Synthesis method of N-[3-[(5-bromo-1H-pyrrolo [2, 3-B] pyridine-3-yl) carbonyl]-2, 4-difluorophenyl]-1-propanesulfonamide

Abstract

The invention discloses a synthesis method of N-[3-[(5-bromo-1H-pyrrolo [2, 3-B] pyridine-3-yl) carbonyl]-2, 4-difluorophenyl]-1-propanesulfonamide. The synthesis method comprises the following steps: firstly, adding a catalyst into a reaction kettle; according to the preparation method, 1, 3-difluorobenzene is taken as an initial raw material, and N-[3-[(5-bromo-1H-pyrrolo [2, 3-B] pyridine-3-yl) carbonyl]-2, 4-difluorophenyl]-1-propanesulfonamide is obtained through an electrophilic aromatic bromination reaction, an electrophilic carboxylation reaction, an esterification reaction, a Buchwald-Harwig coupling reaction, a hydrolysis reaction, a Friedel-Crafts acylation reaction and the like in sequence. The method disclosed by the invention is mild and easy to control, simple in post-treatment, high in yield, economic and environment-friendly, capable of realizing industrial production, in line with the green chemical development trend, low in total production cost and extremely high in application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, an intermediate for the anticancer drug vemurafenib. Background Technology

[0002] Vemurafenib is an oral BRAF kinase inhibitor developed by Plexxikon and first approved by the FDA in the United States in October 2011. It is primarily indicated for patients with BRAF V600E-positive unresectable or metastatic melanoma skin cancer. As an ATP-competitive and reversible BRAF inhibitor, vemurafenib exhibits specific inhibitory activity against BRAF V600 mutants. Against melanoma cell lines carrying this mutation, its half-maximal inhibitory concentration (IC50) is [value missing]. 50 The concentration range is 60–450 nmol / L. Its mechanism of action primarily involves targeting and inhibiting BRAF kinase activity, blocking abnormal transduction of the mitogen-activated protein kinase (MAPK) signaling pathway, thereby inhibiting the uncontrolled proliferation of tumor cells mediated by oncogenes. Furthermore, vemurafenib has no significant effect on the proliferation of normal cells and exhibits good tumor targeting selectivity. Its structural formula is shown below:

[0003] .

[0004] Patent CN102421776A discloses a method using 2,4-difluoroaniline as a starting material. First, benzyl chloroformate is reacted with n-butyllithium and a silane protecting agent (1,2-di-(chloro-dimethylsilyl)ethane) to yield benzyl 3-amino-2,6-difluorobenzoate. Then, benzyl 3-amino-2,6-difluorobenzoate is reacted with propane-1-sulfonyl chloride in dichloromethane in the presence of pyridine to yield benzyl 2,6-difluoro-3-(propane-1-sulfonylamino)benzoate. Subsequently, benzyl 2,6-difluoro-3-(propane-1-sulfonylamino)benzoate undergoes hydrogenolysis in methanol under the catalysis of palladium hydroxide on carbon to remove the benzyl group, yielding 2,6-difluoro-3-(propane-1-sulfonylamino)benzoic acid. Finally, 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid was reacted with thionyl chloride in toluene under reflux to convert to the corresponding acyl chloride intermediate. The obtained acyl chloride intermediate was then subjected to Friedel-Crafts acylation with 5-bromo-1H-pyrrolo[2,3-b]pyridine in dichloromethane under aluminum trichloride catalysis, ultimately yielding the target product 2N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide. The reaction route is shown below:

[0005]

[0006] In this method, the first step uses 1,2-di-(chloro-dimethylsilyl)ethane, a special and expensive silane protecting reagent, which has extremely low atom economy and high production costs. The second step uses pyridine as a base, which has a foul odor and toxicity, seriously affecting the working environment and product purity. The third step uses palladium hydroxide on carbon for hydrogenolysis of benzyl, which is fast but carries the risk of side reactions such as over-reduction or dehalogenation. Moreover, the palladium catalyst is expensive, which greatly increases the production cost. The fifth step uses a large amount of aluminum trichloride as a Lewis acid, generating a large amount of aluminum-containing wastewater. The post-treatment is highly corrosive, increasing environmental costs. Furthermore, the yield of the last step is only 31.4%, and the overall yield is only 21%. The product is also purified by column chromatography multiple times during the reaction process, which greatly limits its application value in industrial production. Summary of the Invention

[0007] To overcome the shortcomings of existing technologies, this invention provides a method for synthesizing N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide. This invention uses 1,3-difluorobenzene as a starting material and proceeds sequentially through electrophilic aromatic bromination, electrophilic carboxylation, esterification, Buchwald–Hartwig coupling, hydrolysis, and Friedel-Crafts acylation to obtain the N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide. This method features mild reaction conditions, simple operation, low cost, high yield, and is safe and reliable, making it suitable for large-scale production.

[0008] The N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide prepared in this invention has the following structure:

[0009] .

[0010] The present invention provides a method for synthesizing N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, comprising the following steps:

[0011] Step 1: Using 1,3-difluorobenzene as a raw material, in the presence of acid, it reacts with dibromohydantoin via an electrophilic aromatic bromination reaction to generate 1-bromo-2,4-difluorobenzene;

[0012] Step 2: Using 1-bromo-2,4-difluorobenzene as a raw material, 3-bromo-2,6-difluorobenzoic acid is generated by electrophilic carboxylation reaction with carbon dioxide in the presence of a base.

[0013] Step 3: Using 3-bromo-2,6-difluorobenzoic acid as a raw material, esterification reaction is carried out with methanol in the presence of acid to generate methyl 3-bromo-2,6-difluorobenzoate;

[0014] Step 4: Using methyl 3-bromo-2,6-difluorobenzoate as a raw material, in the presence of a catalyst, reducing agent, phosphine ligand and base, it undergoes a Buchwald–Hartwig coupling reaction with propylsulfonamide and is then hydrolyzed to generate 2,6-difluoro-3-(propanesulfonamide)benzoic acid.

[0015] Step 5: Using 2,6-difluoro-3-(propanesulfonamide)benzoic acid as a raw material, under the conditions of acyl chloride reagent and catalyst, it undergoes a Friedel-Crafts acylation reaction with 5-bromo-7-azaindole to generate the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide.

[0016] further:

[0017] In step 1, the reaction is carried out in a solvent, which is hexafluoroisopropanol or acetic acid; the acid is m-nitrobenzenesulfonic acid or p-toluenesulfonic acid monohydrate; the reaction temperature is 40-60℃; the molar ratio of 1,3-difluorobenzene to dibromohydantoin is 1:(0.4-0.6), and the molar ratio of 1,3-difluorobenzene to acid is 1:(0.01-0.03).

[0018] In step 2, the reaction is carried out in a solvent, namely tetrahydrofuran; the base is lithium diisopropylamino; the reaction temperature is -70℃; the molar ratio of 1-bromo-2,4-difluorobenzene to carbon dioxide is 1:(5-7.5), and the molar ratio of 1-bromo-2,4-difluorobenzene to lithium diisopropylamino is 1:(1.05-1.1).

[0019] In step 3, the reaction is carried out in a solvent, namely methanol; the acid is a strongly acidic cation exchange resin (H2O). + The reaction temperature is 50-70℃; the amount of strong acid cation exchange resin used is 0.5 times the mass of 3-bromo-2,6-difluorobenzoic acid.

[0020] In step 4, the reaction is carried out in a solvent, namely N,N-dimethylformamide; the catalyst is nickel acetylacetonate (II); the reducing agent is zinc powder; the phosphine ligand is triphenylphosphine; the base is potassium carbonate; the reaction temperature is 130℃; the molar ratio of methyl 3-bromo-2,6-difluorobenzoate to propylsulfonamide is 1:1.51, the molar ratio of methyl 3-bromo-2,6-difluorobenzoate to nickel acetylacetonate (II) is 1:(0.05-0.07), the molar ratio of nickel acetylacetonate (II) to zinc powder is 1:(4-6), the molar ratio of nickel acetylacetonate (II) to triphenylphosphine is 1:(2-4), and the molar ratio of methyl 3-bromo-2,6-difluorobenzoate to potassium carbonate is 1:(2-2.5).

[0021] In step 5, the reaction is carried out in a solvent, namely dichloromethane or 1,2-dichloroethane; the acyl chloride reagent is oxalyl chloride; the catalyst is scandium trifluoromethanesulfonate; the reaction temperature is 45°C; the molar ratio of 2,6-difluoro-3-(propanesulfonamide)benzoic acid to 5-bromo-7-azaindole is 1:(0.9-1.2), the molar ratio of 2,6-difluoro-3-(propanesulfonamide)benzoic acid to oxalyl chloride is 1:(1.1-1.2), and the molar ratio of 2,6-difluoro-3-(propanesulfonamide)benzoic acid to scandium trifluoromethanesulfonate is 1:(0.06-0.09).

[0022] The synthetic route of this invention is shown below:

[0023]

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] This invention provides a method for preparing N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide. Using 1,3-difluorobenzene as the starting material, the method involves sequential electrophilic aromatic bromination, electrophilic carboxylation, esterification, Buchwald–Hartwig coupling, hydrolysis, and Friedel-Crafts acylation to obtain the N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide. The starting material, 1,3-difluorobenzene, is a readily available and affordable chemical raw material with a stable supply, significantly reducing raw material procurement costs and making it more suitable for large-scale industrial production. The esterification reaction is catalyzed by a solid acid, allowing for catalyst recovery and regeneration, and eliminating the generation of acidic wastewater, thus meeting the requirements of green chemical production and significantly reducing wastewater treatment costs. This method avoids the use of expensive metal catalysts, significantly reducing production costs. The post-processing and purification steps are simplified, reducing complex operations and increasing yield. The final step uses the mild and recyclable Lewis acid scandium trifluoromethanesulfonate instead of the traditional corrosive catalyst, and combines it with a one-pot process for the acyl chloride-acylation reaction. This not only solves the problems of strong corrosion, high pollution, and large wastewater volume associated with reagents such as aluminum trichloride, greatly improving operational safety and environmental friendliness, but also effectively reduces production costs due to the recyclability of the catalyst. Furthermore, the one-pot process avoids the separation and purification of unstable acyl chloride intermediates, simplifying the operation steps, reducing material transfer losses, and improving overall reaction efficiency, making this synthetic route more suitable for industrial-scale production. Attached Figure Description

[0026] Figure 1 NMR of 1-bromo-2,4-difluorobenzene in Example 1 1 H NMR spectrum.

[0027] Figure 2 NMR of 3-bromo-2,6-difluorobenzoic acid in Example 1 1 H NMR spectrum.

[0028] Figure 3 NMR of methyl 3-bromo-2,6-difluorobenzoate in Example 1 1 H NMR spectrum.

[0029] Figure 4 NMR of 2,6-difluoro-3-(propanesulfonylamino)benzoic acid in Example 1 1 H NMR spectrum.

[0030] Figure 5The NMR spectrometry of the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide in Example 1 1 H NMR spectrum.

[0031] Figure 6 The image shows the LCMS spectrum of 3-bromo-2,6-difluorobenzoic acid from Example 1. The relative molecular mass of this compound is known to be 236, and the peak with a mass-to-charge ratio (m / z) of 236.9 is [M+H]. + .

[0032] Figure 7 The image shows the LCMS spectrum of 2,6-difluoro-3-(propanesulfonamide)benzoic acid from Example 1. The relative molecular mass of this compound is known to be 279.2, and the peak with a mass-to-charge ratio (m / z) of 278 is [MH]. - .

[0033] Figure 8 The image shows the LCMS spectrum of the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide in Example 1. The relative molecular mass of this compound is known to be 458.3, and the peak with a mass-to-charge ratio m / z of 459.9 is [M+H]. + . Detailed Implementation

[0034] The technical solution of the present invention is further illustrated below through specific embodiments. These embodiments are only for illustrative purposes and are not intended to limit the scope of the invention.

[0035] Example 1:

[0036] In this embodiment, the preparation method of N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide includes the following steps:

[0037] 1. Synthesis of 1-bromo-2,4-difluorobenzene

[0038] Acetic acid (100 ml, 10 V) was added to a 250 ml three-necked flask equipped with a reflux apparatus. Stirring was started, and 1,3-difluorobenzene (10 g, 87.7 mmol) and p-toluenesulfonic acid monohydrate (333 mg, 1.754 mmol) were added separately. Then, pre-ground dibromohydantoin (15 g, 52.9 mmol) powder was slowly added in portions to the reaction mixture, controlling the addition rate to maintain the reaction temperature at 20-30°C. After the addition was complete, the reaction mixture was heated to 50°C and stirred at this temperature for 10 hours. After the reaction was monitored to be complete by TLC (electrolyte: petroleum ether / ethyl acetate = 20:1), the reaction solution was subjected to vacuum distillation to recover most of the acetic acid solvent. After distillation, the remaining crude residue was transferred to a 500 mL separatory funnel, and 200 mL of ice water and 100 mL of dichloromethane were added. Extraction was performed to separate the organic phase. The aqueous phase was extracted twice with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and then subjected to vacuum distillation again. After distillation, a transparent colorless to brown liquid 1-bromo-2,4-difluorobenzene (15.61 g) was obtained, with a yield of 92.3% and an HPLC purity of 98.93%.

[0039] 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.71 (m, 1H), 7.46 (td, J = 9.3, 2.9Hz, 1H), 7.16-7.05 (m, 1H).

[0040] 2. Synthesis of 3-bromo-2,6-difluorobenzoic acid

[0041] Under a nitrogen atmosphere, THF (100 mL, 10 V) and 1-bromo-2,4-difluorobenzene (10 g, 47 mmol) were added to a 250 mL three-necked flask, which was then placed in a dry ice-ethanol bath and stirred until the internal temperature reached -70 °C. Subsequently, a 2 M LDA solution of THF / n-hexane (25.38 mL, 50.76 mmol) was slowly added dropwise using a syringe, controlling the dropping rate to ensure the internal temperature did not exceed -70 °C. After the addition was complete, the mixture was stirred at -70 °C for 1 h. Then, 15.5 g of solid carbon dioxide fragments, pre-washed with anhydrous THF, were added to the reaction mixture in one go. The nitrogen protection device was removed, residual gas was purged using a bubbler, the cooling bath was removed, and the reaction mixture was allowed to slowly warm to room temperature naturally. The mixture was then stirred at room temperature for 12 h. After the reaction was confirmed to be complete by HPLC, the reaction solution was slowly poured into a beaker containing 200 mL of ice water. The mixture was acidified to pH 2-3 with 6 M HCl aqueous solution under ice-water bath cooling, and extracted with ethyl acetate (3 × 150 mL). The organic phases were collected and combined, then washed with saturated brine (500 mL), dried with anhydrous Na2SO4, and finally concentrated under reduced pressure to obtain 18.1 g of white solid product 3-bromo-2,6-difluorobenzoic acid, with a yield of 90.6% and an HPLC purity of 98.62%.

[0042] 1H NMR (400 MHz, DMSO-d6) δ 14.25 (s, 1H), 7.97-7.85 (m, 1H), 7.29-7.18 (m, 1H).

[0043] 3. Synthesis of methyl 3-bromo-2,6-difluorobenzoate

[0044] Dowex® MSC-1 (Strong acid cation exchange resin, H + Pretreatment (type): Take 5.0 g of Dowex® MSC-1 resin, soak it in 50 mL of methanol for 30 minutes, stirring once every five minutes, then filter it through a Buchner funnel for later use.

[0045] Anhydrous methanol (100 mL, 10 V) was added to a 250 mL three-necked flask equipped with a reflux apparatus. Stirring was started, followed by the addition of 3-bromo-2,6-difluorobenzoic acid (10 g, 42.2 mmol) and pretreated Dowex® MSC-1 (5 g). After the addition was complete, the reaction mixture was heated to 60 °C and stirred at this temperature for 7 hours. Once the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed three times with 20 mL of methanol. The filter cake was recovered, and the filtrate was collected. The filtrate was then subjected to vacuum distillation to recover most of the methanol. After distillation, the remaining crude product solution was transferred to a 250 mL separatory funnel, and 80 mL of water and 50 mL of ethyl acetate were added. Extraction was performed, separating the organic phase. The aqueous phase was extracted twice with ethyl acetate (30 mL × 2). The combined organic phases were washed with 100 mL of saturated brine, and then separated. The organic phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation again. The crude product was obtained after distillation. The crude product was added to a 250 ml round-bottom flask, followed by 100 ml of methanol. A reflux apparatus was set up, and stirring was started. The temperature was raised to reflux until the crude product was completely dissolved. Heating was then stopped, and the temperature was controlled at around 45°C. 30 ml of deionized water was added dropwise, and crystals precipitated. The solution was then cooled to room temperature and stirred in an ice-water bath for 10 minutes to allow for complete crystallization. Finally, the mixture was filtered, and the filter cake was dried in a drying oven. After drying, 9.66 g of the target product, methyl 3-bromo-2,6-difluorobenzoate, was obtained, with a yield of 91.2% and an HPLC purity of 98.61%.

[0046] 1H NMR (400 MHz, DMSO-d6) δ 8.03-7.95 (m, 1H), 7.29 (t, J = 9.2 Hz,1H), 3.91 (s, 3H).

[0047] 4. Synthesis of 2,6-difluoro-3-(propanesulfonylamino)benzoic acid

[0048] Methyl 3-bromo-2,6-difluorobenzoate (10 g, 39.8 mmol), propylsulfonamide (7.4 g, 60.1 mmol), K₂CO₃ (12.65 g, 91.54 mmol), Ni(acac)₂ (0.61 g, 2.39 mmol, 5.97 mol%), zinc powder (0.78 g, 11.95 mmol), PPh₃ (1.88 g, 7.17 mmol), and anhydrous DMF (100 mL, 10 V) were sequentially added to a 250 mL three-necked flask. A reflux purging device was then installed, and the mixture was purged with nitrogen three times. Stirring was then initiated, and the reaction mixture was heated to 130 °C under a nitrogen atmosphere and refluxed with stirring for 12–15 h. The reaction was monitored by HPLC, and the endpoint was considered reached when the starting material concentration was < 2%. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove most of the DMF. After distillation, 120 mL of ethyl acetate and 120 mL of 10% ammonia solution were added, and the mixture was stirred for 15 minutes. The solution was then transferred to a separatory funnel, allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted again with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was then washed successively with 80 mL of 5% citric acid solution and 80 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude methyl 2,6-difluoro-3-propylsulfonamide benzoate.

[0049] The crude product was then dissolved in methanol (40 mL) and water (40 mL), and NaOH (3.0 g) was added in portions under ice bath conditions, with the temperature controlled below 40°C. The temperature was then raised to 50-55°C with stirring, and the reaction was monitored to the endpoint by TLC. The reaction solution was then cooled to 40°C, and activated carbon was added for decolorization for 20 minutes. The mixture was then filtered while hot, and the filter cake was washed with hot methanol / water (1:1, 20 mL). The filtrate was then distilled under reduced pressure. After removing the methanol, the remaining aqueous solution was cooled to 0-5°C under ice bath conditions, and concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 2-3. After stirring under ice bath conditions for 1-2 hours, the mixture was filtered, and the filter cake was washed with ice water (20 mL × 2). The filter cake was then collected and dried under vacuum at 55-60°C to obtain 9.52 g of the target product, 2,6-difluoro-3-(propanesulfonylamino)benzoic acid, with a yield of 85.6% and an HPLC purity of 98.21%.

[0050] 1H NMR (400 MHz, DMSO-d6) δ 14.09 (s, 1H), 9.77 (s, 1H), 7.54 (td, J= 8.9, 5.8 Hz, 1H), 7.22 (dd, J = 9.1, 1.7 Hz, 1H), 3.13- 3.03 (m, 2H), 1.73 (dt, J = 15.0, 7.6 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0051] 5. Synthesis of N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide

[0052] 2,6-Difluoro-3-(propanesulfonamide)benzoic acid (10.0 g, 33.2 mmol) was added to a 250 mL three-necked flask, and the flask was purged with nitrogen three times. Then, under a nitrogen atmosphere, dichloromethane (150 mL, 15V) and 0.28 mL DMF were slowly added sequentially. Next, oxaloyl chloride (3.35 mL, 39.2 mmol) was slowly added dropwise to the reaction system while cooling in an ice-water bath at 0-10 °C. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally to room temperature and stirred for 1.5 h. The reaction was monitored by TLC (electrolyte: petroleum ether / ethyl acetate = 1:1). After the acid point of the starting material had essentially disappeared, 5-bromo-7-azaindole (7.54 g, 38.3 mmol) was added to the reaction solution, and the mixture was stirred for 2 minutes. Then, scandium trifluoromethanesulfonate (1.41 g, ...) was added. 2.86 mmol (added in 3 batches) was added. After the addition was complete, the reaction solution was slowly heated to 45 °C and stirred at this temperature for 6 hours. After the reaction was complete, the reaction solution was slowly poured into a 500 mL separatory funnel containing 100 mL of ice-water solution and 20 mL of dilute hydrochloric acid (1 M), and gently shaken to wash. The combined organic phases were washed once with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After distillation, the crude product was transferred to a 100 mL round-bottom flask, methanol (about 40-50 mL) was added, and the mixture was heated to 60-65 °C to completely dissolve the solid. The solution was then slowly cooled to room temperature, and then further cooled and stirred in an ice-water bath for 1 hour to allow the crystals to fully separate. The crystals were then filtered and washed 2-3 times with a small amount of pre-cooled methanol. The filter cake was collected and dried under vacuum at 55-60℃ to obtain 12.85 g of the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, with a yield of 78.3% and an HPLC purity of 98.28%.

[0053] 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.4 Hz, 1H), 8.51 (d, J =2.3 Hz, 1H), 8.29 (s, 1H), 7.59 (td, J = 9.1, 5.9 Hz, 1H), 7.32-7.24 (m, 1H), 3.18- 3.08 (m, 2H), 1.80 – 1.67 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0054] Example 2:

[0055] In this embodiment, the preparation method of N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide includes the following steps:

[0056] 1. Synthesis of 1-bromo-2,4-difluorobenzene

[0057] Acetic acid (100 ml, 10°C) was added to a 250 ml three-necked flask equipped with a reflux apparatus. Stirring was started, and 1,3-difluorobenzene (10 g, 87.7 mmol) and m-nitrobenzenesulfonic acid (167 mg, 0.877 mmol) were added separately. Then, pre-ground dibromohydantoin powder (12.54 g, 43.85 mmol) was slowly added in portions to the reaction mixture, controlling the addition rate to maintain the reaction temperature at 20-30°C. After the addition was complete, the reaction mixture was heated to 50°C and stirred at this temperature for 10 hours. After the reaction was monitored to be complete by TLC (electrolyte: petroleum ether / ethyl acetate = 20:1), the reaction solution was subjected to vacuum distillation to recover most of the acetic acid solvent. After distillation, the remaining crude residue was transferred to a 500 mL separatory funnel, and 200 mL of ice water and 100 mL of dichloromethane were added. Extraction was performed to separate the organic phase. The aqueous phase was extracted twice with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and then subjected to vacuum distillation again. After distillation, a transparent colorless to brown liquid 1-bromo-2,4-difluorobenzene (14.8 g) was obtained, with a yield of 87.5% and an HPLC purity of 97.8%.

[0058] 2. Synthesis of 3-bromo-2,6-difluorobenzoic acid

[0059] Under a nitrogen atmosphere, THF (100 mL, 10 V) and 1-bromo-2,4-difluorobenzene (10 g, 47 mmol) were added to a 250 mL three-necked flask, which was then placed in a dry ice-ethanol bath and stirred until the internal temperature reached -70 °C. Subsequently, a 2 M LDA solution of THF / n-hexane (24.7 mL, 49.4 mmol) was slowly added dropwise using a syringe, controlling the dropping rate to ensure the internal temperature did not exceed -70 °C. After the addition was complete, the mixture was stirred at -70 °C for 1 h. Then, 10.3 g of solid carbon dioxide fragments, pre-washed with anhydrous THF, were added to the reaction mixture in one go. The nitrogen protection device was removed, residual gas was purged using a bubbler, the cooling bath was removed, and the reaction mixture was allowed to slowly warm to room temperature naturally. The mixture was then stirred at room temperature for 12 h. After the reaction was confirmed to be complete by HPLC, the reaction solution was slowly poured into a beaker containing 200 mL of ice water. The mixture was acidified to pH 2-3 with 6 M HCl aqueous solution under ice-water bath cooling, and extracted with ethyl acetate (3 × 150 mL). The organic phases were collected and combined, then washed with saturated brine (500 mL), dried with anhydrous Na2SO4, and finally concentrated under reduced pressure to obtain 17.64 g of white solid product 3-bromo-2,6-difluorobenzoic acid, with a yield of 88.3% and an HPLC purity of 97.3%.

[0060] 3. Synthesis of methyl 3-bromo-2,6-difluorobenzoate

[0061] Dowex® MSC-1 (Strong acid cation exchange resin, H + Pretreatment (type): Take 5.0 g of Dowex® MSC-1 resin, soak it in 50 mL of methanol for 30 minutes, stirring once every five minutes, then filter it through a Buchner funnel for later use.

[0062] Anhydrous methanol (100 mL, 10 V) was added to a 250 mL three-necked flask equipped with a reflux apparatus. Stirring was started, followed by the addition of 3-bromo-2,6-difluorobenzoic acid (10 g, 42.2 mmol) and pretreated Dowex® MSC-1 (5 g). After the addition was complete, the reaction mixture was heated to 50 °C and stirred at this temperature for 7 hours. Once the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed three times with 20 mL of methanol. The filter cake was recovered, and the filtrate was collected. The filtrate was then subjected to vacuum distillation to recover most of the methanol. After distillation, the remaining crude product solution was transferred to a 250 mL separatory funnel, and 80 mL of water and 50 mL of ethyl acetate were added. Extraction was performed, separating the organic phase. The aqueous phase was extracted twice with ethyl acetate (30 mL × 2). The combined organic phases were washed with 100 mL of saturated brine, and then separated. The organic phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation again. The crude product was obtained after distillation. The crude product was added to a 250 ml round-bottom flask, followed by 100 ml of methanol. A reflux apparatus was set up, and stirring was started. The temperature was raised to reflux until the crude product was completely dissolved. Heating was then stopped, and the temperature was controlled at around 45°C. 30 ml of deionized water was added dropwise, and crystals precipitated. The solution was then cooled to room temperature and stirred in an ice-water bath for 10 minutes to allow for complete crystallization. Finally, the mixture was filtered, and the filter cake was dried in a drying oven. After drying, 9.47 g of the target product, methyl 3-bromo-2,6-difluorobenzoate, was obtained, with a yield of 89.4% and an HPLC purity of 97.6%.

[0063] 4. Synthesis of 2,6-difluoro-3-(propanesulfonylamino)benzoic acid

[0064] Methyl 3-bromo-2,6-difluorobenzoate (10 g, 39.8 mmol), propylsulfonamide (7.4 g, 60.1 mmol), K₂CO₃ (13.2 g, 95.52 mmol), Ni(acac)₂ (0.51 g, 2 mmol, 5 mol%), zinc powder (0.52 g, 8 mmol), PPh₃ (1.05 g, 4 mmol), and anhydrous DMF (100 mL, 10 V) were sequentially added to a 250 mL three-necked flask. A reflux purging device was then installed, and the mixture was purged with nitrogen three times. Stirring was then initiated, and the reaction mixture was heated to 130 °C under a nitrogen atmosphere and refluxed with stirring for 12–15 h. The reaction was monitored by HPLC, and the endpoint was considered reached when the starting material concentration was < 2%. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove most of the DMF. After distillation, 120 mL of ethyl acetate and 120 mL of 10% ammonia solution were added, and the mixture was stirred for 15 minutes. The solution was then transferred to a separatory funnel, allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted again with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was then washed successively with 80 mL of 5% citric acid solution and 80 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude methyl 2,6-difluoro-3-propylsulfonamide benzoate.

[0065] The crude product was then dissolved in methanol (40 mL) and water (40 mL), and NaOH (3.0 g) was added in portions under ice bath conditions, with the temperature controlled below 40°C. The temperature was then raised to 50-55°C with stirring, and the reaction was monitored to the endpoint by TLC. The reaction solution was then cooled to 40°C, and activated carbon was added for decolorization for 20 minutes. The mixture was then filtered while hot, and the filter cake was washed with hot methanol / water (1:1, 20 mL). The filtrate was then distilled under reduced pressure. After removing the methanol, the remaining aqueous solution was cooled to 0-5°C under ice bath conditions, and concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 2-3. After stirring under ice bath conditions for 1-2 hours, the mixture was filtered, and the filter cake was washed with ice water (20 mL × 2). The filter cake was then collected and dried under vacuum at 55-60°C to obtain 9.26 g of the target product, 2,6-difluoro-3-(propanesulfonylamino)benzoic acid, with a yield of 83.2% and an HPLC purity of 97.5%.

[0066] 5. Synthesis of N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide

[0067] 2,6-Difluoro-3-(propanesulfonamide)benzoic acid (10.0 g, 33.2 mmol) was added to a 250 mL three-necked flask, and the flask was purged with nitrogen three times. Then, under a nitrogen atmosphere, 1,2-dichloroethane (150 mL, 15 V) and 0.28 mL DMF were slowly added sequentially. Next, oxalyl chloride (3.4 mL, 39.84 mmol) was slowly added dropwise to the reaction system while cooling in an ice-water bath at 0-10 °C. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally to room temperature and stirred for 1.5 h. The reaction was monitored by TLC (electrolyte: petroleum ether / ethyl acetate = 1:1). After the acid point of the starting material had essentially disappeared, 5-bromo-7-azaindole (6.54 g, 33.2 mmol) was added to the reaction solution, and the mixture was stirred for 2 minutes. Then, scandium trifluoromethanesulfonate (1.14 g, ...) was added. 2.32 mmol (added in 3 batches) was added. After the addition was complete, the reaction solution was slowly heated to 45 °C and stirred at this temperature for 6 hours. After the reaction was complete as monitored by TLC (developing solvent: dichloromethane / methanol = 20:1), the reaction solution was slowly poured into a 500 mL separatory funnel containing 100 mL of ice-water solution and 20 mL of dilute hydrochloric acid (1 M), and gently shaken to wash. The combined organic phases were washed once with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After distillation, the crude product was transferred to a 100 mL round-bottom flask, methanol (about 40-50 mL) was added, and the mixture was heated to 60-65 °C to completely dissolve the solid. The solution was then slowly cooled to room temperature, and then further cooled and stirred in an ice-water bath for 1 hour to allow the crystals to fully separate. The crystals were then filtered and washed 2-3 times with a small amount of pre-cooled methanol. The filter cake was collected and dried under vacuum at 55-60℃ to obtain 12.5 g of the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, with a yield of 76.2% and an HPLC purity of 97.3%.

[0068] Example 3:

[0069] In this embodiment, the preparation method of N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide includes the following steps:

[0070] 1. Synthesis of 1-bromo-2,4-difluorobenzene

[0071] Add 100 ml of hexafluoroisopropanol (10 V) to a 250 ml three-necked flask equipped with a reflux apparatus, and start stirring. Then add 1,3-difluorobenzene (10 g, 87.7 mmol) and p-toluenesulfonic acid monohydrate (167 mg, 0.877 mmol). Subsequently, slowly add pre-ground dibromohydantoin (10 g, 35.08 mmol) powder in batches to the reaction mixture, controlling the addition rate to maintain the reaction temperature at 20-30 °C. After the addition is complete, heat the reaction mixture to 60 °C and stir at this temperature for 10 hours. After the reaction was monitored to be complete by TLC (electrolyte: petroleum ether / ethyl acetate = 20:1), the reaction solution was subjected to vacuum distillation to recover most of the acetic acid solvent. After distillation, the remaining crude residue was transferred to a 500 mL separatory funnel, and 200 mL of ice water and 100 mL of dichloromethane were added for extraction. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and then subjected to vacuum distillation again. After distillation, a transparent colorless to brown liquid 1-bromo-2,4-difluorobenzene (14.43 g) was obtained, with a yield of 85.3% and an HPLC purity of 98.2%.

[0072] 2. Synthesis of 3-bromo-2,6-difluorobenzoic acid

[0073] Under a nitrogen atmosphere, THF (100 mL, 10 V) and 1-bromo-2,4-difluorobenzene (10 g, 47 mmol) were added to a 250 mL three-necked flask, which was then placed in a dry ice-ethanol bath and stirred until the internal temperature reached -70 °C. Subsequently, a 2 M LDA solution of THF / n-hexane (25.9 mL, 51.7 mmol) was slowly added dropwise using a syringe, controlling the dropping rate to ensure the internal temperature did not exceed -70 °C. After the addition was complete, the mixture was stirred at -70 °C for 1 h. Then, 12.4 g of solid carbon dioxide fragments, pre-washed with anhydrous THF, were added to the reaction mixture in one go. The nitrogen protection device was removed, residual gas was purged using a bubbler, the cooling bath was removed, and the reaction mixture was allowed to slowly warm to room temperature naturally. The mixture was then stirred at room temperature for 12 h. After the reaction was confirmed to be complete by HPLC, the reaction solution was slowly poured into a beaker containing 200 mL of ice water. The mixture was acidified to pH 2-3 with 6 M HCl aqueous solution under ice water bath cooling, and extracted with ethyl acetate (3 × 150 mL). The organic phases were collected and combined, then washed with saturated brine (500 mL), dried with anhydrous Na2SO4, and finally concentrated under reduced pressure to obtain 17.1 g of white solid product 3-bromo-2,6-difluorobenzoic acid, with a yield of 85.6% and an HPLC purity of 97.6%.

[0074] 3. Synthesis of methyl 3-bromo-2,6-difluorobenzoate

[0075] Dowex® MSC-1 (Strong acid cation exchange resin, H + Pretreatment (type): Take 5.0 g of Dowex® MSC-1 resin, soak it in 50 mL of methanol for 30 minutes, stirring once every five minutes, then filter it through a Buchner funnel for later use.

[0076] Anhydrous methanol (100 mL, 10 V) was added to a 250 mL three-necked flask equipped with a reflux apparatus. Stirring was started, followed by the addition of 3-bromo-2,6-difluorobenzoic acid (10 g, 42.2 mmol) and pretreated Dowex® MSC-1 (5 g). After the addition was complete, the reaction mixture was heated to 70 °C and stirred at this temperature for 7 hours. Once the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed three times with 20 mL of methanol. The filter cake was recovered, and the filtrate was collected. The filtrate was then subjected to vacuum distillation to recover most of the methanol. After distillation, the remaining crude product solution was transferred to a 250 mL separatory funnel, and 80 mL of water and 50 mL of ethyl acetate were added. Extraction was performed, separating the organic phase. The aqueous phase was extracted twice with ethyl acetate (30 mL × 2). The combined organic phases were washed with 100 mL of saturated brine, and then separated. The organic phase was dried over anhydrous sodium sulfate and then subjected to vacuum distillation again. The crude product was obtained after distillation. The crude product was added to a 250 ml round-bottom flask, followed by 100 ml of methanol. A reflux apparatus was set up, and stirring was started. The temperature was raised to reflux until the crude product was completely dissolved. Heating was then stopped, and the temperature was controlled at around 45°C. 30 ml of deionized water was added dropwise, and crystals precipitated. The solution was then cooled to room temperature and stirred in an ice-water bath for 10 minutes to allow for complete crystallization. Finally, the mixture was filtered, and the filter cake was dried in a drying oven. After drying, 9.38 g of the target product, methyl 3-bromo-2,6-difluorobenzoate, was obtained, with a yield of 88.6% and an HPLC purity of 97.5%.

[0077] 4. Synthesis of 2,6-difluoro-3-(propanesulfonylamino)benzoic acid

[0078] Methyl 3-bromo-2,6-difluorobenzoate (10 g, 39.8 mmol), propylsulfonamide (7.4 g, 60.1 mmol), K₂CO₃ (11.55 g, 83.58 mmol), Ni(acac)₂ (0.71 g, 2.79 mmol, 6.97 mol%), zinc powder (1.08 g, 16.74 mmol), PPh₃ (2.93 g, 11.16 mmol), and anhydrous DMF (100 mL, 10 V) were sequentially added to a 250 mL three-necked flask. A reflux purging device was then installed, and the mixture was purged with nitrogen three times. Stirring was then initiated, and the reaction mixture was heated to 130 °C under a nitrogen atmosphere and refluxed with stirring for 12–15 h. The reaction was monitored by HPLC, and the endpoint was considered reached when the starting material concentration was < 2%. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove most of the DMF. After distillation, 120 mL of ethyl acetate and 120 mL of 10% ammonia solution were added, and the mixture was stirred for 15 minutes. The solution was then transferred to a separatory funnel, allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted again with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was then washed successively with 80 mL of 5% citric acid solution and 80 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude methyl 2,6-difluoro-3-propylsulfonamide benzoate.

[0079] The crude product was then dissolved in methanol (40 mL) and water (40 mL), and NaOH (3.0 g) was added in portions under ice bath conditions, with the temperature controlled below 40°C. The temperature was then raised to 50-55°C with stirring, and the reaction was monitored to the endpoint by TLC. The reaction solution was then cooled to 40°C, and activated carbon was added for decolorization for 20 minutes. The mixture was then filtered while hot, and the filter cake was washed with hot methanol / water (1:1, 20 mL). The filtrate was then distilled under reduced pressure. After removing the methanol, the remaining aqueous solution was cooled to 0-5°C under ice bath conditions, and concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 2-3. After stirring under ice bath conditions for 1-2 hours, the mixture was filtered, and the filter cake was washed with ice water (20 mL × 2). The filter cake was then collected and dried under vacuum at 55-60°C to obtain 9.07 g of the target product, 2,6-difluoro-3-(propanesulfonylamino)benzoic acid, with a yield of 81.5% and an HPLC purity of 98.1%.

[0080] 5. Synthesis of N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide

[0081] 2,6-Difluoro-3-(propanesulfonamide)benzoic acid (10.0 g, 33.2 mmol) was added to a 250 mL three-necked flask, and the flask was purged with nitrogen three times. Then, under a nitrogen atmosphere, dichloromethane (150 mL, 15V) and 0.28 mL DMF were slowly added sequentially. Next, oxaloyl chloride (3.26 mL, 38.18 mmol) was slowly added dropwise to the reaction system while cooling in an ice-water bath at 0-10 °C. After the addition was complete, the ice bath was removed, and the reaction solution was allowed to warm naturally to room temperature and stirred for 1.5 h. The reaction was monitored by TLC (electrolyte: petroleum ether / ethyl acetate = 1:1). After the acid point of the starting material had essentially disappeared, 5-bromo-7-azaindole (5.89 g, 29.88 mmol) was added to the reaction solution, and the mixture was stirred for 2 minutes. Then, scandium trifluoromethanesulfonate (0.98 g, ...) was added. 1.99 mmol (added in 3 batches) was added. After the addition was complete, the reaction solution was slowly heated to 45 °C and stirred at this temperature for 6 hours. After the reaction was complete, the reaction solution was slowly poured into a 500 mL separatory funnel containing 100 mL of ice-water solution and 20 mL of dilute hydrochloric acid (1 M), and gently shaken to wash. The combined organic phases were washed once with 50 mL of saturated sodium bicarbonate solution and 50 mL of saturated saline solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After distillation, the crude product was transferred to a 100 mL round-bottom flask, methanol (about 40-50 mL) was added, and the mixture was heated to 60-65 °C to completely dissolve the solid. The solution was then slowly cooled to room temperature, and then further cooled and stirred in an ice-water bath for 1 hour to allow the crystals to fully separate. The crystals were then filtered and washed 2-3 times with a small amount of pre-cooled methanol. The filter cake was collected and dried under vacuum at 55-60°C to obtain 12.55 g of the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, with a yield of 76.5% and an HPLC purity of 97.6%.

[0082] It should be noted that the above description is only a preferred embodiment of the present invention. It should be pointed out that for those skilled in the art, several improvements can be made without departing from the principle of the present invention, and these improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A method for synthesizing N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide, characterized in that... Includes the following steps: Step 1: Using 1,3-difluorobenzene as a raw material, in the presence of acid, it reacts with dibromohydantoin via an electrophilic aromatic bromination reaction to generate 1-bromo-2,4-difluorobenzene; Step 2: Using 1-bromo-2,4-difluorobenzene as a raw material, 3-bromo-2,6-difluorobenzoic acid is generated by electrophilic carboxylation reaction with carbon dioxide in the presence of a base. Step 3: Using 3-bromo-2,6-difluorobenzoic acid as a raw material, esterification reaction is carried out with methanol in the presence of acid to generate methyl 3-bromo-2,6-difluorobenzoate; Step 4: Using methyl 3-bromo-2,6-difluorobenzoate as a raw material, in the presence of a catalyst, reducing agent, phosphine ligand and base, it undergoes a Buchwald–Hartwig coupling reaction with propylsulfonamide and is then hydrolyzed to generate 2,6-difluoro-3-(propanesulfonamide)benzoic acid. Step 5: Using 2,6-difluoro-3-(propanesulfonamide)benzoic acid as a raw material, under the conditions of acyl chloride reagent and catalyst, it undergoes a Friedel-Crafts acylation reaction with 5-bromo-7-azaindole to generate the target product N-[3-[(5-bromo-1H-pyrrolo[2,3-B]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide; The synthesis route is shown below: 。 2. The synthesis method according to claim 1, characterized in that: In step 1, the acid is m-nitrobenzenesulfonic acid or p-toluenesulfonic acid monohydrate.

3. The synthesis method according to claim 2, characterized in that: The molar ratio of 1,3-difluorobenzene to dibromohydantoin is 1:(0.4-0.6), and the molar ratio of 1,3-difluorobenzene to acid is 1:(0.01-0.03).

4. The synthesis method according to claim 1, characterized in that: In step 2, the alkali is lithium diisopropylamino.

5. The synthesis method according to claim 4, characterized in that: In step 2, the molar ratio of 1-bromo-2,4-difluorobenzene to carbon dioxide is 1:(5-7.5), and the molar ratio of 1-bromo-2,4-difluorobenzene to lithium diisopropylaminodimethylbenzene is 1:(1.05-1.1).

6. The synthesis method according to claim 1, characterized in that: In step 3, the acid is a strong acid cation exchange resin; the amount of strong acid cation exchange resin used is 0.5 times the mass of 3-bromo-2,6-difluorobenzoic acid.

7. The synthesis method according to claim 1, characterized in that: In step 4, the catalyst is nickel acetylacetonate (II), the reducing agent is zinc powder, the phosphine ligand is triphenylphosphine, and the base is potassium carbonate.

8. The synthesis method according to claim 7, characterized in that: The molar ratio of methyl 3-bromo-2,6-difluorobenzoate to propylsulfonamide is 1:1.51, the molar ratio of methyl 3-bromo-2,6-difluorobenzoate to nickel acetylacetonate(II) is 1:(0.05-0.07), the molar ratio of nickel acetylacetonate(II) to zinc powder is 1:(4-6), the molar ratio of nickel acetylacetonate(II) to triphenylphosphine is 1:(2-4), and the molar ratio of methyl 3-bromo-2,6-difluorobenzoate to potassium carbonate is 1:(2-2.5).

9. The synthesis method according to claim 1, characterized in that: In step 5, the acyl chloride reagent is oxalyl chloride, and the catalyst is scandium trifluoromethanesulfonate.

10. The synthesis method according to claim 9, characterized in that: The molar ratio of 2,6-difluoro-3-(propanesulfonamide)benzoic acid to 5-bromo-7-azaindole is 1:(0.9-1.2), the molar ratio of 2,6-difluoro-3-(propanesulfonamide)benzoic acid to oxaloyl chloride is 1:(1.1-1.2), and the molar ratio of 2,6-difluoro-3-(propanesulfonamide)benzoic acid to scandium trifluoromethanesulfonate is 1:(0.06-0.09).

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