Preparation method of deuterium coricotinib intermediate 2-methoxy-3-(1-methyl-1, 2, 4-triazole-3-yl) aniline

Abstract

The invention relates to a preparation method of a deuterium coricotinib intermediate 2-methoxy-3-(1-methyl-1, 2, 4-triazole-3-yl) aniline, and discloses a method for preparing the deuterium coricotinib intermediate 2-methoxy-3-(1-methyl-1, 2, 4-triazole-3-yl) aniline, which comprises the following steps: by taking 2-fluoro-3-nitrobenzonitrile as an initial raw material, adding 2-fluoro-1, 2, 4-triazole-3-yl) aniline into a reaction kettle, and reacting at the temperature of 60-80 DEG C to obtain the deuterium coricotinib intermediate 2-methoxy-3-(1-methyl-1, 2, 4-triazole-3-yl) aniline. The 2-methoxy-3-(1-methyl-1, 2, 4-triazole-3-yl) aniline is obtained through etherification / addition, esterification / condensation cyclization and reduction reaction, the raw materials are low in toxicity, economical and easy to obtain, the reaction condition is mild, the steps are few, the yield is high, the selectivity is good, toxic hydrazine and derivatives thereof and an expensive palladium catalyst are not used, the operation is safe, and the method is suitable for industrial production. An efficient and green process route is provided for realizing the industrial scale production of the deuterocoxitinib.

Description

Technical Field

[0001] The present invention relates to the synthesis of Deucravacitinib intermediates, and particularly to a method for preparing 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline from 2-fluoro-3-nitrobenzonitrile as a starting material through etherification / addition, esterification / condensation cyclization, and reduction reactions, belonging to the technical field of organic synthesis. Background Art

[0002] Deucravacitinib, chemical name 6-(cyclopropanecarboxamido)-4-[2-methoxy-3-(1-methyl-1 H -1,2,4-triazol-3-yl)anilino]- N -(trideuteriomethyl)pyridazine-3-carboxamide, has the following chemical structure:

[0003] Deucravacitinib is a tyrosine kinase 2 (TYK2) inhibitor developed by Bristol-Myers Squibb Company in the United States (BLAUVELT A, RICH P, SOFEN H, et al. J Am Acad Dermatol, 2024, 90(4): 775-782), and was approved for marketing by the FDA in September 2022. Clinically, it is mainly used to treat moderate to severe plaque psoriasis (FDA. [2022-09-09]. https: / / www.fda.gov / drugs / novel-drug-approvals-fda / novel-drug-approvals-2022), and also shows promise in treating diseases such as psoriatic arthritis and systemic lupus erythematosus (WANG S, NINGW, TANG H, et al. Arthritis Res Ther, 2024, 26(1): 98; MORAND E, MEROLA JF, TANAKA Y, et al. Nat Rev Rheumatol, 2024, 20(4), 232-240).

[0004] 2-Methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (1) is a key intermediate for the synthesis of Deucravacitinib. There are mainly 7 kinds of literature synthesis routes, which are divided into 3 categories according to the method of constructing the 1,2,4-triazole ring: The first category is to construct the 1,2,4-triazole ring through hydrazine hydrate and substituted benzoate, which is the original research process route of Bristol-Myers Squibb Company.

[0005] Route 1: Using methyl 3-nitrosalicylate (6) as the starting material, reacting with methyl iodide through etherification to obtain methyl 2-methoxy-3-nitrobenzoate (7). After amidation of compound 7 with ammonia water, 2-methoxy-3-nitrobenzamide (8) is obtained. Compound 8 is condensed with N , N -dimethylformamide dimethyl acetal (DMF-DMA) and cyclized with hydrazine hydrate to obtain 3-(2-methoxy-3-nitrophenyl)-1,2,4-triazole (9). Compound 9 undergoes alkylation reaction with methyl iodide to obtain 3-(2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole (5). Compound 5 is catalytically hydrogenated by Pd / C to obtain the target product 1. The total yield is 35% (calculated based on 6) (WROBLESKI ST, MOSLIN R, LIN S, et al. J Med Chem, 2019, 62(20): 8973-8995).

[0006]

[0007] The second category is to construct a 1,2,4-triazole ring through N-methylformylhydrazine and substituted benzonitrile.

[0008] Route 2: The commercial-scale process route of BMS. Using 5-chloro-2-methoxybenzonitrile (10) as the starting material, reacting with N -methylformylhydrazine through addition and cyclization to obtain 3-(5-chloro-2-methoxyphenyl)-1-methyl-1,2,4-triazole (11). Compound 11 is nitrated with nitric acid / sulfuric acid to obtain 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole (12). Compound 12 is catalytically hydrogenated by Pd / C to obtain the target product 1. The total yield is 72% (calculated based on 10) (TREITLER DS, SOUMEILLANT MC, SIMMONS EM, et al. Org Process Res Dev, 2022, 26(4): 1202-1222).

[0009]

[0010] Route 3: Using 2-hydroxybenzonitrile (13) as the starting material, nitrating with nitric acid / acetic acid, then etherifying with methyl iodide, and finally catalytically hydrogenating with Pd / C to obtain 3-amino-2-methoxybenzonitrile (16). Compound 16 reacts with N -methylformylhydrazine through addition and cyclization reaction to obtain the target product 1. The total yield is 24% (calculated based on 13) (CHEN Junhao, MAO Yongjun, LIU Wei, et al. CN 118184591A[P]. 2024-06-14).

[0011]

[0012] Route 4: Using 3-bromo-2-methoxybenzonitrile (17) as the starting material, reacting with N -methylformohydrazide through addition and cyclization reactions to obtain 3-(3-bromo-2-methoxyphenyl)-1-methyl-1,2,4-triazole (18). Compound 18 is subjected to high-temperature amination to obtain the target product 1. The total yield is 87% (calculated based on 17) (Zheng Xuchun, Zhang Yiping, Fu Chenchen. CN 114989103B [P]. 2024-07-09).

[0013]

[0014] The third category is to construct a 1,2,4-triazole ring through 1-Boc-1-methylhydrazine and substituted benzoic acid and its esters.

[0015] Route 5: Using 3-nitrosalicylic acid (19) as the starting material, after etherification with dimethyl sulfate and chlorination with thionyl chloride, 2-methoxy-3-nitrobenzoyl chloride (21) is obtained. Compound 21 undergoes amidation with 1-Boc-1-methylhydrazine to obtain 2-(2-methoxy-3-nitrobenzoyl)-1-methylhydrazine-1-tert-butyl formate (22). Compound 22 undergoes condensation and cyclization with formamidine, and then is catalytically hydrogenated with Pd / C to obtain the target product 1. The total yield is 63% (calculated based on 19) (Qin Tianhong, Kuang Yulong, Wang Xuechao, etc. CN117447353A [P]. 2024-01-26).

[0016]

[0017] Route 6: Using 2-fluoro-3-nitrobenzoic acid (23) as the starting material, through nucleophilic substitution with sodium methoxide to obtain compound 20, compound 20 is chlorinated with oxalyl chloride, and then undergoes amidation with 1-Boc-1-methylhydrazine to obtain 22. Compound 22 is deprotected by removing the tert-butoxycarbonyl (Boc) protecting group, and then undergoes addition and cyclization with potassium thiocyanate to obtain 5-(2-methoxy-3-nitrophenyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (26). Compound 26 is desulfurized with nitric acid and then catalytically hydrogenated with Pd / C to obtain the target product 1. The total yield is 68% (calculated based on 23) (Liu Hao, Li Baichen, Wang Jian, etc. CN 117247360A [P]. 2023-12-19).

[0018]

[0019] Route 7: Starting from compound 6, through methylation with methyl iodide, amidation with ammonia water, and thiation with Lawesson's reagent, 2-methoxy-3-nitrothiobenzamide (27) was obtained. Compound 27 underwent alkylation reaction with methyl iodide to obtain methyl (2-methoxy-3-nitrobenzylidene) sulfate (28). Compound 28 was substituted with 1-Boc-1-methylhydrazine to obtain tert-butyl 2-(imino(2-methoxy-3-nitrophenyl)methyl)-1-methylhydrazine-1-carboxylate (29). After condensation cyclization of compound 29 with formic acid, the target product 1 was obtained by catalytic hydrogenation over Pd / C. The total yield was 49% (calculated based on 6) (Li Pixu, Wang Peng, Zhou Peng. CN 117447411A [P]. 2024-01-26; Chen Mengya, Wu Shi. Journal of Hubei University of Science and Technology (Medical Sciences), 2020, 34(4): 293-295).

[0020]

[0021] In summary, Route 1 has high raw material costs, long reaction steps, low yields, poor regioselectivity of 1,2,4-triazole-1-methylation, and involves toxic hydrazine hydrate reagent with high risks. Routes 2-4 have fewer reaction steps, but N-methylformohydrazine is expensive, the nitration reaction is highly polluting and corrosive to equipment, and the amination reaction requires high temperature, high pressure, and long time. Routes 5-7 have more reaction steps and involve toxic methyl iodide, dimethyl sulfate, and thionyl chloride reagents, causing serious environmental pollution. Except for Route 4, other literature routes use Pd / C-catalyzed hydrogenation to reduce nitro compounds, resulting in high production costs and unsafe operations. Therefore, it is of great research significance to develop a synthesis process of 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline with short process routes, high yields of target products, simple reaction operations, inexpensive and non-toxic reagents, environmental friendliness, and easy industrial production. N Summary of the Invention The technical problem to be solved by the present invention is to provide a preparation method of the key intermediate of deucravacitinib, 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline. This preparation method uses 2-fluoro-3-nitrobenzonitrile (2) as the starting material and obtains 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (1) through etherification / addition, esterification / condensation cyclization, and reduction reactions.

[0022] The present invention is achieved through the following technical solutions:

[0023] A preparation method of 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline, comprising the following steps: ​(1) Potassium hydroxide and methanol were added to a beaker. After stirring and dissolving, a methanol solution of hydroxylamine hydrochloride was added. After stirring and reacting at room temperature, filtration was carried out by suction. The filtrate was transferred to a pear-shaped flask, and 2-fluoro-3-nitrobenzonitrile (2), potassium hydroxide and tetrabutylammonium bromide were added, and the reaction was carried out by heating in an oil bath; after the reaction solution was cooled to room temperature, the pH was adjusted to 6 with glacial acetic acid, and after distillation under reduced pressure to dryness, saturated sodium bicarbonate aqueous solution was added to the residue, stirred in an ice-water bath, filtered by suction, the filter cake was washed with water, and dried in vacuo at 40 °C to obtain N ′-hydroxy-2-methoxy-3-nitrobenzimidamide (3); (2) Compound 3, triethylamine and tetrahydrofuran were added to a pear-shaped flask and cooled to 5 °C. p-Toluenesulfonyl chloride was added in batches. After addition, the reaction was stirred at room temperature; then methylamine hydrochloride and triethyl orthoformate were added, and the reaction was stirred by heating in an oil bath; the reaction solution was cooled to room temperature, water was slowly added, stirred, filtered by suction, the filter cake was washed with a mixed solution of tetrahydrofuran and water, and dried in vacuo at 40 °C to obtain 3-(2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole (5); (3) Compound 5 and methanol were added to a pear-shaped flask. After stirring and dissolving, an aqueous sodium hydroxide solution and thiourea dioxide were added, and the reaction was carried out by heating in an oil bath and cooled in an ice bath; the reaction solution was filtered by suction, the filter cake was washed with cold water, and dried in vacuo at 40 °C to obtain 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (1).

[0024] The specific chemical reaction formula is described as follows:

[0025] In the preparation method of 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline, in step (1), the molar ratio of compound 2 to hydroxylamine hydrochloride is 1:1 to 1.5, preferably 1:1.3; the amount of methanol used is 1 to 4 mL / mmol of compound 2, preferably 2 mL / mmol of compound 2; the molar ratio of compound 2 to potassium hydroxide is 1:2 to 6, preferably 1:4.3; the molar ratio of compound 2 to tetrabutylammonium bromide is 1:0.05 to 0.15, preferably 1:0.075; the oil bath temperature is 60 to 75 °C, preferably 75 °C; the reaction time of heating in an oil bath is 4 to 8 h, preferably 6 h.

[0026] In step (2), the molar ratio of compound 3 to p-toluenesulfonyl chloride is 1:1 to 1.2, preferably 1:1.01; the molar ratio of compound 3 to triethylamine is 1:1 to 1.2, preferably 1:1.03; the molar ratio of compound 3 to methylamine hydrochloride is 1:1 to 1.2, preferably 1:1; the molar ratio of compound 3 to triethyl orthoformate is 1:1 to 2, preferably 1:1.7; the amount of tetrahydrofuran used is 1 to 3 mL / mmol of compound 3, preferably 1.7 mL / mmol of compound 3; the reaction time at room temperature is 0.5 to 3 h, preferably 1 h; the oil bath temperature is 50 to 80 °C, preferably 60 °C; the heating reaction time is 4 to 8 h, preferably 6 h.

[0027] In step (3), the molar ratio of compound 5 to thiourea dioxide is 1:2 to 5, preferably 1:4; the molar ratio of compound 5 to sodium hydroxide is 1:2 to 10, preferably 1:8; the amount of methanol used is 1 to 2 mL / mmol of compound 5, preferably 1.25 mL / mmol of compound 5; the oil bath temperature is 40 to 70 °C, preferably 60 °C; the reaction time is 10 min to 2 h, preferably 30 min.

[0028] In the present invention, in the presence of potassium hydroxide and the phase transfer catalyst tetrabutylammonium bromide, compound 2 reacts with methanol and hydroxylamine hydrochloride by refluxing to obtain N 2'-hydroxy-2-methoxy-3-nitrobenzamidine (3) with a good yield. In this step of the reaction, the potassium methoxide generated by the reaction of potassium hydroxide with methanol is both a nucleophile for the etherification reaction and a catalyst for the addition reaction, enabling the etherification / addition reaction to be completed in one pot, with high atom utilization and good regioselectivity.

[0029] In the present invention, compound 3 reacts with p-toluenesulfonyl chloride (TsCl) at room temperature in the presence of triethylamine to form N 2'-(p-toluenesulfonyloxy)benzamidine intermediate 4, which, without further separation and purification, directly reacts with methylamine hydrochloride and triethyl orthoformate in tetrahydrofuran (THF) to obtain 3-(2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole (5). This step of the reaction has a high yield and good selectivity, avoiding the use of toxic reagents such as hydrazine.

[0030] In the present invention, using thiourea dioxide (TDO) as a reducing agent, in the presence of sodium hydroxide, compound 5 reacts in water / methanol to obtain the target product 1. This step of the reaction has a short reaction time, and the product can be separated by filtration. Thiourea dioxide has strong reducibility, good thermal stability, is convenient for storage and transportation, and is safe to operate.

[0031] Compared with the prior art, the present invention uses 2-fluoro-3-nitrobenzonitrile (2) as the starting material, and obtains 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (1) through etherification / addition, esterification / condensation cyclization and reduction reactions. The raw materials are of low toxicity, economically available, the reaction conditions are mild, the steps are few, the yield is high, and the selectivity is good. The use of toxic hydrazine and its derivatives and expensive palladium catalysts is avoided, and the operation is safe, providing an efficient and green process route for the industrial-scale production of deucravacitinib. Detailed implementation mode

[0032] The present invention is further described below in conjunction with embodiments. The embodiments are only used to explain the present invention and should not be construed as a limitation of the present invention.

[0033] Example 1 N Preparation of ′-hydroxy-2-methoxy-3-nitrobenzimidamide (3) Potassium hydroxide (1.46 g, 26 mmol) and methanol (20 mL) were added to a 100 mL reaction flask and dissolved until clear. Then, a methanol (20 mL) solution of hydroxylamine hydrochloride (1.81 g, 26 mmol) was added. After stirring at room temperature for 20 min, filtration was carried out by suction. The filtrate was transferred to a 100 mL eggplant-shaped flask, and compound 2 (3.32 g, 20 mmol, Shanghai Aladdin Biochemical Technology Co., Ltd.), potassium hydroxide (3.37 g, 60 mmol) and tetrabutylammonium bromide (0.48 g, 1.5 mmol) were added. The temperature was controlled at 75 °C by an oil bath and refluxed for 6 h. After the reaction solution was cooled to room temperature, the pH was adjusted to 6 with glacial acetic acid. After distilling to dryness under reduced pressure, saturated sodium bicarbonate aqueous solution (20 mL) was added to the residue, and it was stirred in an ice-water bath for 30 min. Filtration was carried out by suction, the filter cake was washed with water, and dried in vacuo at 40 °C to obtain yellow solid 3 (3.92 g, 93%). Melting point 92.1 - 93.5 °C.

[0034] 1 H NMR(600 MHz, DMSO-d6),δ: 10.87(s,1H),8.08(dd,J=7.5、1.5 Hz,1H),7.87(dd,J=7.5、1.6 Hz,1H),7.23(t,J=7.5 Hz,1H),5.94(s,2H),3.96(s,3H); 13 C NMR(150MHz, DMSO-d6),δ: 150.98,150.77,139.88,129.63,126.77,126.21,122.02,62.50。

[0035] Example 2 Preparation of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole (5) Compound 3 (3.17 g, 15 mmol), triethylamine (1.56 g, 15.45 mmol) and tetrahydrofuran (25 mL) were added to a 100 mL eggplant-shaped flask, cooled to 5 °C, and p-toluenesulfonyl chloride (2.89 g, 15.15 mmol, Shanghai Aladdin Biochemical Technology Co., Ltd.) was added in 5 portions within 1.5 h. The temperature was raised to 20 °C and stirred for 1 h. Then methylamine hydrochloride (1.01 g, 15 mmol) and triethyl orthoformate (3.78 g, 25.5 mmol) were added, and the temperature was raised to 60 °C and stirred for 6 h. The reaction solution was cooled to room temperature, and water (35 mL) was slowly added within 1 h, stirred for 2 h, filtered by suction, and the filter cake was washed with a mixed solution of tetrahydrofuran and water (volume ratio 1:2) (5 mL × 3), and dried in vacuo at 40 °C to obtain yellow solid 5 (3.24 g, 92%). Melting point 199.4 - 200.8 °C.

[0036] 1 H NMR (600 MHz, DMSO-d6), δ: 8.63 (s, 1H), 8.17 - 8.13 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 4.06 (s, 3H), 3.97 (s, 3H); 13 C NMR (150 MHz, DMSO-d6), δ: 156.60, 150.92, 144.60, 139.07, 133.72, 126.48, 125.43, 121.46, 61.42, 36.39.

[0037] Example 3 Preparation of 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (1) Compound 5 (1.87 g, 8 mmol) and methanol (10 mL) were added to a 200 mL eggplant-shaped flask, stirred until dissolved, 1 mol / L aqueous sodium hydroxide solution (64 mL) and thiourea dioxide (3.46 g, 32 mmol) were added, and the temperature was raised to 60 °C and reacted for 30 min, then cooled in an ice bath. The reaction solution was filtered by suction, and the filter cake was washed with cold water (5 mL × 3), and dried in vacuo at 40 °C to obtain off-white solid 1 (1.45 g, 89%). Melting point 82.6 - 83.7 °C. Purity 99.3% [HPLC normalization method: chromatographic column Diamonsil C18 column (150 mm × 4.6 mm, 3.5 μm); mobile phase a mixed solution of water, methanol and triethylamine (volume ratio 10:90:1), isocratic elution; column temperature 30 °C; detection wavelength 220 nm; flow rate 0.8 mL / min].[[]END]]

[0038] 1 1H NMR (600 MHz, DMSO-d6), δ: 8.60 (s, 1H), 7.43 (dd, J = 7.5, 1.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.90 (dd, J = 7.5, 1.5 Hz, 1H), 5.04 (s, 2H), 4.06 (s, 3H), 3.83 (s, 3H); 13 13C NMR (150 MHz, DMSO-d6), δ: 156.30, 145.73, 144.60, 135.64, 124.26, 123.24, 121.47, 116.31, 61.23, 36.36.

Claims

1. A method for preparing the intermediate of deucravacitinib, 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (Formula I), (Formula I) which is characterized by comprising the following steps: (1) Add 26 mmol of potassium hydroxide and 20 mL of methanol to a reaction flask. After stirring and dissolving, add a 20 mL methanol solution of 26 mmol of hydroxylamine hydrochloride. After stirring at room temperature for 20 min, perform suction filtration. Transfer the filtrate to a pear-shaped flask, add 20 mmol of 2-fluoro-3-nitrobenzonitrile, 60 mmol of potassium hydroxide, and 1.5 mmol of tetrabutylammonium bromide. Control the temperature of the oil bath at 75 °C and reflux for 6 h. After the reaction solution is cooled to room temperature, adjust the pH to 6 with glacial acetic acid. After distilling to dryness under reduced pressure, add 20 mL of saturated sodium bicarbonate aqueous solution to the residue, stir in an ice-water bath for 30 min, perform suction filtration, wash the filter cake with water, and dry it under vacuum at 40 °C to obtain N ′-hydroxy-2-methoxy-3-nitrobenzimidamide; (2) Add N 15 mmol of ′-hydroxy-2-methoxy-3-nitrobenzamidine, 15.45 mmol of triethylamine and 25 mL of tetrahydrofuran to a round-bottomed flask, cool to 5 °C, add 15.15 mmol of p-toluenesulfonyl chloride in portions, warm to 20 °C and stir for 1 h; then add 15 mmol of methylamine hydrochloride and 25.5 mmol of triethyl orthoformate, warm to 60 °C and stir for 6 h; cool the reaction mixture to room temperature, slowly add 35 mL of water, stir for 2 h, filter by suction, wash the filter cake with a mixed solution of tetrahydrofuran and water, and dry in vacuo at 40 °C to obtain 3-(2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole; (3) Add 8 mmol of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1,2,4-triazole and 10 mL of methanol to a eggplant-shaped flask. After stirring and dissolving, add 64 mL of 1 mol / L sodium hydroxide aqueous solution and 32 mmol of thiourea dioxide. After heating to 60 °C and reacting for 30 min, cool in an ice bath; filter the reaction solution by suction, wash the filter cake with cold water, and dry it under vacuum at 40 °C to obtain the target product 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline.

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