Preparation method of deuterocoxitinib

Abstract

The invention discloses a preparation method of deuterocoxitinib, and belongs to the technical field of chemical synthesis. According to the scheme, 4, 6-dichloropyridazine-3-carboxylic acid methyl ester is used as an initial raw material, and a target product is efficiently synthesized through four-step reaction of nucleophilic substitution, ammonolysis / hydrolysis, amide condensation and targeted condensation. A noble metal catalyst is not needed, a key carbon-nitrogen bond is constructed through a high-selectivity nucleophilic substitution process, deuterated methylamine hydrochloride is accurately introduced in a final step, and the reaction stability and selectivity are improved; the process is mild in condition and simple and convenient to operate, the final product yield exceeds 85%, the product purity reaches 99.8% or above, the used solvent and reagent are environment-friendly, free of heavy metal residues, few in waste liquid and waste residue and easy to treat, the green chemistry concept is completely met, and an efficient, economical and safe industrial path is provided for large-scale production of deuterocoxitinib.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing deuterated celexitinib. Background Technology

[0002] Deucravacitinib, chemically named 6-[(cyclopropylcarbonyl)amino]-4-[[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino]-N-(methyl-D3)-3-pyridazine carboxamide, is the world's first and only approved allosteric inhibitor of tyrosine kinase 2 (TYK2). Its structural formula is as follows:

[0003] ;

[0004] This drug was approved by the US FDA in September 2022 (trade name: Sotyktu) for the treatment of adult patients with moderate to severe plaque psoriasis who are suitable for systemic therapy or phototherapy. It was subsequently approved in Europe in March 2023 and in China in October 2023. Its core advantage lies in its precise targeting of the core axis of psoriasis pathogenesis, while also exhibiting good safety and tolerability, without any "black box warnings," and is consistently recommended by authoritative guidelines both domestically and internationally, pioneering a new field of targeted oral therapy for psoriasis.

[0005] From a market perspective, deuterated lecithinib has significant commercial value: global sales reached US$246 million in 2024, a year-on-year increase of 44.7%. With its inclusion in China's National Reimbursement Drug List, clinical accessibility has been further improved, and future sales volume and market size are expected to continue to expand. Therefore, developing efficient, stable, and economical methods for preparing deuterated lecithinib is of great practical significance for promoting its large-scale production and meeting clinical needs.

[0006] Despite the significant clinical value and market potential of deuterocelexitinib, existing synthetic technologies still face numerous bottlenecks. The first-generation synthetic route disclosed by the original manufacturer in patent WO2014 / 074661A is as follows:

[0007] ;

[0008] This route uses ethyl 4,6-dihydroxypyridazine-3-carboxylate as the starting material and proceeds through five steps: ester hydrolysis, phosphorus oxychloride-mediated chlorination, condensation with deuterated methylamine, Buchwald-Hartwig coupling, and aromatic nucleophilic substitution to obtain the target product. This route has significant drawbacks: First, the overall yield is low. In the crucial chlorination and condensation steps, the generated trichloro intermediate (4,6-dichloropyrazine-3-carboxyl chloride) has extremely poor stability and is easily degraded during post-processing. Furthermore, the degradation intensifies with scale-up, resulting in a combined yield of only 15-45%, severely limiting industrial-scale production. Second, the synthesis cost is high. Expensive deuteration reagents are used in large quantities and are frequently lost in the early stages of the reaction. Additionally, the Buchwald-Hartwig coupling requires a palladium catalyst. Third, the product quality and environmental friendliness are insufficient. Palladium catalyst residues are difficult to completely remove, affecting the quality of the active pharmaceutical ingredient, and heavy metal residues pollute the environment. Subsequent processing steps are cumbersome and yield low results.

[0009] Patent CN117756729A discloses another synthetic route for deuterocelexitinib:

[0010]

[0011] This route uses 3-amino-6-chloropyridazine as the starting material and proceeds through six steps: bromination, diazotization-cyanation, cyclopropylamide substitution, Buchwald-Hartwig coupling, acid hydrolysis, and condensation to prepare the product. However, this route also faces several obstacles to industrialization: First, the synthetic route is lengthy, with numerous steps and a relatively low overall yield; second, it carries high safety risks, as the critical diazotization reaction is a strongly exothermic process requiring strict control of low temperatures, resulting in high energy consumption and demanding operation. The generated diazonium salt intermediate has poor chemical stability, is easily decomposed upon heating, and can easily trigger side reactions and safety hazards; third, it still relies on the precious metal palladium catalyst, which increases preparation costs and raises environmental and quality issues related to heavy metal residues, contradicting the principles of green chemistry.

[0012] In summary, existing methods for synthesizing deuterated colescitinib generally suffer from common technical defects that severely restrict its industrial application. These defects can be summarized into four points: First, the process efficiency is low, the synthetic route is long and cumbersome, and the overall yield is low. Second, the preparation cost is high, relying on precious metal catalysts and a large amount of deuterated reagents invested in the early stage, resulting in poor economic efficiency. Third, the safety and controllability are poor, the stability of key intermediates is insufficient, the reaction conditions are harsh, the scale-up effect is significant, and there are high safety risks. Fourth, there are environmental and quality concerns, as the residue of precious metal catalysts pollutes the environment and is difficult to remove, affecting the quality of the active pharmaceutical ingredient.

[0013] The aforementioned shortcomings prevent existing methods from simultaneously meeting the core requirements of industrial production for efficiency, economy, safety, and environmental friendliness. Therefore, developing a novel synthetic method for deuterocelexitinib that is safe and controllable in operation, has simplified process steps, is low-cost, and environmentally friendly has become a key technical challenge to overcome existing technological bottlenecks and promote the large-scale production of this drug, possessing significant industrial application value. Summary of the Invention

[0014] To address the challenges of existing technologies, this invention innovatively proposes a method for preparing deuterocelexitinib. Specifically, it uses methyl 4,6-dichloropyridazine-3-carboxylic acid as the starting material and proceeds through a four-step process: nucleophilic substitution, ammonolysis / hydrolysis, amide condensation, and targeted condensation. This invention abandons the Buchwald-Hartwig noble metal-catalyzed coupling reaction, employing highly selective nucleophilic substitution to construct key carbon-nitrogen bonds, thus avoiding heavy metal residues and high costs from the source. A stable chloropyridazine ester intermediate is selected to improve process safety and scale-up compatibility. Deuterated methylamine hydrochloride is used for the final targeted condensation, reducing its dosage and loss. The process steps are simplified, the reaction conditions are mild, and post-processing is convenient. This method achieves efficient, low-cost, safe, and green synthesis of deuterocelexitinib, overcoming common defects in existing technologies. The overall yield can reach over 85%, with a purity ≥99.8%. The operation is simple, suitable for industrial scale-up, and possesses significant industrial application and economic value.

[0015] To achieve the above objectives, this invention discloses a method for preparing deuterated celexitinib, the specific technical solution of which is as follows: This invention uses methyl 4,6-dichloropyridazine-3-carboxylate (compound I) as the starting material and prepares the target product through a four-step reaction involving nucleophilic substitution, ammonolysis / hydrolysis, amide condensation, and targeted condensation. The preparation route is as follows: .

[0016] The specific steps are as follows: 1) Nucleophilic substitution reaction (preparation of intermediate II): Compound I and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline were added to solvent A, stirred to dissolve, and then a base reagent was added. The nucleophilic substitution reaction was carried out under an inert atmosphere and heated. After the reaction was completed, intermediate II was obtained by post-treatment. 2) Ammonolysis / hydrolysis reaction (preparation of intermediate III): Dissolve intermediate II in solvent B, add ammonolysis reagent, and heat to carry out ammonolysis reaction to replace the chlorine atom on the pyridazine ring. After the reaction is completed, the ammonolysis product is obtained. Dissolve the ammonolysis product in solvent C, add an aqueous solution of alkali to carry out ester hydrolysis reaction, and after the reaction is completed, the intermediate III is obtained by post-treatment. 3) Amide condensation reaction (preparation of intermediate IV): Cyclopropionic acid, condensing agent and base are added to solvent D, stirred evenly, and then solvent D solution of intermediate III is added dropwise under controlled temperature. After the addition is completed, the temperature is raised to carry out amide condensation reaction. After the reaction is completed, intermediate IV is obtained by post-treatment. 4) Targeted condensation reaction (preparation of deuterated celexitinib): Intermediate IV is dissolved in solvent E and condensed with deuterated methylamine hydrochloride under an inert atmosphere in the presence of alkali and condensing agent. After the reaction is completed, the target product deuterated celexitinib is obtained through post-treatment.

[0017] Further, in step 1): solvent A is selected from at least one of water, dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, methyl ethyl ketone, acetonitrile, and isopropanol; the heating reaction temperature is 50~100℃ and the reaction time is 16~24 h; the base reagent is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, and potassium acetate; the molar ratio of compound I to 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline is 1:1.1~1.5; the molar ratio of compound I to the base reagent is 1:0.3~2.0.

[0018] Further, in step 2): solvent B is selected from at least one of dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dioxane, water, methanol, and ethanol; the ammonolysis reagent is selected from any one of concentrated ammonia, ammonia / methanol solution, and ammonia / ethanol solution; the molar ratio of intermediate II to ammonolysis reagent is 1:2.5~7.0; the temperature for heating the ammonolysis reaction is 60~80℃ and the reaction time is 6~8 h; solvent C is selected from at least one of water, methanol, ethanol, acetonitrile, and tetrahydrofuran; the base is selected from any one of lithium hydroxide, sodium hydroxide, and potassium hydroxide, and the molar ratio of intermediate II to base is 1:1.1~4.0; the temperature for ester hydrolysis reaction is 20~30℃ and the reaction time is 2~4 h.

[0019] Further, in step 3): solvent D is selected from at least one of toluene, acetonitrile, dichloromethane, acetone, ethanol, and dioxane; the condensing agent is selected from N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (HATU), benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). Any one of I); the molar ratio of intermediate III to condensing agent is 1:1.1~1.5; the base is selected from at least one of triethylamine and N,N-diisopropylethylamine (DIPEA); the molar ratio of intermediate III to base is 1:1~3; the molar ratio of intermediate III to cyclopropionic acid is 1:1.1~1.5; the temperature of the dropwise addition of intermediate III is controlled at 10~15℃; the temperature of the amide condensation reaction is 20~40℃ and the holding time is 4~10 h.

[0020] Further, in step 4): solvent E is selected from at least one of methanol, ethanol, acetonitrile, tetrahydrofuran, acetone, and N-methylpyrrolidone; condensing agent is selected from N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (HATU), benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and 1-hydroxy The reaction mixture contains at least one of benzotriazole (HOBt); the molar ratio of intermediate IV to condensing agent is 1:0.4~2.2; the base is selected from at least one of triethylamine, N,N-diisopropylethylamine (DIPEA), N-methylimidazolium (NMI), and N-methylmorpholine; the molar ratio of intermediate IV to base is 1:0.6~5; the molar ratio of intermediate IV to deuterated methylamine hydrochloride is 1:1.1~1.5; the condensation reaction is carried out at a temperature of 30~50℃ and a reaction time of 1~4 h.

[0021] The beneficial effects of this invention are as follows: 1. This application innovatively designs a concise four-step process route for the preparation of deuterated colescitinib: nucleophilic substitution, ammonolysis / hydrolysis, amide condensation, and targeted condensation. Compared with existing synthetic methods, this effectively shortens the synthetic path and simplifies the production process. Each reaction adopts a highly selective reaction system, reducing side reactions. The intermediates are safe, stable, and easy to separate and purify. The process has good reproducibility, and the total yield of the final product is increased to over 85%, which is far higher than the existing technology level. Furthermore, this application uses methyl 4,6-dichloropyridazine-3-carboxylate and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline as starting materials. The raw materials are readily available and cost-controllable, reducing the cost waste caused by raw material procurement and loss from the source, and significantly improving production efficiency and economic benefits. 2. Addressing the shortcomings of existing technologies that rely on the Buchwald-Hartwig palladium-catalyzed coupling reaction, this application innovatively employs a highly selective nucleophilic substitution reaction to construct key carbon-nitrogen bonds, completely eliminating the use of precious metal catalysts. This not only saves on the procurement costs of expensive catalysts but also avoids product quality issues and environmental pollution caused by heavy metal residues from the source. It eliminates the need for cumbersome post-processing steps for heavy metal removal, ensuring that the active pharmaceutical ingredient meets pharmaceutical standards. Furthermore, this application eliminates the highly exothermic and safety-risk diazotization reaction and the highly polluting halogenation reaction found in existing technologies. It avoids the formation of unstable diazonium salt intermediates, the release of nitrogen-containing toxic gases, and the use of highly toxic halogenation reagents, significantly reducing the generation of pollutants such as high-salt wastewater and toxic exhaust gases. This greatly improves the safety and environmental friendliness of the process, making it more suitable for large-scale industrial production. 3. This application selects 4,6-dichloropyridazine-3-carboxylic acid methyl ester as the starting material, replacing the easily degradable trichloro intermediate or the chemically unstable diazonium salt intermediate in the prior art. This avoids yield fluctuations and safety risks caused by intermediate degradation, significantly improves process safety and controllability and scale-up compatibility, and is more suitable for large-scale industrial production. In addition, this application adjusts the timing of the deuteration reagent use, using expensive deuterated methylamine hydrochloride in the final targeted condensation step. Compared with the high loss caused by the large amount of deuteration reagent used in the early stage of the reaction in the prior art, this application significantly reduces the amount and loss rate of deuteration reagent, and significantly improves cost economy. 4. The preparation method disclosed in this application has mild reaction conditions in each step, which does not require the strict low temperature and strong exothermic control required for the diazotization reaction in the prior art, nor does it require the harsh high temperature reaction conditions. The reaction temperature is controlled within the conventional range, resulting in lower energy consumption and simple and easy operation. At the same time, the post-processing is simplified, eliminating the need for complex separation and purification equipment and processes, reducing the requirements for production equipment and operators, significantly lowering the threshold for industrial production, and facilitating large-scale production. 5. This application effectively reduces the generation and residue of byproducts through the design of a highly selective reaction system, the selection of stable intermediates, and a simplified post-processing process. The final deuterated oxalixitinib product has a purity of ≥99.8%, which is far higher than the purity level of existing technology products. Moreover, the product quality is stable with small batch-to-batch differences, which can provide a high-quality raw material guarantee for subsequent formulation production and further improve the safety and reliability of the drug in clinical applications. Attached Figure Description

[0022] Figure 1 This is the 1H NMR spectrum of deuterated celexitinib prepared in Example 1; Figure 2 This is the carbon NMR spectrum of deuterated celexitinib prepared in Example 1; Figure 3 This is the mass spectrum of deuterated celexitinib prepared in Example 1; Figure 4 This is a liquid chromatogram of deuterated celexitinib prepared in Example 1. Detailed Implementation

[0023] To enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be further described below in conjunction with the accompanying drawings and embodiments.

[0024] Example 1

[0025] This embodiment discloses a method for preparing deuterated celexitinib, and the overall preparation route is as follows:

[0026]

[0027] The specific preparation steps are as follows:

[0028] 1) Synthesis of intermediate II

[0029] In a four-necked reaction flask equipped with a thermometer and a mechanical stirrer, nitrogen gas was introduced to replace the air in the flask and maintain a nitrogen protective atmosphere. First, methyl 4,6-dichloropyridazine-3-carboxylate (compound I, 60 g, 0.290 mol) and 300 mL of isopropanol were added and stirred until completely dissolved. Then, 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (65.1 g, 0.319 mol) and dipotassium hydrogen phosphate (55.5 g, 0.319 mol) were added sequentially. After thorough stirring, the mixture was heated to 60 °C and maintained at this temperature for 24 h. After the reaction was complete, the mixture was cooled to room temperature, and 1200 mL of water was added to the system. The mixture was stirred for 8 h to allow crystallization. After filtration, the filter cake was dried to obtain 103.2 g of a pale yellow solid, which was intermediate II, with a yield of 95.1% and a purity of 98.39%.

[0030] 2) Synthesis of intermediate III

[0031] In a four-necked reaction flask equipped with a thermometer and stirrer, intermediate II (100 g, 0.267 mol) and 300 mL of dimethyl sulfoxide (DMSO) were first added. After stirring until the materials were completely dissolved, concentrated ammonia (133.5 g, 1.068 mol) was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 80°C, and the reaction was kept in a sealed environment for 6 h. After the reaction was confirmed to be complete by central monitoring, the mixture was cooled to room temperature, and dichloromethane was added to the reaction solution for extraction by stirring. The reaction solution was then washed twice with deionized water, allowed to stand for separation, and the organic phase was retained. The organic phase was concentrated to dryness under reduced pressure, and the residual oily substance was dissolved in 200 mL of ethanol by stirring. Then, 10% sodium hydroxide aqueous solution (215 g, 0.534 mol) was added to the system, and the reaction was carried out at 25°C for 2 h. After the reaction was confirmed to be complete by central monitoring, the ethanol was removed by concentration under reduced pressure, and 3 N dilute hydrochloric acid was added dropwise to the residue to adjust the pH to 5. The mixture was cooled to 5°C and stirred for crystallization for 4 h. After filtration, the filter cake was dried to obtain 77.41 g of pale yellow solid. g, which is intermediate III, has a yield of 85.6% and a purity of 97.4%.

[0032] 3) Synthesis of intermediate IV

[0033] In a four-necked reaction flask equipped with a thermometer and stirrer, cyclopropionic acid (13.87 g, 0.161 mol), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU, 61.1 g, 0.161 mol), N,N-dimethylethylamine (20.8 g, 0.284 mol), and 500 mL of toluene were added. After stirring until homogeneous, the temperature was maintained at 10°C, and a toluene solution (100 mL) of intermediate III (50 g, 0.146 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to 30°C and maintained for 4 h. After the reaction was confirmed to be complete by central monitoring, the mixture was cooled to room temperature, and the insoluble matter in the system was filtered off. Then, 1 N dilute hydrochloric acid aqueous solution was slowly added dropwise to quench the reaction, followed by concentration under reduced pressure to remove toluene from the system. 500 mL of deionized water was added to the remaining aqueous phase, and the mixture was stirred to induce crystallization for 16 h. After filtration, the filter cake was dried to obtain 54.88 g of pale yellow solid. g, or intermediate IV, yield 91.5%, purity 98.3%.

[0034] 4) Synthesis of deuterocelexitinib (compound V)

[0035] In a four-necked reaction flask equipped with a thermometer and stirrer, 120 mL of N-methylpyrrolidone (NMP), N-methylimidazole (NMI, 8.42 g, 0.103 mol), and 120 mL of acetonitrile were added. Under stirring, intermediate IV (60 g, 0.147 mol) and deuterated methylamine hydrochloride (H2N-CD3·HCl, 12.4 g, 0.176 mol) were added. After stirring until homogeneous and purging with nitrogen three times, the mixture was heated to 50°C. 1-hydroxybenzotriazole (HOBt, 9.9 g, 0.074 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 39.5 g, 0.206 mol) were added. The reaction was maintained at this temperature for 1 h. After confirming the reaction was complete by monitoring, the mixture was cooled to room temperature. 1000 mL of deionized water was added to the reaction solution and stirred to induce crystallization. h. After filtration and drying, 54.25 g of a light yellow solid was obtained, which was deuterocolicidinib, with a yield of 87% and a purity of 99.9%.

[0036] NMR data: 1 H NMR (DMSO-d6, 500 MHz): δ 11.32 (s, 1H), 10.99 (s, 1H), 9.13 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.66 (dd, 1H, J = 1.5, 7.5 Hz), 7.52 (dd, 1H, J = 1.5, 7.5 Hz), 7.27 (t, 1H, J = 8.0 Hz), 3.95 (s, 3H), 3.74(s, 3H), 2.09 (p, 1H, J = 6.0 Hz), 0.83 (d, 4H, J = 6.0 Hz). 13 C NMR (DMSO-d6,125 MHz): δ 173.6, 166.5, 158.9, 155.8, 150.6, 145.0, 144.7, 135.0, 132.5,126.2, 126.1, 124.2, 122.7, 96.7, 61.1, 35.9, 25.2(m, CD3), 14.4, 8.0 (2C).

[0037] Mass spectrometry data: HRMS m / z: 426.2089 [M+H] + .

[0038] The 1H NMR spectrum, 1C NMR spectrum, mass spectrum, and liquid chromatogram of the product deuterocelexitinib prepared in this embodiment are shown in the figure below. Figures 1 to 4The “DKL” in the attached diagram is the abbreviation for deuterocelecitinib.

[0039] Example 2

[0040] 1) Synthesis of intermediate II

[0041] In a four-necked reaction flask equipped with a thermometer and a mechanical stirrer, nitrogen was introduced to replace the air in the flask and maintain a nitrogen protective atmosphere. First, methyl 4,6-dichloropyridazine-3-carboxylate (compound I, 60 g, 0.290 mol) and 300 mL of acetonitrile were added. After stirring until the materials were completely dissolved, 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (71.1 g, 0.348 mol) and sodium carbonate (9.2 g, 0.087 mol) were added sequentially. After stirring until homogeneous, the mixture was heated to 55°C and maintained at this temperature for 18 h. After the reaction was complete, the mixture was cooled to room temperature, and 1200 mL of water was added to the system. The mixture was stirred for 8 h to allow crystallization. After filtration, the filter cake was dried to obtain 98.6 g of a pale yellow solid, which was intermediate II, with a yield of 90.8% and a purity of 97.89%.

[0042] 2) Synthesis of intermediate III

[0043] In a four-necked reaction flask equipped with a thermometer and stirrer, intermediate II (100 g, 0.267 mol) and 100 mL of methanol were first added. After stirring until the material was completely dissolved, 190 mL of ammonia / methanol solution (7 N, 1.335 mol) was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 65°C, and the reaction was kept in a sealed environment for 6 h. After the reaction was confirmed to be complete by central monitoring, the mixture was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. Dichloromethane was added to the residue and stirred to dissolve it. The residue was then washed twice with deionized water, allowed to stand for separation, and the organic phase was retained. The organic phase was concentrated to dryness under reduced pressure, and the resulting oily substance was dissolved in 200 mL of methanol. Then, 10% sodium hydroxide aqueous solution (320 g, 0.801 mol) was slowly added to the system, and the reaction was carried out at 25°C for 4 h. After the reaction was confirmed to be complete by central monitoring, 3 N dilute hydrochloric acid was added dropwise to adjust the pH to 5, and the mixture was cooled to 5°C and stirred to crystallize for 5 h. The mixture was then filtered, and the filter cake was washed and dried to obtain 84.6 g of pale yellow solid. g, which is intermediate III, has a yield of 92.9% and a purity of 97.8%.

[0044] 3) Synthesis of intermediate IV

[0045] In a four-necked reaction flask equipped with a thermometer and stirrer, cyclopropionic acid (13.87 g, 0.161 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 32.4 g, 0.169 mol), triethylamine (19.5 g, 0.193 mol), and 500 mL of acetonitrile were added. After stirring until homogeneous, the temperature was maintained at 10°C, and 100 mL of an acetonitrile solution of intermediate III (50 g, 0.146 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to 30°C and maintained for 8 h. After confirming the completion of the reaction by monitoring, the mixture was cooled to room temperature, and the insoluble matter in the system was filtered off. Then, 1 N dilute hydrochloric acid aqueous solution was slowly added dropwise to quench the reaction, followed by concentration under reduced pressure to remove the acetonitrile. 500 mL of deionized water was added to the remaining aqueous phase, and the mixture was stirred to induce crystallization for 18 h. After filtration, the filter cake was dried to obtain 52.6 g of pale yellow solid. g, or intermediate IV, yield 87.7%, purity 98.9%.

[0046] 4) Synthesis of deuterocelexitinib (compound V)

[0047] In a four-necked reaction flask equipped with a thermometer and stirrer, 120 mL of NMP, N,N-diisopropylethylamine (DIPEA, 13.3 g, 0.103 mol), and 120 mL of acetonitrile were first added. Under stirring, intermediate IV (60 g, 0.147 mol) and deuterated methylamine hydrochloride (H2N-CD3·HCl, 12.4 g, 0.176 mol) were added. After stirring until homogeneous and purging with nitrogen three times, the mixture was heated to 30°C. HOBt (8.0 g, 0.059 mol) and EDCI (47.9 g, 0.250 mol) were added, and the mixture was kept at this temperature and stirred for 3 h. After confirming the completeness of the reaction by monitoring, the mixture was cooled to room temperature. 1000 mL of deionized water was added to the reaction solution, and the mixture was stirred to crystallize for 6 h. The mixture was then filtered, and the filter cake was dried to obtain 55.6 g of a light yellow solid, which was deuterated colicitinib, with a yield of 89.2% and a purity of 99.8%.

[0048] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. However, the above description is merely a specific embodiment of the present invention, and the technical features of the present invention are not limited thereto. Any other embodiments derived by those skilled in the art without departing from the technical solution of the present invention should be covered within the scope of the present invention.

Claims

1. A method for preparing deuterocelexitinib, characterized in that, The preparation route is as follows: ； The specific steps are as follows: 1) Compound I and 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline were added to solvent A, stirred to dissolve, and then a base reagent was added. The mixture was heated under an inert atmosphere to carry out a nucleophilic substitution reaction to obtain intermediate II. 2) Dissolve intermediate II in solvent B, add ammonolysis reagent, and heat to carry out ammonolysis reaction to replace the chlorine atom on the pyridazine ring. Dissolve the ammonolysis product in solvent C, add an aqueous solution of alkali to carry out ester hydrolysis reaction to obtain intermediate III. 3) Add cyclopropionic acid, condensing agent and base to solvent D, stir evenly, and then add solvent D solution of intermediate III dropwise under controlled temperature. After the addition is complete, raise the temperature to carry out amide condensation reaction to obtain intermediate IV. 4) Dissolve intermediate IV in solvent E, and under the action of alkali and condensing agent, react with deuterated methylamine hydrochloride in an inert atmosphere to obtain the target product deuterocelexitinib.

2. The method for preparing deuterated celexitinib as described in claim 1, characterized in that, In step 1): Solvent A is selected from at least one of water, dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, methyl ethyl ketone, acetonitrile, and isopropanol; The heating reaction temperature is 50~100℃, and the reaction time is 16~24 h; The alkaline reagent is selected from any one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, dipotassium hydrogen phosphate, and potassium acetate. The molar ratio of compound I to 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline is 1:1.1~1.5; The molar ratio of compound I to the base reagent is 1:0.3~2.

0.

3. The method for preparing deuterated celexitinib as described in claim 1, characterized in that, In step 2): Solvent B is selected from at least one of dimethyl sulfoxide, dimethylformamide, dioxane, water, methanol, and ethanol; The ammonolysis reagent is selected from any one of concentrated ammonia water, ammonia / methanol solution, or ammonia / ethanol solution; The molar ratio of intermediate II to ammonolysis reagent is 1:2.5~7.0; The ammonolysis reaction is carried out at a temperature of 60-80℃ for a reaction time of 6-8 hours. Solvent C is selected from at least one of water, methanol, ethanol, acetonitrile, and tetrahydrofuran; The alkali is selected from any one of lithium hydroxide, sodium hydroxide, and potassium hydroxide; The molar ratio of intermediate II to base is 1:1.1~4.0; The temperature for the ester hydrolysis reaction is 20~30℃ and the reaction time is 2~4 h.

4. The method for preparing deuterated celexitinib as described in claim 1, characterized in that, In step 3): Solvent D is selected from at least one of toluene, acetonitrile, dichloromethane, acetone, ethanol, and dioxane; The condensing agent is selected from any one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; The molar ratio of intermediate III to condensing agent is 1:1.1~1.5; The base is selected from at least one of triethylamine and N,N-diisopropylethylamine; The molar ratio of intermediate III to base is 1:1~3; The molar ratio of intermediate III to cyclopropionic acid is 1:1.1~1.5; The temperature during the dropwise addition of intermediate III was controlled at 10~15℃; The temperature for the amide condensation reaction is 20~40℃, and the holding time is 4~10 h.

5. The method for preparing deuterated celexitinib as described in claim 1, characterized in that, In step 4): Solvent E is selected from at least one of methanol, ethanol, acetonitrile, tetrahydrofuran, acetone, and N-methylpyrrolidone; The condensing agent is selected from at least one of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole; The molar ratio of intermediate IV to condensing agent is 1:0.4~2.2; The base is selected from at least one of triethylamine, N,N-diisopropylethylamine, N-methylimidazolium, and N-methylmorpholine; The molar ratio of intermediate IV to base is 1:0.6~5; The molar ratio of intermediate IV to deuterated methylamine hydrochloride is 1:1.1~1.5; The condensation reaction is carried out at a temperature of 30~50℃ and a reaction time of 1~4 h.

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