acid (0.35 g, 3 mol) was added, and the mixture was stirred for 1 h before filtration. The filter cake was recrystallized to give a white solid (0.71 g), with a reaction yield of 69%.

[0110] S7 1 H-spectrum: 1 H NMR(500MHz, DMSO-d6) δ 2.47(s, 3H), 3.94 (s, 2H), 6.49(s, 2H), 6.52 (d, J = 1.75 Hz, 1H), 7.08-7.11 (m, 1H), 7.20-7.25 (m, 2H),7.50-7.55 (m, 1H), 7.61 (dd, J1 = 4.85 Hz, J2 = 8.25 Hz, 1H), 7.80 (d, J =1.75 Hz, 1H), 7.88-7.90 (m, 1H), 8.56 (d, J = 2.25 Hz, 1H), 8.88 (dd, J1 =1.55 Hz, J2 = 4.8 Hz, 1H), 9.87 (brs, 3H).

[0111] S7 13 C-spectrum: 13 C NMR (125 MHz, DMSO-d6) δ168.83, 160.65 (d, J CF = 246Hz), 155.52, 147.30, 135.67, 135.18, 134.64, 133.13, 132.21 (d,J CF = 9 Hz),128.83, 125.04, 124.87, 124.38 (d, J CF = 4 Hz), 121.04, 118.91, 118.78, 115.76(d, J CF = 21 Hz), 44.03, 32.27.

Claims

1. A method for preparing intermediate S4 for the preparation of vonoprazan fumarate, characterized in that, Includes the following steps: (1) Mix S1 and S2 in organic solvent A, add saturated ammonium chloride aqueous solution and zinc powder, quench the reaction with an aqueous acid solution after the reaction is completed, extract with ethyl acetate, remove the solvent, and recrystallize to obtain product S3; (2) Mix S3 in organic solvent B, add electrophilic reagent and base, extract with ethyl acetate after the reaction is complete, remove solvent, and recrystallize to obtain S4; The reaction route is as follows: ; Among them, R 1 Selected from p-toluenesulfonyl, tert-butyl, R 2 Selected from methyl ester, ethyl ester, and tert-butyl ester; The reaction temperature in step (1) is 0℃-50℃, and the reaction time is 1h-6h. In step (1), the ratio of organic solvent A to saturated ammonium chloride aqueous solution is 1:(1-4). In step (1), the molar ratio of S1 and S2 to zinc powder is 1:(1.5-3):(1.5-3). The electrophilic reagent in step (2) is any one of bromine, iodine, NBS, NIS, NCS, dichlorohydantoin, and dibromohydantoin; In step (2), the molar ratio of S3, electrophilic reagent and base is 1:3:(3-4). The reaction temperature in step (2) is 0℃-50℃, and the reaction time is 4h-10h.

2. A method for preparing vonoprazan fumarate, characterized in that, Includes the following steps: (1) Mix S1 and S2 in organic solvent A, add saturated ammonium chloride aqueous solution and zinc powder, quench the reaction with an aqueous acid solution after the reaction is completed, extract with ethyl acetate, remove the solvent, and recrystallize to obtain S3; (2) Mix S3 in organic solvent B, add electrophilic reagent and base, extract with ethyl acetate after the reaction is complete, remove solvent, and recrystallize to obtain S4; (3) Mix S4 in organic solvent C, add base A, acidify after the reaction is complete, extract with ethyl acetate, evaporate to dryness, add organic solvent D, add base B, dehydrating agent and methylamine hydrochloride, add water after the reaction is complete, extract with ethyl acetate, remove solvent, recrystallize to obtain product 5-(2-fluorophenyl)-N-methyl-1H-pyrrole-3-carboxamide S5; (4) Mix S5 in organic solvent E, add pyridine-3-sulfonyl chloride, base and DMAP. After the reaction is complete, add water and extract with ethyl acetate to remove the solvent. Recrystallize to obtain product 5-(2-fluorophenyl)-N-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxamide S6. (5) Mix S6 in organic solvent F, add reducing agent, react under nitrogen protection, extract with ethyl acetate after reaction, dry and filter; then add fumaric acid, stir and filter, recrystallize the filter cake to obtain product 5-(2-fluorophenyl)-1-(3-pyridylsulfonyl)-3-methylaminomethyl-1H-pyrrole fumarate S7, i.e., vonoprazan fumarate; the synthetic route is as follows: Among them, R 1 Selected from p-toluenesulfonyl, tert-butyl, R 2 Selected from methyl ester, ethyl ester, and tert-butyl ester; The reaction temperature in step (1) is 0℃-50℃, and the reaction time is 1h-6h. In step (1), the ratio of organic solvent A to saturated ammonium chloride aqueous solution is 1:(1-4). In step (1), the molar ratio of S1 and S2 to zinc powder is 1:(1.5-3):(1.5-3). The electrophilic reagent in step (2) is any one of bromine, iodine, NBS, NIS, NCS, dichlorohydantoin, and dibromohydantoin; In step (2), the molar ratio of S3, electrophilic reagent and base is 1:3:(3-4). The reaction temperature in step (2) is 0℃-50℃, and the reaction time is 4h-10h.

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