Method for preparing deucravacitinib and intermediates thereof

Abstract

Disclosed in the present invention are a method for synthesizing deucravacitinib and intermediates thereof. An intermediate 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline is prepared by subjecting 2,3-dichloronitrobenzene to an etherification reaction and a cyanation reaction to prepare 2-methoxy-3-nitrobenzonitrile; then reacting 2-methoxy-3-nitrobenzonitrile with ammonium chloride under the action of an alkali to generate 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole; and finally, carrying out a catalytic reduction reaction to obtain the target product. Another intermediate N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide is prepared by subjecting 3-amino-6-chloropyridazine to a bromination reaction to prepare 3-amino-4-bromo-6-chloropyridazine, then reacting 3-amino-4-bromo-6-chloropyridazine with sodium nitrite under low-temperature condition and in the presence of an acid to generate a diazonium salt, and then adding a cyanate reagent to generate 4-bromo-6-chloro-3-cyanopyridazine; and finally carrying out a substitution reaction to obtain a target product (I). Deucravacitinib is obtained by subjecting these intermediates to a Buchwald-Hartwig coupling reaction, carrying out nitrile hydrolysis, and carrying out condensation.

Description

Preparation method of deuterated lexitinib and its intermediates Technical Field

[0001] The present invention relates to the field of organic drug synthesis, and in particular to a method for synthesizing a deuterated corticosteroid intermediate and a method for synthesizing deuterated corticosteroid. Background Art

[0002] Deuterated lexitinib is a novel anti-inflammatory drug and an allosteric inhibitor of TYK2 with high potency, selectivity, and oral bioavailability for the treatment of plaque psoriasis.

[0003] Patent documents CN110475774A, CN110914260A, and CN112236425A disclose preparation methods thereof. Specifically, starting from compound 28, the cyano group is directly cyclized to form methyltriazole, which is then subjected to a nitration reaction and then reduced to obtain compound 7. The synthetic route is as follows:

[0004] This synthesis route has the following disadvantages: high raw material cost, strong acid is used in the nitration reaction, special equipment is required for both the hydrogenation reaction and the nitration reaction, the equipment requirements are stringent, a large amount of post-treatment wastewater is generated, the use of Pd / C is costly, and it is prone to ignition, which is not conducive to industrial production.

[0005] Another compound 22-02 was prepared from compound 41 by treatment with tributylphosphine and acetic acid ring closure to obtain compound 8. Compound 8 was then treated with phosphorus oxychloride to obtain pyrazine ring chlorinated compound 18. Compound 18 was hydrolyzed in the presence of DIPEA and lithium bromide to obtain compound 22-02. The synthetic route is as follows:

[0006] This synthetic route has the following disadvantages: impurities may be generated and difficult to purify; the raw material benzenesulfonyl azide used has the risk of explosion, which is not conducive to industrial production.

[0007] The above-mentioned compound 7 and compound 22-02 react in the presence of Lewis acid zinc acetate and organic solvent isopropanol to obtain compound 23-02. Compound 23-02 and compound 14 are coupled by palladium catalysis to obtain compound 24-02. Compound 24-02 is decarboxylated under EDCI / HOBT conditions to obtain deuterated lexitinib. The synthesis route is as follows:

[0008] This synthetic route has the following disadvantages: the reaction is highly active, contains many impurities, is difficult to control, and has high requirements for process equipment, resulting in complex operation and post-processing processes, which is not conducive to industrial production.

[0009] Therefore, it is necessary to develop a preparation method of deuterocelexin with high yield, high purity, safety, low cost and easy industrial production. Summary of the Invention

[0010] One of the purposes of the present invention is to provide a novel method for synthesizing a deuterated corticosteroid intermediate to solve the problems of low preparation yield, high cost, complex post-processing and unfavorable industrial production in existing methods for synthesizing deuterated corticosteroid intermediates.

[0011] In order to achieve the above object, the first aspect of the present invention provides a novel synthesis method of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, which comprises the following steps:

[0012] (1) In a solvent and under the action of a base, 2,3-dichloronitrobenzene undergoes an etherification reaction to obtain 1-chloro-2-methoxy-3-nitrobenzene;

[0013] (2) 1-Chloro-2-methoxy-3-nitrobenzene is subjected to cyanidation reaction in the presence of a cyaniding agent to prepare 2-methoxy-3-nitrobenzonitrile;

[0014] (3) 2-Methoxy-3-nitrobenzonitrile reacts with ammonium chloride in the presence of a base to generate 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole;

[0015] (4) 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole is subjected to catalytic reduction reaction 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;

[0016] The process route is as follows:

[0017]

[0018] Preferably, the method and conditions for the etherification reaction in step (1) are conventional methods and conditions in the art. The solvent is preferably an alcohol solvent, and the alcohol solvent is methanol; the base is sodium methoxide; and the molar ratio of the base to 2,3-dichloronitrobenzene is 1:1 to 3:1.

[0019] Preferably, the cyaniding reagent 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; the cyaniding reaction is carried out in a solvent, and the solvent is any one of N,N-dimethylformamide, N-methylpyrrolidone, nitrobenzene or pyridine.

[0020] Preferably, the base 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-lutidine, and 1,8-diazabicyclo[5.4.0]-7-undecene; and the molar ratio of the base to 2-methoxy-3-nitrobenzonitrile is 2 to 5:1.

[0021] 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.

[0022] The raw materials and reagents used in the above preparation method are all known compounds in the prior art and can be obtained commercially.

[0023] The second aspect of the present invention also provides a novel synthesis method of N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide, which comprises the following steps:

[0024] (5) In a solvent and in the presence of a base, 3-amino-6-chloropyridazine reacts with a brominating reagent to produce 3-amino-4-bromo-6-chloropyridazine;

[0025] (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 a cyanate reagent is added to generate 4-bromo-6-chloro-3-pyridazinecarbonitrile;

[0026] (7) 4-Bromo-6-chloro-3-pyridazinecarbonitrile is reacted in the presence of an aprotic solvent to prepare N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide;

[0027] The process route is as follows:

[0028]

[0029] Preferably, the bromination reagent 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.

[0030] Preferably, the low temperature in step (6) is a temperature ≤ 5°C, the acid is any one of acetic acid, sulfuric acid, hydrochloric acid or hydrobromic acid, and the cyanate reagent is tert-butyl isocyanate.

[0031] Preferably, the aprotic solvent in step (7) is tetrahydrofuran or 1,4-dioxane.

[0032] By utilizing the special structure of pyridazine and the high activity of N-ortho-substituted halogen, the reaction can easily occur without the need for base or catalyst.

[0033] The present invention also provides a novel method for synthesizing deuterated lexitinib, which comprises the following steps:

[0034] (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-cyanopyrazin-3-yl)cyclopropanecarboxamide prepared by the above-mentioned synthesis method;

[0035] (9) Compound A is hydrolyzed with nitrile to prepare carboxylic acid compound B;

[0036] (10) Compound B reacts with deuterated methylamine hydrochloride in the presence of a condensing agent and an activating agent under alkaline and solvent conditions to generate deuterated methylamine hydrochloride;

[0037] The process route is as follows:

[0038]

[0039] Preferably, the Buchwald–Hartwig coupling reaction in step (8) is carried out in the presence of a palladium catalyst and a base, wherein the palladium catalyst is any one of palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium, bistriphenylphosphine palladium dichloro, tris(dibenzylideneacetone)dipalladium, allylpalladium chloride (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; and the B The Uchwald–Hartwig coupling reaction can also include a phosphine ligand, optionally selected from triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl. The solvent can be 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.

[0040] Preferably, the nitrile hydrolysis in step (9) is acid hydrolysis, which is carried out using concentrated sulfuric acid in water or a water-ethanol solvent. In order to complete the hydrolysis, sodium nitrite can be added to promote the hydrolysis reaction.

[0041] Preferably, the condensing agent in step (10) is any one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); the activating agent is any one of 4-N,N-dimethylpyridine (DMAP) or 1-hydroxybenzotriazole (HOBt); in order to improve the condensation yield, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt) are used in combination; a base is added in the condensation reaction, and commonly used bases are N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, and benzotriazole-1-yl-oxytripyrrolidone hexafluorophosphate; the amount of the base added is 2 to 3 times the equivalent of compound B; and the solvent is dichloromethane or N,N-dimethylformamide.

[0042] The application of the technical solution of the present invention avoids the use of expensive raw materials and reduces costs; and the post-processing is simple, which is conducive to industrialized scale-up production. DETAILED DESCRIPTION

[0043] For the convenience of understanding the present invention, the present invention is given below with examples. It should be understood by those skilled in the art that the examples are only for the purpose of helping to understand the present invention and should not be regarded as specific limitations of the present invention.

[0044] Example 1 Synthesis of 1-chloro-2-methoxy-3-nitrobenzene

[0045]

[0046] At room temperature, 34.8g of sodium methoxide (625mmol, 1.2eq) was dissolved in 680mL of methanol to prepare a solution for use. 100g of 2,3-dichloronitrobenzene (520.8mmol) and 700mL of methanol were added to a 2000mL three-necked reaction flask, replaced with nitrogen three times, stirred and dissolved at room temperature, then cooled to 0~5°C, and the methanol solution of sodium methoxide was slowly added dropwise, controlling the temperature to be less than 20°C. After the dropwise addition, the reaction was carried out at 50°C for 16h. The reaction was complete by gas phase detection, and the solution was concentrated under reduced pressure to 1 / 3 of the volume. 1L of water was added and the mixture was extracted with 800mL of ethyl acetate. The aqueous phase was extracted with 200mL of ethyl acetate, the organic phase was concentrated, 1000mL of toluene and 10g of activated carbon were added, and the mixture was decolorized at 80°C for 30min. Hot filtration was performed, and the filtrate was concentrated to obtain crude 1-chloro-2-methoxy-3-nitrobenzene, which was then purified by 500mL of ethanol. The mixture was slurried with n-hexane, 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%.

[0047] Its mass spectrum data is as follows: MS m / z: 189.1[M+H] + .

[0048] Example 2 Synthesis of 2-methoxy-3-nitrobenzonitrile

[0049]

[0050] 75 g of 1-chloro-2-methoxy-3-nitrobenzene (400 mmol) was dissolved in 400 mL of N-methylpyrrolidone, followed by the addition of 53.8 g of cuprous cyanide (600 mmol, 1.5 eq). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 190°C for 6 h. The reaction was complete as determined 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 aqueous ammonium chloride, passed through a flash silica gel column, and concentrated to afford 59.1 g of 2-methoxy-3-nitrobenzonitrile as a light yellow solid in an 83% yield.

[0051] The mass spectrum data are as follows: MS m / z: 179.02 [M+H] + .

[0052] Example 3 Synthesis of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole

[0053]

[0054] At room temperature, 48.5 g of sodium methoxide (898 mmol, 2.0 eq) was dissolved in 800 mL of methanol to prepare a solution for later use. 80 g of 2-methoxy-3-nitrobenzonitrile (449 mmol) was dissolved in 400 mL of methanol and replaced with nitrogen three times. The reaction solution was cooled to 10°C and then the methanol solution of sodium methoxide was added dropwise. After the addition, the reaction was allowed to react 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 continued at room temperature for 12 h. The reaction was complete when detected by HPLC. The product was concentrated under reduced pressure, the solid was dispersed and slurried with ethanol, filtered, the filtrate was collected, and the solvent was concentrated to obtain 102 g of the intermediate as a white solid with a yield of 98.1%. 102 g of the intermediate was dissolved in 500 mL of DMF, followed by the addition of 60.4 g of CuCl₂ (449 mmol, 1 eq) and 95.3 g of K₃PO₄ (449 mmol, 1 eq). The reaction solution was heated to 100°C and stirred for 16 h. After completion, 1500 mL of water was added, followed by extraction with ethyl acetate (3 × 500 mL). The organic phase was dried over magnesium sulfate and concentrated. Purification by flash silica gel column chromatography (hexane / ethyl acetate = 4 / 1) afforded 75.7 g of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole as a light yellow solid in a 72% yield.

[0055] Its nuclear magnetic hydrogen spectrum data are shown below: 1 H-NMR (DMSO-d6, 400MHz): 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).

[0056] MS m / z:235.1[M+H] + .

[0057] Example 4 Synthesis of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0058]

[0059] 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 atmosphere was replaced with nitrogen three times and then heated to 55°C. 56.4 g (1.41 mol, 3 eq) of 80 wt% hydrazine hydrate was slowly added dropwise over about 1 h. After completion of the addition, the mixture was reacted at 50°C for 5 h. The reaction was complete as determined by HPLC. The reaction solution was cooled to room temperature and dissolved in 500 mL of ethyl acetate. The mixture was filtered, and the filtrate was concentrated and recrystallized by adding 300 mL of toluene. The filter cake was washed with toluene and dried in vacuo to obtain 91.1 g of pure 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline as a light yellow solid in a yield of 95%.

[0060] Its nuclear magnetic hydrogen spectrum data are shown below: 1 H-NMR (DMSO-d6, 400MHz): 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).

[0061] MS m / z:205.1[M+H] + .

[0062] Example 5 Synthesis of 3-amino-4-bromo-6-chloropyridazine

[0063]

[0064] 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 atmosphere was replaced 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 reaction was stirred and allowed to react overnight. HPLC confirmed the reaction was complete. The reaction solution was poured into 500 g of an 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 obtain 65.2 g of 3-amino-4-bromo-6-chloropyridazine as a yellow solid in a yield of 81%.

[0065] The mass spectrum data are as follows: MS m / z: 209.2[M+H] + .

[0066] Example 6 Synthesis of 4-bromo-6-chloro-3-pyridazinecarbonitrile

[0067]

[0068] 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, and the atmosphere was replaced with nitrogen three times. The mixture was then heated to 80°C and stirred to dissolve. The mixture 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, and the temperature was controlled below 10°C. After the addition was complete, stirring was continued for 1-2 h until the solution became clear. 64.8 g of tert-butyl isocyanate (779.5 mmol, 2.5 eq) was then added dropwise. The mixture was allowed to complete dropwise addition in about 3 h. The reaction was stirred at room temperature overnight and monitored by thin layer chromatography (TLC). After the reaction was completed, 1000 mL of water was added and the mixture was washed with ethyl acetate (3 × 4 ethyl acetate). The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 45.6 g of 4-bromo-6-chloro-3-pyridazinecarbonitrile as a light yellow solid in a yield of 67%.

[0069] Its mass spectrum data are as follows: MS m / z: 219.1[M+H] + .

[0070] Example 7 Synthesis of N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide

[0071]

[0072] 30 g of 4-bromo-6-chloro-3-pyridazinecarbonitrile (137.3 mmol) was dissolved in 300 mL of 1,4-dioxane, and then 14.0 g of cyclopropanecarboxamide (164.8 mmol) was added. The atmosphere was replaced with nitrogen three times, and then heated to 60°C with stirring for 16 h. After the completion of the reaction, the reaction solution was cooled to room temperature and stirred for 2-3 h. The reaction was filtered, and the filter cake was washed with n-hexane and dried to obtain 33 g of N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide as a yellow solid in a yield of 90%.

[0073] Its nuclear magnetic hydrogen 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).

[0074] Example 8 Synthesis of Compound A

[0075]

[0076] A 500 mL reaction flask was charged with 100 mL of toluene, 10 g of N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide (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). The mixture was then heated at 120°C for 12 h. After cooling to ambient temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate, concentrated, and purified by column chromatography (v dichloromethane / v methanol = 20 / 1) to afford 10.6 g of compound A as a yellow solid in a 76% yield.

[0077] The mass spectrum data are as follows: MS m / z: 391.2 [M+H] + .

[0078] Example 9 Synthesis of Compound B

[0079]

[0080] 25 g of compound A (64.0 mmol) was dissolved in 300 mL of ethanol, followed by the addition of 150 mL of sulfuric acid (50 wt %). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 90°C with stirring for 16 h. After completion of the reaction, the reaction solution was cooled to room temperature, 500 mL of water was added, and the pH was adjusted to neutral with 6N aqueous sodium hydroxide solution. The mixture was then extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain 20.2 g of crude compound B as a light yellow solid in a yield of 77.2%.

[0081] Its nuclear magnetic hydrogen 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).

[0082] The mass spectrum data are as follows: MS m / z: 432.1 [M+Na] + .

[0083] Example 10 Synthesis of Compound I

[0084]

[0085] To a reaction flask, 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. The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 20-30°C for 24 h. HPLC confirmed the reaction was complete. 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 yield 6.5 g of compound I as a pale yellow solid in a 71% yield.

[0086] Its nuclear magnetic hydrogen 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, 2 H), 3.93 (s, 3H), 3.76 (s, 3H), 2.06-1.97 (m, 1H), 1.01– 0. 42 (m, 4H).

[0087] The mass spectrum data are as follows: MS m / z: 426.3 [M+H] + .

[0088] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be 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, It includes the following steps: (1) Under the action of a base in a solvent, 2,3-dichloronitrobenzene undergoes an etherification reaction to obtain 1-chloro-2-methoxy-3-nitrobenzene; (2) 1-Chloro-2-methoxy-3-nitrobenzene is prepared into 2-methoxy-3-nitrobenzonitrile through a cyanation reaction in the presence of a cyanation reagent; (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 undergoes a catalytic reduction reaction under the action 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 as follows: 。 2. The synthesis method according to claim 1, characterized in that, The solvent described in step (1) is an alcohol solvent, and the alcohol solvent is methanol; the base is sodium methoxide; the molar ratio of the base to 2,3-dichloronitrobenzene is 1:1 to 3:

1.

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

2.

4. The synthesis method according to claim 1, wherein, The base described 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, 1,8-diazabicyclo[5.4.0]-7-undecene; the molar ratio of the base to 2-methoxy-3-nitrobenzonitrile is 2 to 5:

1.

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

6. A method for synthesizing N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide, characterized in that, It 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 bromination reagent to prepare 3-amino-4-bromo-6-chloropyridazine; (6) Under low-temperature conditions and in the presence of an acid, 3-amino-4-bromo-6-chloropyridazine reacts with sodium nitrite to form a diazonium salt, and then a cyanate reagent is added to form 4-bromo-6-chloro-3-pyridazinecarbonitrile; (7) 4-Bromo-6-chloro-3-pyridazinecarbonitrile is prepared into N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide through a substitution reaction in the presence of an aprotic solvent; The process route is as follows: 。 7. The synthesis method according to claim 6, characterized in that, The bromination reagent described 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 according to claim 6, characterized in that, The low temperature described in step (6) is a temperature ≤ 5 °C, 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 deucravacitinib, characterized in that, It includes the following steps: (8) The 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline prepared in Claims 1 to 5 and the N-(5-bromo-6-cyanopyrazin-3-yl)cyclopropanecarboxamide prepared in Claims 6 to 8 are subjected to Buchwald–Hartwig coupling reaction to obtain Compound A; (9) Compound A is subjected to nitrile hydrolysis to prepare carboxylic acid Compound B; (10) Under the action of a condensing agent and an activator, compound B undergoes a condensation reaction with deuterated methylamine hydrochloride under basic and solvent conditions to produce deucravacitinib; the process route is as follows: 。 10. The synthesis method according to claim 9, wherein, The Buchwald–Hartwig coupling reaction described 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, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(triphenylphosphine)dichloropalladium, tris(dibenzylideneacetone)dipalladium, allylpalladium(II) dimer, 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, N,N-diisopropylamine. The Buchwald–Hartwig coupling reaction can also add a phosphine ligand, and the phosphine ligand is any one of triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl, 2-bis(cyclohexylphosphino)-2’,6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-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, acetonitrile. The reaction temperature is generally between 60 and 120 °C.

11. The synthesis method according to claim 9, characterized in that, The nitrile hydrolysis described in step (9) is acid hydrolysis, which is carried out using concentrated sulfuric acid in a solvent of water or water-ethanol. Preferably, sodium nitrite is added.

12. The synthesis method according to claim 9, characterized in that, The condensing agent described 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); preferably, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt) are used in combination; preferably, a base is added in the condensation reaction, and the base is N,N-diisopropylethylamine, N-methylmorpholine, triethylamine, pyridine, benzotriazol-1-yl-oxytripyrrolidinium hexafluorophosphate; the addition amount of the base is 2 to 3 times the equivalent of Compound B; the solvent is dichloromethane or N,N-dimethylformamide.

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