A tyrosine kinase inhibitor intermediate, a preparation method and application thereof

Abstract

The application discloses a preparation method of a compound of formula V-1, and comprises the following steps: a, a compound of formula I-1, 5-chlorosalicylic acid, is reacted with dimethyl sulfate to obtain a compound of formula II-1; the compound of formula II-1 is reacted with an ammonia source reagent to obtain a compound of formula III-1; the compound of formula III-1 is reacted with a methyl source compound to obtain a compound of formula IV-1; and the compound of formula IV-1 is reacted with methylhydrazine under the condition of an alkaline reagent to obtain the compound of formula V-1. The method improves the yield of a triazole ring obtained through cyclization of a compound of formula V, thereby improving the yield of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline; the preparation method of the compound of formula V is simple and easy to obtain, the cost is greatly reduced, and the method is convenient for industrialization.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a preparation method of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline. BACKGROUND

[0002] Deucalixibini is an oral selective tyrosine kinase 2 (TYK2) allosteric inhibitor developed by BMS, which is the first oral drug approved in the past 10 years for the treatment of moderate to severe plaque psoriasis. It was approved for marketing by the US FDA in September 2022. The Chinese name of deucalixibini is 6-

[0003] (Cyclopropylcarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenyl) amino)-N-trideuteromethyl pyridazine-3-carboxamide, wherein 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline is a key intermediate of deucalixibini:

[0004]

[0005] The original research patent WO2014074661 introduces a method for synthesizing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline. The starting material is 3-nitrosalicylic acid methyl ester, which is expensive. The subsequent selection of methyl iodide for phenolic hydroxyl methylation also uses methyl iodide, which is also relatively expensive. The 3-nitro-2-methoxybenzamide obtained by the ammonia solution and ammonia water for ester ammonolysis is subjected to ring closure with DMF-DMA and hydrazine hydrate system, and then methylated with methyl iodide. The selectivity is poor, the target product is difficult to separate, and the subsequent nitro reduction also selects high-cost hydrogenation reduction. In summary, this route has high cost, poor selectivity, and great difficulty in separation and purification, which is not conducive to commercial production.

[0006]

[0007] The original research patent WO2021237121 reports a new idea for synthesizing the target product, as shown below. 3-bromo-2-methoxy aniline is used as the starting material, which is also expensive. The bromine is replaced by reacting with bis(pinacolato)diboron, which requires the use of expensive palladium catalyst. Then, the Suzuki coupling reaction of 3-bromo-1-methyl-1H-1,2,4-triazole directly obtains the target product. The biggest feature of this route is short, but at the same time, the raw materials and catalysts are expensive, which is only suitable for small-scale laboratory research, not conducive to commercial production. At the same time, the naked amino group has a great influence on the overall reaction, and the total yield is low.

[0008]

[0009] WO2018183649 reported a synthetic route as shown below, which selected 5-chloro-2-methoxybenzonitrile as a starting material, and N-methyl formylhydrazine underwent a pinner reaction under the catalysis of sodium tert-butoxide, then dehydrated and ring-closed to obtain the 1,2,4-triazole moiety, and the product was obtained by nitration using a cheap concentrated nitric acid / concentrated sulfuric acid nitration system, and then reduced by palladium carbon catalytic reduction under hydrogen atmosphere to obtain the target product. This route is short and has high total yield. The biggest disadvantage is that the expensive 5-chloro-2-methoxybenzonitrile is selected as the starting material, which is not conducive to cost control.

[0010]

[0011] CN114989103 reported a method for synthesizing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline, as shown below. This route uses 3-bromo-2-methoxybenzonitrile as a starting material, which is cyclized with N-methyl formylhydrazine under the catalysis of a base to prepare 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole, and then the bromine is replaced with ammonia to obtain the target product. The starting material of this route is expensive, and N-methyl formylhydrazine is also used in the cyclization reaction. The use of a high-pressure reactor in the process of replacing bromine with ammonia poses a safety risk and is not conducive to large-scale production.

[0012]

[0013] These reactions all start with expensive starting materials, which increases the cost from the source and is not conducive to large-scale production on the market, and the competitiveness is weak. SUMMARY

[0014] In view of the deficiencies in the prior art, the present application provides a compound of formula V and a preparation method of the compound, and further discloses a method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline, which is a key intermediate for preparing dacomitinib, by using the compound of formula V. This method improves the yield of the cyclization to obtain the triazole ring, thereby improving the yield of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline. The preparation method of the compound of formula V is simple and easy to obtain, which greatly reduces the cost and is convenient for industrialization.

[0015] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0016] The first object of the present application is to disclose a compound of formula V:

[0017]

[0018] wherein X is Cl, Br, I.

[0019] Also disclosed are the following compounds:

[0020]

[0021] A second object of the present application is to disclose a process for the preparation of a compound of formula V, comprising the steps of:

[0022] reacting a compound of formula IV, methylhydrazine, a basic reagent to obtain a compound of formula V,

[0023]

[0024] wherein X is Cl, Br, I.

[0025] A third object of the present application is to disclose a process for the preparation of a compound of formula V-1, comprising the steps of:

[0026] a. reacting a compound of formula I-1, 5-chlorosalicylic acid, with dimethyl sulfate to obtain a compound of formula II-1,

[0027]

[0028] b. reacting a compound of formula II-1 with an ammonia source reagent to obtain a compound of formula III-1,

[0029]

[0030] c. reacting a compound of formula III-1 with a methyl source compound to obtain a compound of formula IV-1,

[0031]

[0032] d. reacting a compound of formula IV-1 with methylhydrazine, under the conditions of a basic reagent to obtain a compound of formula V-1,

[0033]

[0034] A fourth object of the present application is to disclose a process for the preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, comprising the steps of:

[0035] cyclyzing a compound of formula V, under acidic conditions, to obtain a compound of formula VI,

[0036]

[0037] A fifth object of the present application is to disclose a method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, characterized in that it comprises the following steps:

[0038] e. cyclization of the compound of formula V-1 under acidic conditions to obtain a compound of formula VI-1,

[0039]

[0040] f. nitration of the compound of formula VI-1 to obtain a compound of formula VII-1,

[0041]

[0042] g. reduction of the compound of formula VII-1 to obtain a compound of formula VIII 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline,

[0043]

[0044] A sixth object of the present application is the use of a compound of formula V for the preparation of deucalixibat, characterized in that the compound of formula V is used for the preparation of deucalixibat,

[0045] wherein X is Cl, Br, I.

[0046] Compared with the prior art, the present application has the following beneficial effects:

[0047] The present application relates to a novel synthesis method of a key intermediate 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline of deucalixibat, which refluxs the triazole ring in the way of N-methylbenzimidoyl hydrazide moiety and formic acid, has fast reaction speed, simple operation, avoids the generation of N-methylation by-products, well utilizes methylhydrazine, improves the route yield, greatly reduces the production cost, and obtains high-purity product, and is more suitable for industrialized production. DETAILED DESCRIPTION

[0048] The present application is further described below and specific embodiments are given.

[0049] The present application discloses a preparation method of formula V, comprising the following steps:

[0050] The compound of formula IV, methylhydrazine and an alkaline reagent are reacted to obtain the compound of formula V,

[0051]

[0052] wherein X is Cl, Br, I.

[0053] Methylhydrazine includes methylhydrazine sulfate, methylhydrazine hydrochloride, methylhydrazine aqueous solution, methylhydrazine.

[0054] Basic reagent includes potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine.

[0055] Reaction solvent includes N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane.

[0056] The reaction temperature is 0-80℃, and further is 50-70℃.

[0057] The molar ratio of the compound of formula IV to methylhydrazine is 1:0.8-1.2, and preferably is 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2. The molar ratio of the compound of formula IV to basic reagent is 1:2-4, and preferably is 1:2, 1:3, 1:4.

[0058] The application also discloses a preparation method of formula V-1, comprising the following steps:

[0059] a, the compound of formula I-1 is reacted with dimethyl sulfate to obtain the compound of formula II-1,

[0060]

[0061] The reaction condition of step a further comprises: being carried out under the condition of a basic reagent, and the basic reagent includes potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, LDA, and n-butyllithium instead; preferably, the basic reagent is potassium carbonate or sodium carbonate.

[0062] Reaction solvent includes N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane instead.

[0063] The reaction temperature is 40-60℃.

[0064] The molar ratio of the compound of formula I-1 to dimethyl sulfate is 1:1.8-2.5, and preferably is 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5.

[0065] The molar ratio of the compound of formula I-1 to basic reagent is 1:1-4, and preferably is 1:1, 1:2, 1:3, 1:4.

[0066] b. reacting the compound of formula II-1 with an ammonia source reagent to obtain a compound of formula III-1,

[0067]

[0068] The molar ratio of the compound of formula II-1 to the ammonia source reagent is 1 : 2.0 to 5.0, preferably 1 : 2.0, 1 : 3.0, 1 : 3.5, 1 : 4.0, 1 : 4.5, 1 : 5.0.

[0069] The reaction conditions further include slow addition of the basic reagent, and stirring the reaction at a temperature of 50 to 65 °C.

[0070] The molar ratio of the compound of formula II-1 to the basic reagent is 1 : 1 to 3, preferably 1 : 1, 1 : 2, 1 : 3.

[0071] The ammonia source reagent includes formamide, ammonium methanol solution, ammonium ethanol solution, ammonium isopropanol solution, or aqueous ammonia, ammonia gas.

[0072] The reaction conditions further include addition of the basic reagent, which includes potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, LDA, n-butyllithium.

[0073] c. reacting the compound of formula III-1 with a methyl source compound to obtain a compound of formula IV-1,

[0074]

[0075] The reaction conditions further include a reaction temperature of 70 to 85 °C.

[0076] The methyl source compound includes dimethyl sulfate, dimethyl carbonate, triethyl orthoformate, dimethyl phosphate instead,

[0077] The reaction solvent can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane.

[0078] The molar ratio of the compound of formula III-1 to the methyl source compound is 1 : 1 to 5, preferably 1 : 1, 1 : 2, 1 : 3, 1 : 4, 1 : 5.

[0079] d. reacting the compound of formula IV-1 with methyl hydrazine under the condition of a basic reagent to obtain a compound of formula V-1,

[0080]

[0081] The reaction conditions further include heating to 50 to 70 °C and stirring the reaction;

[0082] The molar ratio of the compound of formula IV to methylhydrazine is 1:0.8-1.2, preferably 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2.

[0083] The molar ratio of the compound of formula IV to the basic reagent is 1:2-4, preferably 1:2, 1:3, 1:4.

[0084] The methylhydrazine includes methylhydrazine sulfate, methylhydrazine hydrochloride, methylhydrazine aqueous solution, methylhydrazine,

[0085] The basic reagent includes potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine.

[0086] The reaction solvent includes acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane.

[0087] The application also discloses a preparation method of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline, which comprises the following steps: subjecting a compound of formula V to cyclization under acidic conditions to obtain a compound of formula VI,

[0088] X is Cl, Br or I.

[0089] The reaction condition further comprises stirring reaction at a temperature of 100-110 DEG C, after the reaction is completed, the temperature is lowered, pH is adjusted, filtration is carried out, the filtrate is dissolved, and the salt is obtained by filtering the filtrate.

[0090] The acidic reagent includes formic acid,

[0091] The molar ratio of the compound of formula V to the acidic reagent is 1:20-25, preferably 1:20, 1:21, 1:22, 1:23, 1:24, 1:25.

[0092] The formed salt includes concentrated sulfuric acid, hydrochloric acid, hydrobromic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, phosphoric acid.

[0093] The solvent used in the salt formation includes ethyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane, isopropyl acetate, methyl tert-butyl ether or a mixed solvent of any two or more thereof.

[0094] The application also discloses another preparation method of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline, e, a compound of formula V-1 is subjected to cyclization under acidic conditions to obtain a compound of formula VI-1,

[0095]

[0096] The reaction conditions further include heating to 100-110°C and stirring the reaction, after the reaction is completed, cooling, adjusting pH, filtering, dissolving the filtrate, and obtaining the salt from the filtrate.

[0097] The acidic reagent includes formic acid,

[0098] The molar ratio of the compound of formula V-1 to the acidic reagent is 1:20-25, preferably 1:20, 1:21, 1:22, 1:23, 1:24, 1:25.

[0099] The formed salt includes concentrated sulfuric acid, hydrochloric acid, hydrobromic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, phosphoric acid.

[0100] The solvent used in the salt formation includes ethyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane, isopropyl acetate, methyl tert-butyl ether, or a mixed solvent of any two or more thereof.

[0101] f, nitration of the compound of formula VI-1 to obtain a compound of formula VII-1,

[0102]

[0103] The reaction conditions include adding concentrated sulfuric acid, cooling to -10-10°C, adding the compound of formula IV into the concentrated sulfuric acid, stirring, dropwise adding the digestion reagent, filtering, and recrystallizing.

[0104] The mass ratio of the compound of formula VI-1 to the concentrated sulfuric acid is 1:3-6, preferably 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:5.5, 1:6.0.

[0105] The molar ratio of the compound of formula VI-1 to the nitric acid is 1:1-1.5, preferably 1:1.0, 1:1.1, 1:1.2, 1.25, 1:1.3, 1:1.4, 1:1.5.

[0106] The concentrated sulfuric acid is commercially available and is of an analytical grade with a content of 95%-98%.

[0107] The nitration reagent includes 65%-68% nitric acid, fuming nitric acid, potassium nitrate, zinc nitrate, sodium nitrate.

[0108] The recrystallization system includes methanol / water system, ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane, isopropyl acetate, methyl tert-butyl ether or a mixture of any two or more thereof.

[0109] g, the compound of formula VII-1 is reduced to obtain the compound of formula VIII 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline,

[0110]

[0111] The route involving the compound of formula V-1 is as follows:

[0112]

[0113] The use of the compound of formula V for the preparation, characterized in that the compound of formula V is used for the preparation of dacomitinib,

[0114] Wherein, X is Cl, Br, I.

[0115] Example 1

[0116]

[0117] A four-necked flask was charged with the compound of formula I-1 5-chlorosalicylic acid (100 g, 58 mmol) and potassium carbonate (240.27 g, 174 mmol), then acetone (800 g) was added and stirred uniformly, and the temperature was raised to 40-60°C. Dimethyl sulfate (153.50 g, 122 mmol) was added dropwise to the reaction system. After the dropwise addition was completed, the temperature was maintained at 40-60°C for reaction. After the reaction was completed, the reaction system was cooled, and the inorganic salt was filtered off. The filter cake was rinsed with acetone (200 g). The filtrates were combined, and the solvent was removed by concentration to obtain a light yellow oily product, the compound of formula II-1 (110.05 g, yield 94.66%).

[0118] Example 2

[0119]

[0120] A three-necked flask was charged with compound of formula II-1, methyl 5-chloro-2-methoxybenzoate (20 g, 100 mmol) and formamide (20 g, 450 mmol), and methanol (100 g) was added and stirred to dissolve, then sodium methoxide (10.77 g, 200 mmol) was slowly added and stirred to dissolve, then the temperature was raised to 50-65°C and stirred to react, after the reaction was completed, the temperature was lowered, 400 g of water was added to the reaction flask, and the temperature was lowered to -5-0°C while stirring, then filtered, the filter cake was washed with cold water (100 g), and vacuum dried to obtain white solid product, compound of formula III-1 (14.33 g, yield 77.44%)

[0121] MS (ESI) m / z = 185.9 [M+H] +

[0122] 1 H NMR (400 MHz, DMSO) δ 7.73 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 9.2 Hz, 2H), 7.51 (dd, J = 8.9, 2.8 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H).

[0123] Example 3

[0124]

[0125] A three-necked flask was charged with compound of formula III-1, 5-chloro-2-methoxybenzamide (10 g, 54 mmol) and dimethyl sulfate (20.39 g, 162 mmol), and heated to 70-85°C and stirred to react, after the reaction was completed, the temperature was lowered, tetrahydrofuran (100 g) and methyl tert-butyl ether (50 g) were added to the reaction flask, stirred for 2 hours, and white solid was precipitated, then filtered under nitrogen protection and dried to obtain white solid product, monomethyl sulfate salt of compound of formula IV-1 (12.27 g, yield 73.01%).

[0126] MS (ESI) m / z = 200.25 [M+H] +

[0127] 1 H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 7.80 (s, 1H), 7.80-7.77 (m, 1H), 7.45-7.30 (m, 1H), 4.20 (s, 3H), 3.95 (s, 3H).

[0128] Example 4

[0129]

[0130] To a three-necked flask was added compound of formula IV-1, 5-chloro-2- methoxyphenylhydrazine (2 g, 10 mmol) and methylhydrazine sulfate (1.59 g, 11 mmol), potassium carbonate (4.15 g, 30 mmol) and acetonitrile (20 g) were added, the reaction was stirred at 50-70 °C, after the reaction was completed, the temperature was lowered, the insoluble matter was removed by filtration, the filtrate was concentrated to remove the solvent to obtain the compound of formula V-1 as a light yellow oil (crude product, 100% yield).

[0131] MS (ESI) m / z = 212.0 [M-H] -

[0132] Example 5

[0133]

[0134] To a three-necked flask was added compound of formula V-1, 5-chloro-2- methoxy-N'-methylphenylhydrazine (2.14 g, 10 mmol) and formic acid (10 g, 220 mmol), the reaction was stirred at 100-110 °C, after the reaction was completed, the temperature was lowered, water (20 g) was added to the reaction flask, the white solid was precipitated after adjusting the pH to 9-10, the white solid product 6 (1.36 g, 65%) was obtained by filtration. Alternatively, the white solid was dissolved in ethyl acetate (20 ml), concentrated sulfuric acid was added to precipitate the sulfate salt of compound of formula VI-1 as a light yellow solid, the product was obtained after filtration and drying.

[0135] MS (ESI) m / z = 224.0 [M+H] +

[0136] 1 H NMR (400 MHz, D20) δ = 9.43 (s, 1H), 7.48 (d, J = 2.7, 1H), 7.25 (dd, J = 9.0, 2.7, 1H), 6.88 (d, J = 9.1, 1H), 4.01 (s, 3H), 3.74 (s, 3H).

[0137] Example 6

[0138]

[0139] Into a three-necked flask was added concentrated sulfuric acid (18.27 g), and the temperature was lowered to -10-10 °C. A compound of formula VI-1, 3-(5-chloro-2-methoxyphenyl)-l-methyl-lH-l,2,4-triazole (4.5 g, 20 mmol) was slowly added to the concentrated sulfuric acid, and the system was stirred to dissolve. The temperature of the system was controlled between -10-10 °C, and 65%-68% nitric acid (2.32 g, 25 mmol) was added dropwise. After the dropwise addition was completed, the reaction was continued. After the reaction was completed, water (45 g) was added dropwise to the reaction flask. After the dropwise addition was completed, a large amount of white solid was precipitated. The solid was filtered, and the filter cake was washed to obtain a white solid of the crude compound 7. The crude compound was recrystallized from a methanol / water system to obtain a yellowish solid of the compound of formula VII-1 (4.5 g, 83%).

[0140] MS (ESI) m / z = 269.0 [M+H] +

[0141] 1 H NMR (400 MHz, CDC13) δ 8.26 (d, J = 2.7 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J = 2.7 Hz, 1H), 4.05 (s, 3H), 3.96 (s, 3H).

[0142] Example 7

[0143]

[0144] Into a hydrogenation flask was added a compound of formula VII-1, 3-(5-chloro-2-methoxy-3-nitrophenyl)-l-methyl-lH-l,2,4-triazole compound 7 (2 g, 7.5 mmol), sodium carbonate (1.18 g, 11 mmol), 10% palladium-carbon (46 mg), and methanol (24 ml). After the reaction flask was sealed, the system was replaced with nitrogen, and then hydrogen was introduced. The pressure was maintained at 0.5-2.0 MPa, and the reaction was stirred while the temperature was maintained at 35-40 °C. After the reaction was completed, the reaction solution was removed, and the insoluble matter was filtered off. The methanol was removed by concentration. The solid after the concentration was dissolved in dichloromethane, and then washed with brine. The organic phase was dried with anhydrous sodium sulfate, and then dichloromethane was removed by concentration under reduced pressure to obtain a white solid of the compound of formula VIII (1.36 g, 90%).

[0145] MS (ESI) m / z = 205.0 [M+H] +

[0146] 1H NMR (400 MHz, CDC13) δ = 8.07 (s, 1H), 7.33 (dd, J = 7.8, 1.6, 1H), 6.98 (t, J = 7.8, 1H), 6.80 (dd, J = 7.8, 1.6, 1H), 3.97 (s, 3H), 3.94 (s, 2H), 3.76 (s, 3H).

[0147] Finally, it should be pointed out that the above examples are merely intended to illustrate the technical solutions of the present application and not to limit the same. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or equivalently replaced without departing from the spirit and scope of the present application, and all such modifications and equivalents should be encompassed within the scope of the claims of the present application.

Claims

1. A compound of formula V: ,in, X can be Cl, Br, or I.

2. A method for preparing a compound of formula V, characterized in that, The process includes the following steps: reacting compound IV, methylhydrazine, and a basic reagent to prepare compound V. ， Where X represents Cl, Br, or I.

3. A method for preparing a compound of formula V-1, characterized in that, The structure of compound V-1 is as follows: This includes the following steps: a. Compound I-1, 5-chlorosalicylic acid, reacts with dimethyl sulfate to give compound II-1. ； b. The compound of formula II-1 reacts with an ammonia source reagent to give the compound of formula III-1. ; c. The reaction of compound III-1 with a methyl source compound yields compound IV-1. ； d. Compound IV-1 reacts with methylhydrazine under alkaline conditions to give compound V-1. 。 4. The method for preparing a compound of formula V-1 according to claim 3, characterized in that, In step d, the molar ratio of compound IV-1 to methylhydrazine is 1:0.8~1.2, the molar ratio of compound IV-1 to basic reagent is 1:2~4, and the reaction temperature is 50~70℃.

5. The method for preparing a compound of formula V-1 according to claim 4, characterized in that, The reaction conditions in step c also include a reaction temperature of 70-85°C and a molar ratio of compound III-1 to methyl source compound of 1:1-5.

6. A method for preparing 2-methoxy-3-(1-methyl-1H-1,2,3-triazol-3-yl)halobenzene, characterized in that, Compound V is cyclized under acidic conditions to yield compound VI. ， Where X represents Cl, Br, or I.

7. A method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, characterized in that, Includes the following steps: e. Compound V-1 is cyclized under acidic conditions to yield compound VI-1. ； f. Nitrosating compound VI-1 yields compound VII-1. ； g. The compound of formula VII-1 is reduced to give compound VIII, 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline. 。 8. The method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline according to claim 7, characterized in that: In step e, compound V is cyclized under acidic conditions, which include an acidic reagent, and the molar ratio of compound V to the acidic reagent is 1:20~25; the reaction is carried out at a temperature of 100~110℃ with stirring.

9. The method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline according to claim 8, characterized in that: In step f, add concentrated sulfuric acid, cool to -10~10℃, add compound IV to concentrated sulfuric acid, stir, add digestion reagent dropwise, filter, and recrystallize.

10. The use of compound V for the preparation of deuterated celexitinib. ,in, X can be Cl, Br, or I.

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