Process for the preparation of deuterated cediranib and intermediates thereof

Abstract

This invention discloses a method for synthesizing deuterated celexitinib and its intermediates. The intermediate 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline is prepared from 2,3-dichloronitrobenzene via etherification and nitrification to obtain 2-methoxy-3-nitrobenzene nitrile; then, it reacts with ammonium chloride under alkaline conditions to generate 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole; finally, the target product is obtained via catalytic reduction. Another intermediate... N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide was prepared by bromination of 3-amino-6-chloropyridazine to obtain 3-amino-4-bromo-6-chloropyridazine. Then, under low temperature and in the presence of acid, it reacted with sodium nitrite to form a diazonium salt. Then, a cyanate reagent was added to generate 4-bromo-6-chloro-3-pyridazine formonitrile. Finally, the target product was obtained by substitution reaction. The above intermediate was subjected to Buchwald-Hartwig coupling reaction, nitrile hydrolysis, and condensation to obtain deuterated celexitinib.

Description

Technical Field

[0001] This invention relates to the field of organic drug synthesis, and more specifically, to a method for synthesizing a deuterated cecoxitinib intermediate, and further to a method for synthesizing deuterated cecoxitinib. Background Technology

[0002] Deuterocelexitinib is a novel anti-inflammatory drug, a TYK2 allosteric inhibitor, with high selectivity and oral bioavailability, used to treat plaque psoriasis.

[0003] Patent documents CN110475774A, CN110914260A, and CN112236425A disclose the preparation method, specifically starting from compound 28, directly cyclizing the cyano group to form methyltriazole, followed by nitration and reduction to obtain compound 7. The synthetic route is as follows:

[0004] The synthetic route has the following disadvantages: the raw material cost is high, the nitration reaction uses strong acid, both the hydrogenation and nitration reactions require special equipment, the equipment requirements are stringent, there is a lot of wastewater after treatment, the cost of using Pd / C is high, it is easy to ignite, and it is not conducive to industrial production.

[0005] The preparation of another compound, 22-02, started from compound 41, followed by treatment with tributylphosphine, cyclization with acetic acid to obtain compound 8, compound 8 in the presence of phosphorus oxychloride to obtain pyridazine cyclochlorinated compound 18, and hydrolysis of compound 18 in the presence of DIPEA and lithium bromide to obtain compound 22-02. The synthetic route is as follows:

[0006] The synthetic route has the following drawbacks: it generates impurities that are difficult to purify; and the raw material benzenesulfonyl azide used has the risk of explosion, which is not conducive to industrial production.

[0007] Compound 7 and compound 22-02 were reacted in the presence of the Lewis acid zinc acetate and the organic solvent isopropanol to give compound 23-02. Compound 23-02 and compound 14 were coupled by palladium catalysis to prepare compound 24-02. Compound 24-02 was decarboxylated under EDCI / HOBT conditions to give deuterated celexitinib. The synthetic route is as follows:

[0008] The synthetic route has the following drawbacks: the reaction is highly reactive and contains many impurities, making it difficult to control. It also requires sophisticated equipment, resulting in complex operation and post-processing, which is not conducive to industrial production.

[0009] Therefore, there is a need to develop a method for preparing deuterocelexitinib with high yield, high purity, safety, low cost, and ease of industrial production. Summary of the Invention

[0010] One of the objectives of this invention is to provide a novel method for synthesizing deuterated celexitinib intermediates, in order to solve the problems of low yield, high cost, complex post-processing, and unfavorable conditions for industrial production in existing methods for synthesizing deuterated celexitinib intermediates.

[0011] To achieve the above objectives, a first aspect of the present invention provides a novel method for synthesizing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, the method comprising the following steps: (1) In a solvent and under the action of alkali, 2,3-dichloronitrobenzene is etherified to give 1-chloro-2-methoxy-3-nitrobenzene; (2) 1-Chloro-2-methoxy-3-nitrobenzene is reacted with cyanide in the presence of a cyaniding agent to produce 2-methoxy-3-nitrobenzene nitrile; (3) 2-Methoxy-3-nitrobenzonitrile reacts with ammonium chloride under the action of a base to generate 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole; (4) 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole is catalytically reduced in the presence of a reducing agent and a catalyst to obtain 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline; The process route is shown below: .

[0012] Preferably, the etherification reaction method and conditions described in step (1) are conventional methods and conditions in the art. The solvent is preferably an alcohol solvent, specifically methanol; the base is sodium methoxide; and the molar ratio of the base to 2,3-dichloronitrobenzene is 1:1 to 3:1.

[0013] Preferably, the cyaniding agent in step (2) is cuprous cyanide or potassium ferrocyanide; the molar ratio of the cyaniding agent to 1-chloro-2-methoxy-3-nitrobenzene is 1:1 to 1:2; the cyanidation reaction is carried out in a solvent, which is any one of N,N-dimethylformamide, N-methylpyrrolidone, nitrobenzene or pyridine.

[0014] Preferably, the base mentioned in step (3) is one or more of sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, sodium hydride, potassium carbonate, sodium carbonate, potassium phosphate, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, pyridine, imidazole, tetrabutylammonium fluoride, 2,6-dimethylpyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene; the molar ratio of the base to 2-methoxy-3-nitrobenzonitrile is 2~5:1.

[0015] Preferably, the reaction in step (4) is carried out in a solvent, wherein the solvent is methanol or ethanol, the reducing agent is hydrazine hydrate, and the catalyst is ferric chloride and activated carbon.

[0016] The raw materials and reagents used in the above preparation method are all known compounds in the prior art and can be obtained commercially.

[0017] A second aspect of the present invention also provides a novel method for synthesizing N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide, the method comprising the following steps: (5) In a solvent and in the presence of a base, 3-amino-6-chloropyridazine undergoes a bromination reaction with a brominating reagent to prepare 3-amino-4-bromo-6-chloropyridazine; (6) Under low temperature conditions and in the presence of acid, 3-amino-4-bromo-6-chloropyridazine reacts with sodium nitrite to form a diazonium salt, and then cyanate reagent is added to form 4-bromo-6-chloro-3-pyridazine formonitrile; (7) N-(5-bromo-6-chloro-3-pyridazine carboxynitrile) was prepared by substitution reaction in the presence of an aprotic solvent; The process route is shown below: .

[0018] Preferably, the brominating agent in step (5) is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromo-succinimide, or bromine, the base is sodium acetate or sodium bicarbonate, and the solvent is an alcohol solvent, such as methanol or ethanol.

[0019] Preferably, the low temperature in step (6) is ≤5 ℃, the acid is any one of acetic acid, sulfuric acid, hydrochloric acid or hydrobromic acid, and the cyanate reagent is tert-butyl isocyanate.

[0020] Preferably, the aprotic solvent in step (7) is tetrahydrofuran or 1,4-dioxane.

[0021] Taking advantage of the unique structure of pyridazines and the high reactivity of N-ortho-substituted halogens, they can readily react without the need for bases or catalysts.

[0022] This invention also provides a novel method for synthesizing deuterocelexitinib, the method comprising the following steps: (8) Compound A was prepared by Buchwald-Hartwig coupling reaction of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline and N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide obtained by the above synthesis method; (9) Compound A is hydrolyzed with nitrile to prepare carboxylic acid compound B; (10) Compound B reacts with deuterated methylamine hydrochloride under alkaline and solvent conditions with condensing agent and activator to generate deuterated colexitinib; The process route is shown below: .

[0023] Preferably, the Buchwald-Hartwig coupling reaction in step (8) is carried out in the presence of a palladium catalyst and a base. The palladium catalyst is any one of palladium acetate, palladium chloride, tetra(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, tris(dibenzylacetone)dipalladium, allyl palladium(II) dimer, and palladium acetylacetonate. The base is any one of sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, triethylamine, potassium tert-butoxide, lithium carbonate, potassium acetate, and N,N-diisopropylamine. The uchwald-Hartwig coupling reaction can also incorporate a phosphine ligand, which can be any one of triphenylphosphine, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl. The solvent can be any one of toluene, xylene, tetrahydrofuran, DME, 1,4-dioxane, N,N-dimethylformamide, NMP, dimethyl sulfoxide, or acetonitrile. The reaction temperature is generally between 60 and 120°C.

[0024] Preferably, the nitrile hydrolysis in step (9) is acid hydrolysis, which is carried out using concentrated sulfuric acid in water or water-ethanol solvent. In order to ensure complete hydrolysis, sodium nitrite can be added to promote the hydrolysis reaction.

[0025] Preferably, the condensing agent in step (10) is any one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); the activator is any one of 4-N,N-dimethylpyridine (DMAP) or 1-hydroxybenzotriazole (HOBt); to improve the condensation yield, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt) are used together; a base is added in the condensation reaction, and commonly used bases are N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, and benzotriazole-1-yl-oxytripyrrolidine hexafluorophosphate; the amount of base added is 2 to 3 equivalents of compound B; the solvent is dichloromethane or N,N-dimethylformamide.

[0026] By applying the technical solution of this invention, the use of expensive raw materials is avoided, thus reducing costs; and the post-processing is simple, which is conducive to industrial-scale production. Detailed Implementation

[0027] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0028] Example 1 Synthesis of 1-chloro-2-methoxy-3-nitrobenzene

[0029] 34.8 g of sodium methoxide (625 mmol, 1.2 eq) was dissolved in 680 mL of methanol at room temperature to prepare a solution for later use. 100 g of 2,3-dichloronitrobenzene (520.8 mmol) and 700 mL of methanol were added to a 2000 mL three-necked reaction flask. The mixture was purged with nitrogen three times and stirred at room temperature until dissolved. The solution was then cooled to 0–5 °C, and the methanol solution of sodium methoxide was slowly added dropwise, maintaining the temperature below 20 °C. After the addition was complete, the reaction was carried out at 50 °C for 16 h. Gas chromatography confirmed complete reaction. The solution was concentrated to 1 / 3 volume under reduced pressure, and 1 L of water was added. The solution was extracted with 800 mL of ethyl acetate, and the aqueous phase was further extracted with 200 mL of ethyl acetate. The organic phase was concentrated, and 1000 mL of toluene and 10 g of activated carbon were added for decolorization at 80 °C for 30 min. The solution was hot-filtered, and the filtrate was concentrated to obtain crude 1-chloro-2-methoxy-3-nitrobenzene. Then, 500 mL of... Hexane was slurried, filtered, and the filter cake was dried under vacuum to obtain 90 g of pure 1-chloro-2-methoxy-3-nitrobenzene as a yellow solid, with a yield of 92%.

[0030] Its mass spectrometry data are shown below: MS m / z: 189.1 [M+H]+ .

[0031] Example 2 Synthesis of 2-methoxy-3-nitrobenzonitrile

[0032] 75 g of 1-chloro-2-methoxy-3-nitrobenzene (400 mmol) was dissolved in 400 mL of N-methylpyrrolidone, and then 53.8 g of cuprous cyanide (600 mmol, 1.5 eq) was added. The mixture was purged with nitrogen three times and then heated to 190 °C for 6 h. The reaction was confirmed to be complete by HPLC. The reaction solution was cooled to room temperature, 1.5 L of water was added, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was dissolved in 500 mL of ethyl acetate, washed three times with saturated ammonium chloride aqueous solution, passed through a rapid silica gel column, and concentrated to give 59.1 g of 2-methoxy-3-nitrobenzene nitrile as a pale yellow solid, with a yield of 83%.

[0033] Its mass spectrometry data are shown below: MS m / z: 179.02 [M+H] + .

[0034] Example 3 Synthesis of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole

[0035] 48.5 g of sodium methoxide (898 mmol, 2.0 eq) was dissolved in 800 mL of methanol at room temperature to prepare a solution for later use. 80 g of 2-methoxy-3-nitrobenzonitrile (449 mmol) was dissolved in 400 mL of methanol. The mixture was purged with nitrogen three times, and the reaction solution was cooled to 10 °C. Then, the methanol solution of sodium methoxide was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. Then, 72.1 g of ammonium chloride (1.35 mol, 3.0 eq) was added, and the reaction was allowed to continue at room temperature for another 12 h. The reaction was confirmed to be complete by HPLC. The solution was concentrated under reduced pressure, and the solid was dispersed in ethanol and slurryed. The mixture was filtered, the filtrate was collected, and the solvent was concentrated to obtain 102 g of intermediate, a white solid, with a yield of 98.1%. 102 g of the intermediate was dissolved in 500 mL of DMF, then 60.4 g of CuCl2 (449 mmol, 1 eq) and 95.3 g of K3PO4 (449 mmol, 1 eq) were added. The reaction mixture was heated to 100 °C and stirred for 16 h. After the reaction was complete, 1500 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 500 mL). The organic phase was dried over magnesium sulfate and concentrated. The solution was then passed through a rapid silica gel column (hexane / ethyl acetate = 4 / 1) to give 75.7 g of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole as a pale yellow solid, in 72% yield.

[0036] Its 1H NMR spectrum data are shown below: 1 H-NMR (DMSO-d6, 400 MHz): δ 8.57 (s, 1H), 8.20-8.17(m, 1H), 8.05-8.02(m, 1H), 7.44-7.41(m, 1H), 3.98(s, 3H), 3.89(s, 3H). MS m / z: 235.1 [M+H] + .

[0037] Example 4 Synthesis of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0038] 110 g of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (469.6 mmol), 5.5 g of activated carbon, 5.5 g of ferric chloride, and 1000 mL of methanol were added to a 2000 mL three-necked reaction flask. The mixture was purged with nitrogen three times, then heated to 55 °C. 56.4 g (1.41 mol, 3 eq) of 80 wt% hydrazine hydrate was slowly added dropwise over approximately 1 h. After the addition was complete, the mixture was reacted at 50 °C for 5 h. HPLC analysis confirmed the reaction was complete. The reaction solution was cooled to room temperature, dissolved in 500 mL of ethyl acetate, filtered, concentrated, and recrystallized in 300 mL of toluene. The mixture was filtered again, the filter cake was washed with toluene, and dried under vacuum to obtain 91.1 g of pure 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline as a pale yellow solid, with a yield of 95%.

[0039] Its 1H NMR spectrum data are shown below: 1 H-NMR (DMSO-d6, 400 MHz): δ 8.52 (s, 1H) ,7.21-7.17(m, 1H) ,7.01-6.98(m, 1H) ,6.82-6.79(m, 1H) , 4.80(s, 2H) , 3.99(s,3H) , 3.75(s,3H). MS m / z: 205.1 [M+H] + .

[0040] Example 5 Synthesis of 3-amino-4-bromo-6-chloropyridazine

[0041] 50 g of 3-amino-6-chloropyridazine (386.0 mmol), 48.6 g of sodium bicarbonate (579.0 mmol, 1.5 eq), and 500 mL of methanol were added to a 1 L three-necked reaction flask. The mixture was purged with nitrogen three times and then cooled to -20 °C. 58.6 g of bromine (80%, 366.7 mol, 0.95 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred overnight. The reaction was confirmed to be complete by HPLC. The reaction solution was poured into a 500 g ice-water mixture, and the reaction was quenched with sodium sulfite. The mixture was filtered, the filter cake was washed with water, and dried to give 65.2 g of 3-amino-4-bromo-6-chloropyridazine as a yellow solid, with a yield of 81%.

[0042] Its mass spectrometry data are shown below: MS m / z: 209.2 [M+H] + .

[0043] Example 6 Synthesis of 4-bromo-6-chloro-3-pyridazine carboxynitrile

[0044] 65 g of 3-amino-4-bromo-6-chloropyridazine (311.8 mmol) and 350 mL of acetic acid were added to a 1 L three-necked reaction flask. The mixture was purged with nitrogen three times, then heated to 80 °C with stirring to dissolve. The solution was then slowly cooled to 0–5 °C to obtain a suspension. 60 mL of sodium nitrite aqueous solution (28.0 g, 405.4 mmol, 1.3 eq) was slowly added dropwise to the suspension, maintaining the temperature below 10 °C. After the addition was complete, stirring was continued for 1–2 h until the solution was clear. Then, 64.8 g of tert-butyl isocyanate (779.5 mmol, 2.5 eq) was added dropwise over approximately 3 h. The reaction was allowed to proceed overnight at room temperature with stirring. Thin-layer chromatography (TLC) was used to monitor the reaction completion. Finally, 1000 mL of water was added, and the solution was diluted with ethyl acetate (3 × 200 mL). Extracted by mL, the organic layer was dried with magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 45.6 g of 4-bromo-6-chloro-3-pyridazine carboxynitrile, a pale yellow solid, with a yield of 67%.

[0045] Its mass spectrometry data are shown below: MS m / z: 219.1 [M+H] + .

[0046] Example 7 Synthesis of N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide

[0047] 30 g of 4-bromo-6-chloro-3-pyridazine carboxynitrile (137.3 mmol) was dissolved in 300 mL of 1,4-dioxane, and then 14.0 g of cyclopropionamide (164.8 mmol) was added. The mixture was purged with nitrogen three times, and then heated to 60 °C with stirring for 16 h. After the reaction was completed by thin-layer chromatography (TLC), the reaction solution was cooled to room temperature and stirred for another 2–3 h. The mixture was filtered, the filter cake was washed with n-hexane, and dried to give 33 g of yellow solid N-(5-bromo-6-cyanopyridazine-3-yl)cyclopropane carboxamide, with a yield of 90%.

[0048] Its 1H NMR spectrum data are shown below: 1 H-NMR (DMSO-d6, 400 MHz): δ 8.47 (s, 1H), 2.02-1.92 (m, 1H), 0.99-0.32 (m, 4H). Example 8 Synthesis of Compound A

[0049] In a 500 mL reaction flask, 100 mL of toluene, 10 g of N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide (37.4 mmol, 1.0 eq), 7.3 g of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (35.6 mmol, 0.95 eq), 45 mg of Pd(OAc)2 (0.19 mmol, 0.5%), 118 mg of BINAP (0.19 mmol, 0.5%), and 7.8 g of K2CO3 (56.1 mmol, 1.5 eq) were added, and the mixture was heated at 120 °C for 12 h. After cooling to ambient temperature, 100 mL of water was added, followed by extraction with ethyl acetate, concentration, and column chromatography (V). 二氯甲烷 / V 甲醇 =20 / 1) Purification yielded 10.6 g of compound A, a yellow solid, in a yield of 76%.

[0050] Its mass spectrometry data are shown below: MS m / z: 391.2 [M+H] + .

[0051] Example 9 Synthesis of Compound B

[0052] 25 g of compound A (64.0 mmol) was dissolved in 300 mL of ethanol, and then 150 mL of sulfuric acid (50 wt%) was added. The mixture was purged with nitrogen three times, and then heated to 90 °C with stirring for 16 h. After the reaction was completed by thin-layer chromatography (TLC), the reaction solution was cooled to room temperature, 500 mL of water was added, and the pH was adjusted to neutral with 6 N sodium hydroxide aqueous solution. Then, dichloromethane was added for extraction, the organic phase was dried with magnesium sulfate, filtered, and concentrated to give 20.2 g of crude compound B as a pale yellow solid, with a yield of 77.2%.

[0053] Its 1H NMR spectrum data are shown below: 1H-NMR (DMSO-d6, 400HZ): δ 11.87 (s, 1H), 10.84 (s, 1H), 9.09(s, 1H), 8.63 (s, 1H), 8.01 (s, 1H), 7.47-7.38 (m, 1H), 7.29-7.20 (m, 2H) , 3.92 (s, 3H) , 3.74 (s, 3H) , 2.03-1.94 (m, 1H) , 1.00-0.38 (m, 4H) . Its mass spectrometry data are shown below: MS m / z: 432.1 [M+Na] + .

[0054] Example 10 Synthesis of Compound I

[0055] 8.8 g of compound B (21.5 mmol), 1.8 g of deuterated methylamine hydrochloride (25.8 mmol, 1.2 eq), 4.4 g of HOBT (32.3 mmol, 1.5 eq), 6.2 g of EDCI (32.3 mmol, 1.5 eq), 5.6 g of DIPEA (43.0 mmol, 2.0 eq), and 40 mL of DMF were added to a reaction flask. The mixture was purged with nitrogen three times and reacted at 20–30 °C for 24 h. The reaction was confirmed to be complete by HPLC. 200 mL of water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 6.5 g of compound I as a pale yellow solid, with a yield of 71%.

[0056] Its 1H NMR spectrum data are shown below: 1 H-NMR (DMSO-d6, 400HZ): δ 11.34 (s, 1H) ,10.97(s, 1H) , 9.11 (s, 1H) , 8.55 (s, 1H) , 8.10 (s, 1H) , 7.61-7.53 (m, 1H), 7.43-7.31 (m, 2H) , 3.93 (s, 3H) , 3.76 (s, 3H) , 2.06-1.97 (m, 1H) , 1.01-0.42 (m, 4H) . Its mass spectrometry data are shown below: MS m / z: 426.3 [M+H] + .

[0057] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, characterized in that, Includes the following steps: (1) In a solvent and under the action of alkali, 2,3-dichloronitrobenzene is etherified to give 1-chloro-2-methoxy-3-nitrobenzene; (2) 1-Chloro-2-methoxy-3-nitrobenzene was cyanided in the presence of a cyaniding agent to produce 2-methoxy-3-nitrobenzene nitrile; (3) 2-Methoxy-3-nitrobenzonitrile reacts with ammonium chloride in the presence of sodium methoxide to obtain an intermediate; the intermediate is reacted in DMF, CuCl2 and K3PO4 to generate 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole; (4) 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole is catalytically reduced in the presence of a reducing agent and a catalyst to yield 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline; the process route is shown below: 。 2. The synthesis method as described in claim 1, characterized in that, The solvent mentioned in step (1) is an alcohol solvent, specifically methanol; the base is sodium methoxide; and the molar ratio of the base to 2,3-dichloronitrobenzene is 1:1 to 3:

1.

3. The synthesis method as described in claim 1, characterized in that, The cyaniding reagent mentioned in step (2) is cuprous cyanide or potassium ferrocyanide; the molar ratio of the cyaniding reagent to 1-chloro-2-methoxy-3-nitrobenzene is 1:1 to 1:

2.

4. The synthesis method as described in claim 1, characterized in that, The molar ratio of sodium methoxide to 2-methoxy-3-nitrobenzonitrile in step (3) is 2~5:

1.

5. The synthesis method as described in claim 1, characterized in that, The reducing agent in step (4) is hydrazine hydrate, and the catalyst is ferric chloride and activated carbon.

6. A method for synthesizing N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide, characterized in that, Includes the following steps: (5) In a solvent and in the presence of a base, 3-amino-6-chloropyridazine undergoes a bromination reaction with a brominating reagent to prepare 3-amino-4-bromo-6-chloropyridazine; (6) Under low temperature conditions and in the presence of acid, 3-amino-4-bromo-6-chloropyridazine reacts with sodium nitrite to form a diazonium salt, and then cyanate reagent is added to form 4-bromo-6-chloro-3-pyridazine formonitrile; (7) N-(5-bromo-6-chloro-3-pyridazinonium)cyclopropaneformamide was prepared by substitution reaction in the presence of an aprotic solvent; the process route is shown below: 。 7. The synthesis method as described in claim 6, characterized in that, The brominating agent mentioned in step (5) is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), N-bromo-succinimide or bromine, the base is sodium acetate or sodium bicarbonate, and the solvent is an alcohol solvent.

8. The synthesis method as described in claim 6, characterized in that, The low temperature mentioned in step (6) is ≤5 ℃, the acid is any one of acetic acid, sulfuric acid, hydrochloric acid or hydrobromic acid, and the cyanate reagent is tert-butyl isocyanate.

9. A method for synthesizing deuterocelexitinib, characterized in that, Includes the following steps: (8) 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline is prepared by any one of the synthetic methods of claims 1 to 5, and N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide is prepared by any one of the synthetic methods of claims 6 to 8. Compound A is obtained by Buchwald–Hartwig coupling reaction of the prepared 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline and the prepared N-(5-bromo-6-cyanopyridazin-3-yl)cyclopropaneformamide. (9) Compound A is hydrolyzed with nitrile to prepare carboxylic acid compound B; (10) Compound B undergoes a condensation reaction with deuterated methylamine hydrochloride under alkaline and solvent conditions in the presence of a condensing agent and an activator to produce deuterated colescitinib; the process route is shown below: ； ； 。 10. The synthesis method according to claim 9, characterized in that, The Buchwald–Hartwig coupling reaction in step (8) is carried out in the presence of a palladium catalyst and a base. The palladium catalyst is any one of palladium acetate, palladium chloride, tetra(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(triphenylphosphine)palladium dichloride, tris(dibenzylacetone)dipalladium, allyl palladium(II) dimer, and palladium acetylacetonate. The base is any one of sodium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, triethylamine, potassium tert-butoxide, lithium carbonate, potassium acetate, and N,N-diisopropylamine. The Buchwald–Hartwig… The coupling reaction involves the addition of a phosphine ligand, which is any one of triphenylphosphine, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; the solvent is any one of toluene, xylene, tetrahydrofuran, DME, 1,4-dioxane, N,N-dimethylformamide, NMP, dimethyl sulfoxide, and acetonitrile; the reaction temperature is between 60 and 120°C.

11. The synthesis method as described in claim 9, characterized in that, The nitrile hydrolysis described in step (9) is an acid hydrolysis, which is carried out using concentrated sulfuric acid in water or water-ethanol solvent.

12. The synthesis method according to claim 11, characterized in that, Sodium nitrite is added during the acid hydrolysis described in step (9).

13. The synthesis method as described in claim 9, characterized in that, The condensing agent mentioned in step (10) is any one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); the activator is any one of 4-N,N-dimethylpyridine (DMAP) or 1-hydroxybenzotriazole (HOBt); the base is any one of N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, or benzotriazole-1-yl-oxytripyrrolidine hexafluorophosphate; the amount of base added is 2 to 3 equivalents of compound B; and the solvent is dichloromethane or N,N-dimethylformamide.

14. The synthesis method according to claim 13, characterized in that, The condensing agent in step (10) is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and the activator is 1-hydroxybenzotriazole (HOBt).

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