A method for preparing a pyrrole compound

Abstract

The present application relates to the field of pharmaceutical chemistry, and in particular to a preparation method of a pyrrole compound. The method comprises reacting a raw material with propylene under the condition of a phase transfer catalyst and an alkaline reagent, and then performing a ring closure reaction, a substitution reaction, a sulfonylation reaction and a condensation reaction to obtain the target compound. The method route is relatively short, simple and easy to implement, and can be used for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing pyrrole compounds, belonging to the field of medicinal chemistry technology. Background Technology

[0002] Vonoprazan, with the structural formula shown in Formula 06 below, is a gastric acid secretion inhibitor with rapid, strong, and long-lasting gastric acid secretion inhibition, and also has a premature termination effect on gastric acid secretion.

[0003] In existing technologies, the synthetic route for vonoprazan involves numerous reaction steps and results in low yields, which is not conducive to scale-up production. In existing synthetic routes for vonoprazan, the compound shown in Formula 03 is a crucial intermediate.

[0004]

[0005] Therefore, this invention proposes a new synthetic route that can efficiently synthesize the intermediate compound of vonoprazan, shown in formula O3.

[0006] Using compound 03, this invention also provides a synthetic route for vonoprazan. The vonoprazan synthetic route provided by this invention is short, simple, has low environmental pollution, is safe and stable, and is conducive to scale-up production. Summary of the Invention

[0007] The inventors, through research, have developed a method for preparing compound O3. This invention also provides a method for preparing compound O6 using compound O3 via a reaction; this method involves fewer steps and is simple and safe to operate.

[0008] On one hand, the present invention provides a method for preparing compound O3, comprising: in an organic solvent, compound O2 undergoes a ring-closure reaction in the presence of a palladium catalyst and hydrogen gas; after the reaction is complete, compound O3 is obtained through post-processing.

[0009]

[0010] In the ring-closing reaction, the organic solvent includes at least one selected from 1,4-dioxane, DMF, and tetrahydrofuran.

[0011] In the ring-closing reaction, in some embodiments, the organic solvent comprises 1,4-dioxane; in some embodiments, the organic solvent comprises DMF; in some embodiments, the organic solvent comprises tetrahydrofuran. In some embodiments, the organic solvent in the ring-closing reaction is 1,4-dioxane.

[0012] In the ring-closing reaction, the amount of organic solvent used for each gram of compound O2 can be 3 ml to 10 ml.

[0013] In the cyclization reaction, the reaction temperature can be 40℃-100℃.

[0014] The palladium catalyst can be palladium on carbon, palladium hydroxide, palladium chloride, or a combination thereof. In some embodiments, the palladium catalyst is palladium on carbon.

[0015] The mass ratio of the palladium catalyst to compound O2 can be 0.05%-10%. In some embodiments, the mass ratio of the palladium catalyst to compound O2 is 0.1%-10%. In some embodiments, the mass ratio of the palladium catalyst to compound O2 is 1%-10%. In some embodiments, the mass ratio of the palladium catalyst to compound O2 is 5%.

[0016] The post-processing for obtaining compound 03 from compound 02 includes: cooling the reaction solution and filtering it; mixing the filtrate with water under stirring; cooling to induce crystallization; filtering; and drying to obtain compound 03. In some embodiments, the post-processing includes: cooling the reaction solution to -5°C to -40°C, filtering it; mixing the filtrate with water under stirring to induce crystallization; cooling it again to -5°C to -15°C and filtering it; and drying the solid to obtain compound 03. In some embodiments, the post-processing includes: cooling the reaction solution to 0°C to -40°C and filtering it under vacuum; adding water to the filtrate under stirring to induce crystallization; cooling it again to -5°C to -5°C and filtering it under vacuum; and drying the solid to obtain compound 03. In some embodiments, the post-processing includes: cooling the reaction solution to 20°C to -40°C and filtering it under vacuum; adding water to the filtrate under stirring to induce crystallization; cooling it again to -5°C to -5°C and filtering it under vacuum; and drying the solid to obtain compound 03.

[0017] In some embodiments, a method for preparing compound O3 includes: in an organic solvent, compound O2 undergoes a ring-closure reaction at 40°C-100°C under the action of a palladium catalyst and hydrogen; after the reaction is complete, the reaction solution is cooled to 0°C-40°C, filtered, water is added to the filtrate under stirring to crystallize, the solution is then cooled to -5°C-15°C and filtered again, the solid is dried, and after post-processing, compound O3 is obtained.

[0018] In some embodiments, a method for preparing compound O3 includes: in 1,4-dioxane, compound O2 undergoes a ring-closure reaction in the presence of palladium on carbon and hydrogen at 40°C-100°C; after the reaction is complete, compound O3 is obtained through post-processing; the post-processing includes: cooling the reaction solution to 0°C-40°C, filtering, adding water to the filtrate while stirring to induce crystallization, cooling the solution to -5°C-5°C, filtering again, and drying the solid to obtain compound O3.

[0019] The method for preparing compound O2 includes: reacting compound O1 with propionitrile in an organic reaction solvent, under the conditions of a phase transfer catalyst and an optional base reagent; after the reaction is complete, and following post-processing, compound O2 is obtained.

[0020]

[0021] The alkaline reagent includes at least one selected from sodium carbonate, potassium carbonate, and N,N-diisopropylethylamine. In some embodiments, the alkaline reagent includes sodium carbonate; in some embodiments, the alkaline reagent includes potassium carbonate; and in some embodiments, the alkaline reagent includes N,N-diisopropylethylamine. In some embodiments, sodium carbonate is preferred as the alkaline reagent, which is beneficial for the reaction and processing.

[0022] The molar ratio of the alkaline reagent to compound O1 can be 1:1 to 2.5:1. In some embodiments, the molar ratio of the alkaline reagent to compound O1 is 1:1 to 2:1. In some embodiments, the molar ratio of the alkaline reagent to compound O1 is 1.1:1 to 1.5:1.

[0023] The phase transfer catalyst includes tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, benzyltriethylammonium chloride, or combinations thereof. In some embodiments, the catalyst is tetrabutylammonium bromide, which is beneficial for the reaction to proceed and for obtaining the target product. The molar ratio of the phase transfer catalyst to compound 01 can be 0.01:1 to 0.5:1. In some embodiments, the molar ratio of the phase transfer catalyst to compound 01 is 0.05:1 to 0.2:1.

[0024] The organic reaction solvent used in the preparation of compound 02 includes at least one selected from ethyl acetate, acetonitrile, and tetrahydrofuran. In some embodiments, the organic reaction solvent includes ethyl acetate; in some embodiments, the organic reaction solvent includes acetonitrile; and in some embodiments, the organic reaction solvent includes tetrahydrofuran. In some embodiments, the organic reaction solvent is ethyl acetate, which is advantageous for operation and obtaining the target product.

[0025] For each gram of compound 01, the amount of the organic reaction solvent used can be 3 ml-15 ml or 5 ml-10 ml.

[0026] Compound 01 reacts with propionitrile at temperatures ranging from 20°C to 60°C. In some embodiments, the reaction of compound 01 with propionitrile is carried out at temperatures ranging from 30°C to 50°C.

[0027] The process of preparing compound 02 from compound 01 involves post-processing, which includes: adding water after cooling, extracting and concentrating the organic phase, adding toluene, xylene or a combination of solvents, heating, pulping, cooling, filtering, and drying to obtain compound 02.

[0028] In some embodiments, the post-treatment includes: cooling the reaction solution to -5°C to -40°C, adding water, extracting and separating the liquid to obtain an organic phase, concentrating the organic phase, adding toluene, xylene, or a combination of solvents thereof, heating to 40°C to -100°C, stirring for 0.5 h to 4 h, then cooling to -5°C to -25°C, filtering, and drying the solid to obtain compound O2. In some embodiments, the post-treatment includes: cooling to 20°C to -40°C, adding water, extracting and separating the liquid to obtain an organic phase, then concentrating under reduced pressure, adding toluene, xylene, or a combination of solvents thereof, heating to 70°C to -90°C, stirring for 1 h to 3 h, then cooling to -5°C to -15°C, filtering, and drying the solid to obtain compound O2. In some embodiments, cooling to 0°C to -10°C, filtering, and drying the solid to obtain compound O2.

[0029] In some embodiments, a method for preparing compound O2 includes: reacting compound O1 with propionitrile in an organic reaction solvent under the conditions of a phase transfer catalyst and an alkaline reagent at 0°C-60°C; after the reaction is complete, cooling the reaction solution to 0°C-40°C and adding water; extracting and separating the liquid to obtain an organic phase; concentrating the organic phase; adding toluene or xylene or a combination thereof as solvent; heating to 40°C-100°C and stirring for 0.5h-4h; then cooling to -5°C-25°C; filtering; and drying the solid to obtain compound O2.

[0030] In some embodiments, a method for preparing compound 02 includes: reacting compound 01 with propionitrile in ethyl acetate under the conditions of tetrabutylammonium bromide and sodium carbonate at 20°C-50°C; after the reaction is complete, and after post-treatment, compound 02 is obtained; the post-treatment includes: cooling the reaction solution to 0°C-40°C, adding water, extracting and separating to obtain an organic phase, concentrating the organic phase under reduced pressure to dryness, adding toluene or xylene or a combination of solvents thereof, heating to 40°C-100°C, slurrying for 0.5h-4h, then cooling to -5°C-15°C, filtering, and drying the solid to obtain compound 02.

[0031] In some embodiments, a method for preparing compound 03 includes: reacting compound 01 with propionitrile in ethyl acetate under the conditions of tetrabutylammonium bromide and sodium carbonate at 20°C-50°C; after the reaction is complete, and after post-treatment, preparing compound 02; the post-treatment includes: cooling the reaction solution to 0°C-40°C, adding water, extracting and separating to obtain an organic phase, concentrating the organic phase, adding toluene or xylene or a combination thereof, heating to 40°C-100°C, stirring for 0.5h-4h, then cooling to -5°C-15°C, filtering, and drying the solid to obtain compound 02; in an organic solvent, compound 02 undergoes a ring-closure reaction under the action of palladium on carbon and hydrogen at 40°C-100°C; after the reaction is complete, and after post-treatment, preparing compound 03; the post-treatment includes: cooling the reaction solution to 20°C-40°C, filtering, adding water to the filtrate under stirring to precipitate crystals, then cooling to -5°C-5°C, filtering, and drying the solid to obtain compound 03.

[0032] On the other hand, the present invention provides a method for preparing compound 06. A method for preparing compound 06 includes: subjecting the aforementioned compound 03 to a substitution reaction to obtain compound 04; subjecting compound 04 to a sulfonation reaction to obtain compound 05; and subjecting compound 05 to a condensation reaction to obtain compound 06.

[0033]

[0034] In some embodiments, a method for preparing compound 06 includes: preparing compound 03 according to the aforementioned method for preparing compound 03, obtaining compound 04 by a substitution reaction of compound 03, obtaining compound 05 by a sulfonation reaction of compound 04, and obtaining compound 06 by a condensation reaction of compound 05.

[0035] The preparation method of compound 04 may include: in an organic solvent, under the action of azobisisobutyronitrile, the aforementioned compound 03 undergoes a substitution reaction with N-bromosuccinimide, followed by post-treatment to prepare compound 04.

[0036] In the substitution reaction, the organic solvent includes at least one selected from acetonitrile and dichloroethane. In some embodiments, the organic solvent includes acetonitrile; in some embodiments, the organic solvent includes dichloroethane. In some embodiments, the organic solvent is acetonitrile.

[0037] In the substitution reaction, for each gram of compound O3, the amount of organic solvent used can be 3 ml-20 ml, or 5 ml-15 ml.

[0038] The molar ratio of azobisisobutyronitrile to compound O3 can be 0.9:1 to 1.1:1.

[0039] The molar ratio of N-bromosuccinimide to compound O3 can be 1:1 to 2.5:1. In some embodiments, the molar ratio of N-bromosuccinimide to compound O3 is 1.2:1 to 2:1.

[0040] The reaction temperature of the substitution reaction can be controlled at 20℃-80℃, 40℃-80℃, or 20℃-40℃.

[0041] After the substitution reaction is complete, the post-treatment includes: adding water and dichloromethane to the reaction solution, extracting and separating the liquid to obtain an organic phase, concentrating the organic phase, mixing the result with acetonitrile, ethyl acetate, acetone, methanol, or a combination of solvents, slurrying for 0.5-4 hours, controlling the temperature at -5°C to 30°C, filtering, and drying the solid to obtain compound O4. In some embodiments, the post-treatment includes: cooling the reaction solution to below 40°C, adding water and dichloromethane, extracting and separating the liquid to obtain an organic phase, concentrating the organic phase under reduced pressure, mixing the result with acetonitrile, ethyl acetate, acetone, methanol, or a combination of solvents, slurrying at 40°C to 80°C for 0.5-4 hours, cooling to -5°C to 20°C, filtering, and drying the solid to obtain compound O4.

[0042] In some embodiments, a method for preparing compound 04 includes: in an organic solvent, under the action of azobisisobutyronitrile, compound 03 and N-bromosuccinimide undergo a substitution reaction at 0°C-80°C; after the reaction is complete, the reaction solution is kept at 0°C-40°C, water and extraction solvent are added, the organic phase is obtained by extraction and separation and concentration, the product is mixed with acetonitrile, ethyl acetate, acetone, methanol or a combination thereof, and slurryed for 0.5 hours-4 hours, while the temperature is kept at -5°C-20°C, filtered, and the solid is dried to obtain compound 04.

[0043] In some embodiments, a method for preparing compound 04 includes: in acetonitrile, under the action of azobisisobutyronitrile, the aforementioned compound 03 undergoes a substitution reaction with N-bromosuccinimide at 0°C-80°C. After the reaction is complete, the reaction solution is kept at 0-40°C, water and dichloromethane are added, the mixture is extracted and separated to obtain an organic phase, concentrated under reduced pressure, the product is mixed with acetonitrile, slurried for 0.5-4 hours, kept at -5°C-15°C, filtered, and the solid is dried to obtain compound 04.

[0044] The preparation method of compound 05 includes: in an organic solvent, under the conditions of an organic base and 4-dimethylaminopyridine, compound 04 and pyridinesulfonyl chloride undergo a sulfonation reaction to prepare compound 05.

[0045] In the sulfonation reaction, the organic solvent includes at least one selected from dichloromethane and tetrahydrofuran. In some embodiments, the organic solvent includes dichloromethane; in some embodiments, the organic solvent includes tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane.

[0046] For each gram of compound 04, the amount of the organic solvent used can be 3 ml-20 ml or 5 ml-15 ml.

[0047] The molar ratio of compound 04 to pyridine sulfonyl chloride can be 1:1-1:1.5 or 1:1-1:1.3.

[0048] The organic base is triethylamine, N,N-diisopropylethylamine, pyridine, isopropylamine, or a combination thereof. The molar ratio of the organic base to compound O4 can be 1:1-3:1 or 1.2:1-2:1.

[0049] The reaction temperature for the sulfonation reaction can be 0℃-60℃, or 20℃-40℃, or 20℃-60℃, or 30℃-60℃.

[0050] After the sulfonation reaction is complete, post-processing can be performed to obtain compound 05. The post-processing includes: adding water to the reaction solution, separating and concentrating the organic phase, mixing the result with acetonitrile, ethyl acetate, acetone, methanol, or a combination thereof, stirring for 0.1-2 hours, cooling to -5℃-15℃, filtering, and drying the solid to obtain compound 05. In some embodiments, after the sulfonation reaction is complete, post-processing is performed, which includes: adding water to the reaction solution, separating and concentrating the organic phase, mixing the result with acetonitrile, ethyl acetate, acetone, methanol, or a combination thereof, stirring at 40℃-80℃ for 0.1-2 hours, cooling to -5℃-5℃, filtering, and drying the solid to obtain compound 05.

[0051] In some embodiments, a method for preparing compound 05 includes: in an organic solvent, under the conditions of an organic base and 4-dimethylaminopyridine, compound 04 is reacted with pyridinesulfonyl chloride at 0°C-60°C via a sulfonation reaction, and after the reaction is complete; water is added to the reaction solution, the organic phase is separated and concentrated, the product is mixed with acetonitrile, ethyl acetate, acetone, methanol or a combination thereof, slurryed for 0.1-2 hours, cooled to -5°C-5°C, filtered, and the solid is dried to obtain compound 05.

[0052] In some embodiments, a method for preparing compound 05 includes: in an organic solvent, under the conditions of triethylamine and 4-dimethylaminopyridine, compound 04 is reacted with pyridinesulfonyl chloride at 0°C-60°C through a sulfonation reaction; after the reaction is complete, compound 05 is prepared by post-treatment; the post-treatment includes: adding water to the reaction solution, separating and concentrating the organic phase, mixing the result with acetonitrile, slurrying for 0.1-2 hours, cooling to -5°C-5°C, filtering, and drying the solid to obtain compound 05.

[0053] The preparation method of compound 06 includes: in an organic solvent, under the action of potassium carbonate and potassium iodide, compound 05 and methylamine or its hydrochloride undergo a condensation reaction to prepare compound 06.

[0054] In the condensation reaction, the organic solvent includes at least one selected from dichloromethane, DMF, DMAC, acetonitrile, tetrahydrofuran, and ethyl acetate. In some embodiments, the organic solvent includes dichloromethane; in some embodiments, the organic solvent includes DMF; in some embodiments, the organic solvent includes DMAC; in some embodiments, the organic solvent includes acetonitrile; in some embodiments, the organic solvent includes tetrahydrofuran; and in some embodiments, the organic solvent includes ethyl acetate. In some embodiments, the organic solvent is dichloromethane.

[0055] In the condensation reaction, for each gram of compound 05, the amount of the organic solvent used can be 5 ml-25 ml, or 10 ml-20 ml, or 8 ml-15 ml.

[0056] The molar ratio of compound 05 to methylamine or its hydrochloride can be 1:1-1:2.5 or 1:1-1:2.

[0057] The molar ratio of compound 05 to potassium carbonate can be 1:1 to 1:2.5. In some embodiments, the molar ratio of compound 05 to potassium carbonate can be 1:1 to 1:2.

[0058] The molar ratio of potassium iodide to compound 05 can be 1:1 to 2:1. In some embodiments, the molar ratio of potassium iodide to compound 05 is 1:1.1 to 1.6:1.

[0059] The reaction temperature of the condensation reaction can be 30℃-100℃. In some embodiments, the reaction temperature of the condensation reaction is 40℃-60℃, or 50℃-80℃, or 60℃-100℃.

[0060] After the condensation reaction is complete, post-processing can be performed to obtain compound 06. The post-processing includes: adding water to the reaction solution, extraction and separation, further extraction and separation of the aqueous phase using an extraction solvent, combining and concentrating the organic phases, adding n-hexane, cyclohexane, isopropanol, or a combination thereof as a solvent for slurry mixing, cooling to -5°C to 30°C, filtering, and drying the solid to obtain compound 06. In some embodiments, the post-processing includes: controlling the temperature of the reaction solution at 0°C to 30°C, adding water, extraction and separation, further extraction and separation of the aqueous phase using an extraction solvent, combining and concentrating the organic phases, adding n-hexane, cyclohexane, isopropanol, or a combination thereof as a solvent, slurry mixing at 30°C to 70°C for 0.5 hours to 4 hours, cooling to -5°C to 20°C, filtering, and drying the solid to obtain compound 06. In some embodiments, the post-processing includes: adding water to the reaction solution at a controlled temperature of 0°C-30°C, extracting and separating the aqueous phase, extracting and separating the aqueous phase again with dichloromethane, combining the organic phases and concentrating them, adding n-hexane and stirring at 30°C-70°C for 0.5-4 hours, cooling to -5°C-10°C, filtering, and drying the solid to obtain compound 06.

[0061] In some embodiments, a method for preparing compound 06 includes: in an organic solvent, under the action of potassium carbonate and potassium iodide, compound 05 undergoes a condensation reaction with methylamine or its hydrochloride at 30°C-100°C until the reaction is complete; water is added to the reaction solution, the aqueous phase is extracted and separated, the aqueous phase is further extracted and separated with an extraction solvent, the organic phases are combined and concentrated, n-hexane, cyclohexane, isopropanol or a combination of solvents are added, the mixture is stirred at 30°C-70°C for 0.5 hours-4 hours, cooled to -5°C-30°C, filtered, and the solid is dried to obtain compound 06.

[0062] In some embodiments, a method for preparing compound 06 includes: in an organic solvent, under the action of potassium carbonate and potassium iodide, compound 05 and methylamine hydrochloride undergo a condensation reaction at 30°C-100°C. After the reaction is complete, compound 06 is prepared by post-processing. The post-processing includes: adding water to the reaction solution at a controlled temperature of -5°C-30°C, extracting and separating the liquid phase, extracting and separating the aqueous phase again with an extraction solvent, combining the organic phases and concentrating them, adding n-hexane and slurrying, cooling to -5°C-10°C, filtering, and drying the solid to obtain compound 06.

[0063] In some embodiments, a method for preparing compound 06 includes:

[0064] (1) In an organic reaction solvent, under the conditions of phase transfer catalyst and alkaline reagent, compound 01 reacts with propionitrile at 0℃-60℃. After the reaction is completed, the reaction solution is cooled to -5℃-40℃ and water is added. The mixture is extracted and separated to obtain an organic phase. The organic phase is concentrated and toluene or xylene or a combination of solvents is added. The temperature is raised to 40℃-100℃ and the mixture is slurried for 0.5h-4h. Then the temperature is lowered to -5℃-25℃, filtered, and the solid is dried to prepare compound 02.

[0065] (2) In an organic solvent, compound 02 undergoes a ring-closing reaction at 40℃-100℃ under the action of palladium catalyst and hydrogen. After the reaction is completed, the reaction solution is cooled to -5℃-40℃, filtered, and water is added to the filtrate under stirring to crystallize. The solution is then cooled to -5℃-15℃ and filtered again. The solid is dried and post-processed to obtain compound 03.

[0066] (3) In an organic solvent, under the action of azobisisobutyronitrile, compound 03 and N-bromosuccinimide undergo a substitution reaction at 0℃-80℃. After the reaction is complete, the reaction solution is kept at -5℃-40℃. Water and extraction solvent are added, and the organic phase is obtained by extraction and separation and concentration. The product is mixed with acetonitrile, ethyl acetate, acetone or a combination of solvents, and slurryed for 0.5-4 hours. The temperature is kept at -5℃-30℃. The mixture is filtered and the solid is dried to obtain compound 04.

[0067] (4) In an organic solvent, under the conditions of an organic base and 4-dimethylaminopyridine, compound 04 and pyridinesulfonyl chloride undergo a sulfonation reaction at 0℃-60℃. After the reaction is complete, water is added to the reaction solution, the organic phase is separated and concentrated, and the product is mixed with acetonitrile, ethyl acetate, acetone or a combination of solvents, slurryed for 0.1-2 hours, cooled to -5℃-15℃, filtered, and the solid is dried to obtain compound 05.

[0068] (5) In an organic solvent, under the action of potassium carbonate and potassium iodide, compound 05 reacts with methylamine or its hydrochloride at 30℃-100℃ through a condensation reaction. After the reaction is completed, water is added to the reaction solution at -5℃-30℃, and the mixture is extracted and separated. The aqueous phase is then extracted and separated again with an extraction solvent. The organic phases are combined and concentrated. Hexane, cyclohexane, isopropanol or a combination of solvents are added and the mixture is stirred at 30℃-70℃ for 0.5 hours-4 hours. The mixture is then cooled to -5℃-30℃, filtered, and the solid is dried to obtain compound 06.

[0069] In some embodiments, a method for preparing compound 06 includes:

[0070] (1) In ethyl acetate, under the conditions of tetrabutylammonium bromide and sodium carbonate, compound 01 reacted with propionitrile at 20℃-50℃. After the reaction was completed, the reaction solution was cooled to 0℃-40℃ and water was added. The mixture was extracted and separated to obtain an organic phase. The organic phase was concentrated, toluene was added, and the temperature was raised to 40℃-100℃. The mixture was stirred for 0.5h-4h, then cooled to -5℃-25℃, filtered, and the solid was dried to prepare compound 02.

[0071] (2) In 1,4-dioxane, compound 02 undergoes a ring-closing reaction at 40℃-100℃ under the action of palladium on carbon and hydrogen. After the reaction is complete, the reaction solution is cooled to 0℃-40℃, filtered, and water is added to the filtrate under stirring to crystallize. The solution is then cooled to -5℃-15℃ and filtered again. The solid is dried and post-processed to prepare compound 03.

[0072] (3) In acetonitrile, under the action of azobisisobutyronitrile, compound 03 and N-bromosuccinimide undergo a substitution reaction at 0℃-80℃. After the reaction is completed, the temperature of the reaction solution is controlled at 0℃-40℃, water and dichloromethane are added, the organic phase is obtained by extraction and separation and concentration, the product is mixed with acetonitrile, slurryed for 0.5 hours-4 hours, the temperature is controlled at -5℃-20℃, filtered, and the solid is dried to obtain compound 04;

[0073] (4) In dichloromethane, under the conditions of triethylamine and 4-dimethylaminopyridine, compound 04 and pyridinesulfonyl chloride were subjected to sulfonation reaction at 0℃-60℃. After the reaction was completed, water was added to the reaction solution, the organic phase was separated and concentrated, the product was mixed with acetonitrile, slurried for 0.1-2 hours, cooled to -5℃-5℃, filtered, and the solid was dried to obtain compound 05.

[0074] (5) In dichloromethane, under the action of potassium carbonate and potassium iodide, compound 05 and methylamine hydrochloride undergo a condensation reaction at 30℃-100℃. After the reaction is completed, water is added to the reaction solution at 0℃-30℃, and the mixture is extracted and separated. The aqueous phase is then extracted and separated again with dichloromethane. The organic phases are combined and concentrated. Hexane is added and the mixture is stirred at 30℃-70℃ for 0.5-4 hours. The mixture is then cooled to -5℃-10℃, filtered, and the solid is dried to obtain compound 06.

[0075] In the above methods, when extraction is involved, the extraction solvents that can be used are organic solvents that can react with the aqueous layer, such as dichloromethane, toluene, and ethyl acetate.

[0076] In the above methods, when drying is involved, the solid is dried to constant weight or the weight change before and after drying does not exceed ±1%; when concentration is involved, it can be distilled under reduced pressure or other conditions until no obvious fractions are distilled off.

[0077] The preparation method of compound 06 provided by this invention is relatively simple, with a short process route, easy to operate and implement, and suitable for large-scale production. Detailed Implementation

[0078] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0079] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0080] In this invention, "reaction complete" means that the remaining amount of raw materials is no more than 5%, 3%, 1%, or 0.5% of the input amount; this can be confirmed by HPLC (high performance liquid chromatography) or TLC (thin layer chromatography).

[0081] In this invention, room temperature refers to ambient temperature, which is between 15℃ and 35℃, or between 20℃ and 30℃, or between 23℃ and 28℃, or between 25℃.

[0082] In this invention, g: gram; mL: milliliter; ℃: degree Celsius; h: hour; min: minute; MS: mass spectrometry; HPLC: high performance liquid chromatography. DMF: N,N-dimethylformamide; DMAC: N,N-dimethylacetamide; TABA: tetrabutylammonium bromide; NBS: N-bromosuccinimide; TEA: triethylamine; DMAP: 4-dimethylaminopyridine.

[0083] Example 1

[0084] Preparation of compound 02

[0085]

[0086] 100.00 g of compound 01, 33.00 g of propionitrile, 121.89 g of sodium carbonate, 16.12 g of tetrabutylammonium bromide, and 600 ml of ethyl acetate were added to a reaction flask at room temperature. After the addition was complete, the temperature was raised to 40 °C, and the reaction was carried out for 4 h under stirring. The sample was taken for analysis, and the HPLC results showed that the starting material reacted completely, so the reaction was stopped. The temperature was lowered to 30 °C, 250 ml of water was added, and the mixture was extracted and separated to obtain the organic phase. The organic phase was concentrated to dryness under reduced pressure at 35 °C, 100 ml of toluene was added, and the temperature was raised to 80 °C and stirred for 2 h. The temperature was lowered to 20 °C and filtered. The filter cake was dried under vacuum at 80 °C for 12 h to obtain 76.11 g of compound 01 as a yellow solid product, with a yield of 86.40% and a purity of 96.31%.

[0087] MS: [M+1] = 192.11;

[0088] MRI 1 H NMR (400MHz, DMSO) δ7.89-7.96 (m, 2H), 7.25-7.36 (m, 2H), 3.21 (m, J = 14.3Hz, 1H), 2.66-3.03 (dd, 2H), 1.51 (t, 3H).

[0089] Example 2

[0090] Preparation of compound 03

[0091]

[0092] 70.00 g of compound 02, 3.50 g of 10% palladium on carbon, and 250 ml of 1,4-dioxane were added to a reaction flask at room temperature. After the addition was complete, hydrogen gas was displaced, and the temperature was raised to 80 °C. The reaction was carried out for 16 h under stirring. Samples were taken for analysis, and HPLC results showed that the starting material had reacted completely, so the reaction was stopped. The temperature was lowered to 30 °C and filtered. 250 ml of water was added to the filtrate under stirring to induce crystallization. After the addition was complete, the temperature was lowered to 10 °C and filtered. The filter cake was dried under vacuum at 80 °C for 12 h to obtain 46.30 g of compound 03 as a yellow solid product, with a yield of 72.18% and a purity of 97.22%.

[0093] MS: [M+1] = 176.11;

[0094] MRI 1 H NMR (400MHz, DMSO) δ9.79 (s, 1H), 7.69-7.81 (m, 2H), 7.52 (m, 1H), 7.33 (m, 1H), 6.71 (s, 1H), 6.35 (s, 1H), 2.12 (s, 3H).

[0095] Example 3

[0096] Preparation of compound 04

[0097]

[0098] 50.00 g of compound 03, 103.23 g of NBS, 47.62 g of azobisisobutyronitrile, and 500 ml of acetonitrile were added to a reaction flask at room temperature. After the addition was complete, the temperature was raised to 80 °C, and the reaction was carried out for 16 h under stirring. The sample was taken for analysis, and the HPLC results showed that the starting material reacted completely, so the reaction was stopped. The temperature was lowered to 30 °C, 500 ml of water and 500 ml of dichloromethane were added, and the mixture was extracted and separated to obtain the organic phase. The organic phase was concentrated to dryness under reduced pressure at 35 °C, and 200 ml of acetonitrile was added. The temperature was raised to 60 °C and stirred for 2 h. The temperature was lowered to 20 °C and filtered. The filter cake was dried under vacuum at 60 °C for 12 h to obtain 45.55 g of compound 04 as a yellow solid product, with a yield of 62.81% and a purity of 95.44%.

[0099] MS: [M+1] = 254.05;

[0100] MRI 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 7.69-7.81 (m, 2H), 7.52 (m, 1H), 7.33 (m, 1H), 6.71 (s, 1H), 6.35 (s, 1H), 4.52 (s, 2H).

[0101] Example 4

[0102] Preparation of compound 05

[0103]

[0104] 50.00 g of compound 04, 46.18 g of pyridine-3-sulfonyl chloride, 40.48 g of triethylamine, 2.44 g of 4-dimethylaminopyridine, and 500 ml of dichloromethane were added to a reaction flask at room temperature. After the addition was complete, the temperature was raised to 40 °C, and the reaction was carried out for 8 h under stirring. The sample was taken for analysis, and the HPLC results showed that the starting material reacted completely, so the reaction was stopped. The temperature was lowered to 30 °C, 500 ml of water was added, and the mixture was extracted and separated to obtain the organic phase. The organic phase was concentrated to dryness under reduced pressure at 35 °C, and 200 ml of acetonitrile was added. The temperature was raised to 50 °C and stirred for 1 h. The mixture was then cooled to 0 °C and filtered. The filter cake was dried under vacuum at 60 °C for 12 h to obtain 64.32 g of compound 05 as a yellow solid product, with a yield of 83.36% and a purity of 96.43%.

[0105] MS: [M+1] = 395.00;

[0106] MRI 1 H NMR (400MHz, DMSO) δ8.89 (d, 1H), 8.64 (s, 1H), 7.85 (dd, 1H), 7.76 (s, 1H), 7.55-7.64 (m, 1H), 7.49-7.54 (m, 1H), 7.29-7.38 (m, 2H), 7.17-7.25 (m, 2H), 7.00-7.05 (m, 1H), 6.41-6.46 (d, 1H), 4.57-4.65 (s, 2H).

[0107] Example 5

[0108] Preparation of compound 06

[0109]

[0110] 50.00 g of compound 05, 17.56 g of methylamine hydrochloride, 35.93 g of potassium carbonate, 33.20 g of potassium iodide, and 600 ml of dichloromethane were added to a reaction flask at room temperature. After the addition was complete, the temperature was raised to 40 °C, and the reaction was carried out for 8 hours with stirring. The sample was taken for analysis, and the HPLC results showed that the starting material reacted completely, so the reaction was stopped. The temperature was lowered to 30 °C, 500 ml of water was added, and the mixture was extracted and separated. The aqueous phase was extracted and separated again with 500 ml of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure at 35 °C, and 250 ml of n-hexane was added. The temperature was raised to 60 °C and stirred for 2 hours. The temperature was lowered to 20 °C and filtered. The filter cake was dried under vacuum at 80 °C for 12 hours to obtain 35.96 g of compound 06 as a yellow solid product, with a yield of 82.31% and a purity of 98.34%.

[0111] MS: [M+1] = 346.15;

[0112] MRI 1H NMR (400MHz, DMSO) δ8.79 (d, 1H), 8.62 (s, 1H), 7.89 (dd, 1H), 7.78 (s, 1H), 7.60-7.64 (m, 1H), 7.49-7.54 (m, 1H), 7 .28-7.38(m, 2H), 7.15-7.25(m, 2H), 7.02-7.07(m, 1H), 6.40-6.46(d, 1H), 3.77-3.85(s, 2H), 2.51-3.60(s, 3H).

[0113] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing compound O3, comprising: In an organic solvent, compound O2 undergoes a ring-closure reaction in the presence of a palladium catalyst and hydrogen gas. After the reaction is complete, compound O3 is prepared through post-processing. The organic solvent is selected from at least one of 1,4-dioxane, DMF, and tetrahydrofuran; the palladium catalyst is palladium on carbon, palladium hydroxide, palladium chloride, or a combination thereof.

2. The preparation method according to claim 1 further includes: In an organic reaction solvent, under the conditions of a phase transfer catalyst and a basic reagent, compound 01 reacts with propionitrile. After the reaction is complete, compound 02 is prepared through post-treatment. The organic reaction solvent is selected from at least one of ethyl acetate, acetonitrile, and tetrahydrofuran.

3. The preparation method according to claim 2, wherein the alkaline reagent is selected from at least one of sodium carbonate, potassium carbonate, and N,N-diisopropylethylamine; And / or the molar ratio of the alkaline reagent to compound O1 is 1:1 to 2.5:

1.

4. According to the preparation method of claim 2, the reaction temperature of the cyclization reaction is 40℃-100℃; and / or compound 01 reacts with propionitrile at 20℃-60℃.

5. The preparation method according to any one of claims 1-4, wherein after the cyclization reaction is completed, the post-processing includes: The reaction solution is cooled to -5℃ to 40℃, filtered, and the filtrate is mixed with water under stirring to induce crystallization. The mixture is then cooled to -5℃ to 15℃ and filtered again. The solid is dried to obtain compound 03. The post-processing of the preparation method of compound 02 includes: cooling the reaction solution to -5℃ to 40℃, adding water, extracting and separating the organic phase, concentrating the organic phase, adding toluene, xylene, or a combination of these solvents, heating to 40℃ to 100℃, slurrying for 0.5h to 4h, then cooling to -5℃ to 25℃, filtering, and drying the solid to obtain compound 02.

6. A method for preparing compound 06, comprising: In an organic solvent, under the action of azobisisobutyronitrile, compound 03 undergoes a substitution reaction with N-bromosuccinimide, followed by post-treatment to prepare compound 04; in an organic solvent, under the conditions of an organic base and 4-dimethylaminopyridine, compound 04 undergoes a sulfonation reaction with pyridinesulfonyl chloride, followed by post-treatment to prepare compound 05; in an organic solvent, under the action of potassium carbonate and potassium iodide, compound 05 undergoes a condensation reaction with methylamine or its hydrochloride, followed by post-treatment to prepare compound 06; wherein the organic base is triethylamine, N,N-diisopropylethylamine, pyridine, isopropylamine, or a combination thereof; The preparation method of compound 06 further includes the following step: preparing compound 03 according to the method of claim 1.

7. The preparation method according to claim 6, wherein, In the substitution reaction, the organic solvent is selected from at least one of acetonitrile and dichloroethane; and / or in the sulfonation reaction, the organic solvent is selected from at least one of dichloromethane and tetrahydrofuran; and / or in the condensation reaction, the organic solvent is selected from at least one of dichloromethane, DMF, DMAC, acetonitrile, tetrahydrofuran, and ethyl acetate.

8. The preparation method according to claim 6, wherein, The reaction temperature for substitution reactions is 20℃-80℃; and / or the reaction temperature for sulfonation reactions is 0℃-60℃; and / or the reaction temperature for condensation reactions is 30℃-100℃.

9. The preparation method according to any one of claims 6-8, wherein after the substitution reaction is completed, the post-processing includes: Water and dichloromethane are added to the reaction solution, and the mixture is extracted and separated to obtain an organic phase. The organic phase is concentrated, and the product is mixed with acetonitrile, ethyl acetate, acetone, methanol, or a combination of solvents thereof. The mixture is stirred for 0.5-4 hours at a controlled temperature of -5°C to 30°C, filtered, and dried as a solid to obtain compound 04. After the sulfonation reaction is completed, the post-treatment includes: adding water to the reaction solution, separating and concentrating the organic phase, and mixing the product with acetonitrile, ethyl acetate, acetone, methanol, or a combination of solvents thereof. The mixture is stirred for 0.1-2 hours, cooled to -5°C to 15°C, filtered, and dried as a solid to obtain compound 05. After the condensation reaction is completed, the post-treatment includes: adding water to the reaction solution, extracting and separating the aqueous phase, extracting and separating the aqueous phase again with an extraction solvent, combining and concentrating the organic phases, adding n-hexane, cyclohexane, isopropanol, or a combination of solvents thereof, stirring, cooling to -5°C to 30°C, filtering, and drying as a solid to obtain compound 06.

10. The preparation method according to any one of claims 6-8, wherein, It also includes the following steps: Compound O3 is prepared by the method according to any one of claims 1-4.

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