A pyrazine compound, a preparation method and application thereof, a nitro pyrazine compound, a preparation method and application thereof, and a preparation method of an upatinib intermediate

Abstract

The application provides a pyrazine compound and a preparation method and application thereof, a nitryl pyrazine compound and a preparation method and application thereof, and a preparation method of an upatin intermediate, and relates to the technical field of drug synthesis. The pyrazine compound with the structure shown in formula IV is subjected to an addition reaction with nitromethane to obtain a nitryl pyrazine compound with the structure shown in formula III, and then, under the condition of an alkaline reagent, an intramolecular cyclization-aromatization reaction is performed to obtain an upatin intermediate with the structure shown in formula II. Compared with the prior art, the application does not need to use expensive metal catalysts (such as a palladium catalyst) and other expensive silicon reagents, but only needs to use inexpensive and easily available formaldehyde aqueous solution and nitromethane, so that the production cost of the upatin intermediate is greatly reduced; and compared with the use of acetaldehyde gas, the application uses formaldehyde aqueous solution, and the operation is more simple, and the application is more conducive to industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, and particularly relates to a pyrazine compound, a preparation method and application thereof, a nitryl pyrazine compound, a preparation method and application thereof, and a preparation method of an upadacitinib intermediate. BACKGROUND

[0002] Upadacitinib (CAS: 1310726-60-3, structural formula as shown in formula I) is a small molecule oral targeted drug developed by Abvie, an international leading biopharmaceutical company, and has been approved for use in the treatment of adult and 12-year-old and older adolescents with atopic dermatitis (AD), rheumatoid arthritis (RA) and psoriatic arthritis (PsA), and has become the most selective JAK1 inhibitor covering the most indications in China. In the clinical trials of treating various autoimmune diseases and inflammatory diseases, upadacitinib has shown good efficacy.

[0003]

[0004] At present, the preparation method of upadacitinib mainly includes the following steps: compound II-1 is subjected to protection, aromatic nucleophilic substitution reaction to obtain compound E, then compound E is subjected to substitution, ring closure and deprotection to obtain compound A, and finally urea condensation reaction is performed to prepare upadacitinib, and the reaction route is as follows:

[0005]

[0006] As can be seen from the above reaction route, compound II-1 is one of the key intermediates of upadacitinib. The preparation methods of compound II-1 mainly include routes 1-3.

[0007] Route 1: Compound V-1 is coupled with a silicon reagent (compound I) in the presence of a palladium and copper catalyst to obtain compound H, and then ring closure is performed with a strong base to prepare compound II-1. However, the silicon reagent and the palladium catalyst used in the above preparation method are expensive, the production cost is high, and industrial production is difficult to realize.

[0008]

[0009] Route 2: Compound V-1 is directly reacted with acetaldehyde in the presence of a palladium catalyst to obtain compound II-1. Although this route is simple and only has one reaction step, it also has obvious shortcomings. Not only is acetaldehyde gas used, which is inconvenient to operate, but also the palladium catalyst is expensive, and the cost of industrial production is high.

[0010]

[0011] Route 3: Compound V-1 is coupled with compound L (2-methyl-3-butyn-2-ol) under the catalysis of a combination of a palladium catalyst and a copper catalyst to generate compound K, and then ring closure with a strong base to prepare compound II-1. This route replaces the expensive silicon reagent in route 2 with the cheaper compound L, but still does not solve the problem of using an expensive palladium catalyst, resulting in high production cost.

[0012]

[0013] Therefore, it is urgent to develop a method for preparing upatinib intermediate II-1 with low production cost. SUMMARY

[0014] Therefore, the purpose of the present application is to provide a pyrazine compound, a preparation method and application thereof, a nitro-pyrazine compound, a preparation method and application thereof, and a preparation method of upatinib intermediate. The pyrazine compound having the structure shown in formula IV and the nitro-pyrazine compound having the structure shown in formula III are used as intermediates to prepare the upatinib intermediate having the structure shown in formula II. The production cost of the upatinib intermediate is low, the yield of the product is high, and the operation is simple.

[0015] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions:

[0016] The present application provides a pyrazine compound having the structure shown in formula IV:

[0017]

[0018] In the formula, X is halogen.

[0019] The present application also provides a preparation method of the pyrazine compound according to the above technical solutions, comprising the following steps:

[0020] The compound V, an aqueous formaldehyde solution, an acid and a solvent are mixed, and the obtained mixture is subjected to a condensation reaction to obtain the pyrazine compound;

[0021]

[0022] Preferably, the molar ratio of the compound V to formaldehyde in the aqueous formaldehyde solution is 1:1-10;

[0023] The formaldehyde is used in the form of an aqueous formaldehyde solution, and the mass concentration of the aqueous formaldehyde solution is 1-50%;

[0024] The acid includes one or more of hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, formic acid and phosphoric acid;

[0025] The pH value of the mixed solution is 0-6.

[0026] The solvent comprises one or more of water, a lower alcohol, tetrahydrofuran, acetonitrile, dimethylformamide and dimethyl sulfoxide.

[0027] Preferably, the temperature of the condensation reaction is 0-100 DEG C, and the time is 0.5-10 h.

[0028] The application further provides a nitro-pyrazine compound having a structure shown in formula III.

[0029]

[0030] X is halogen.

[0031] The application further provides a preparation method of the nitro-pyrazine compound in the above technical solution, comprising the following steps: mixing the pyrazine compound in the above technical solution, nitromethane and a first organic solvent, and performing an addition reaction to obtain the nitro-pyrazine compound.

[0032] Preferably, the molar ratio of the pyrazine compound to nitromethane is 1:1-20.

[0033] The first organic solvent comprises one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, toluene, diethyl ether, isopropyl ether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane and N-methyl pyrrolidone.

[0034] The temperature of the addition reaction is-30-100 DEG C, and the time is 1-20 h.

[0035] The application further provides an application of the pyrazine compound in the above technical solution or the nitro-pyrazine compound in the above technical solution in preparation of an upatin intermediate.

[0036] The application further provides a preparation method of an upatin intermediate, comprising the following steps: mixing the nitro-pyrazine compound in the above technical solution, an alkaline reagent and a second organic solvent, and performing an intramolecular cyclization-aromatization reaction to obtain an upatin intermediate having a structure shown in formula II.

[0037]

[0038] X is halogen.

[0039] Preferably, the alkaline reagent comprises one or more of a nitrogen-containing organic base, an alkali metal hydroxide, an alkali metal carbonate, an alkali metal alcoholate and an alkali metal hydride.

[0040] The molar ratio of the nitro-pyrazine compound to the basic reagent is 1:1-5.

[0041] The second organic solvent comprises one or more of dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, sulfolane, N-methyl pyrrolidone, toluene, diethyl ether, isopropyl ether, acetonitrile, 1,4-dioxane, THF, dichloromethane, chloroform, ethyl acetate, isopropyl acetate and acetone.

[0042] The temperature of the intramolecular cyclization-aromatization reaction is 0-180℃, and the time is 1-20h.

[0043] The pyrazine compound having the structure shown in formula IV is subjected to addition reaction with nitromethane to obtain a nitro-pyrazine compound having the structure shown in formula III, and then an intermediate of upatinid having the structure shown in formula II is obtained through intramolecular cyclization-aromatization reaction in the presence of a basic reagent. The intermediate of upatinid having the structure shown in formula II is prepared by using the pyrazine compound having the structure shown in formula IV and the nitro-pyrazine compound having the structure shown in formula III as intermediates. Compared with the prior art, the present application does not need to use expensive metal catalysts (such as palladium catalysts) and other expensive silicon reagents, but only uses inexpensive and readily available formaldehyde aqueous solution and nitromethane, which greatly reduces the production cost of the intermediate of upatinid; and compared with the use of acetaldehyde gas, the present application uses formaldehyde aqueous solution, which is more convenient to operate and more conducive to industrialized production. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 The hydrogen spectrum of the compound having the structure shown in IV-1;

[0045] Figure 2 The hydrogen spectrum of the compound having the structure shown in IV-2;

[0046] Figure 3 The hydrogen spectrum of the intermediate of upatinid having the structure shown in II-1;

[0047] Figure 4 The hydrogen spectrum of the intermediate of upatinid having the structure shown in II-2. DETAILED DESCRIPTION

[0048] The present application provides a pyrazine compound having the structure shown in formula IV:

[0049]

[0050] X is halogen, which can be fluorine, chlorine, bromine or iodine in specific embodiments.

[0051] The application further provides a preparation method of the pyrazine compound, comprising the following steps: mixing compound V, formaldehyde aqueous solution, acid and solvent, and performing condensation reaction on the obtained mixture to obtain the pyrazine compound.

[0052]

[0053] X is halogen, which can be fluorine, chlorine, bromine or iodine in specific embodiments.

[0054] Unless otherwise specified, the materials and equipment used in the application are commercially available in the art.

[0055] In the application, the molar ratio of compound V to formaldehyde in the formaldehyde aqueous solution can be 1:1-10, which can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5 or 1:10 in specific embodiments.

[0056] In the application, the mass concentration of the formaldehyde aqueous solution can be 1-50%, which can be 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 38%, 40%, 45% or 50% in specific embodiments.

[0057] In the application, the acid can include one or more of hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, formic acid and phosphoric acid, which can be hydrochloric acid in specific embodiments. In the application, the pH value of the mixture can be 0-6, which can be 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 in specific embodiments.

[0058] In the application, the solvent can include one or more of water, low alcohol, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), which can be water in specific embodiments; the low alcohol can include one or more of methanol, ethanol and isopropanol. In the application, the use amount ratio of compound V to solvent can be 1 mol:0.5-5 L, which can be 1 mol:0.5 L, 1 mol:1 L, 1 mol:1.2 L, 1 mol:1.5 L, 1 mol:1.8 L, 1 mol:2 L, 1 mol:2.5 L, 1 mol:3 L, 1 mol:3.5 L, 1 mol:4 L, 1 mol:4.5 L or 1 mol:5 L in specific embodiments.

[0059] In the present application, the mixing of compound V, aqueous formaldehyde solution, acid and solvent can include: adding compound V and solvent, adding acid to adjust pH value, and dropping aqueous formaldehyde solution at 0-10℃. In the present application, the temperature of the mixing can be 0-60℃, and in specific embodiments, it can be 0℃, 10℃, room temperature (20-30℃), 40℃, 50℃ or 60℃; the mixing time can be 5-100min, and in specific embodiments, it can be 5min, 10min, 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min or 100min.

[0060] In the present application, the temperature of the condensation reaction can be 0-100℃, and in specific embodiments, it can be 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃ or 100℃; the time of the second condensation reaction can be 0.5-10h, and in specific embodiments, it can be 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h or 10h.

[0061] After the condensation reaction is completed, the present application can further include post-treatment, which can include: adding water, cooling to 0-10℃, adding a basic reagent to adjust the pH value to 7-12 (in specific embodiments, it can be 7, 8, 9, 10, 11 or 12), precipitating the solid, filtering, drying the obtained solid component after water washing, to obtain the pyrazine compound. In the present application, the basic reagent can include alkali metal carbonate and / or alkali metal hydroxide, and in specific embodiments, it can be one or more of potassium carbonate, sodium carbonate, KOH and NaOH. In the present application, the drying can include vacuum drying, and the present application does not have special limitations on the conditions of the drying, and drying to constant weight is sufficient.

[0062] The present application also provides a nitryl pyrazine compound, which has the structure shown in formula III:

[0063]

[0064] In the present application, X is halogen, and in specific embodiments, it can be fluorine, chlorine, bromine or iodine.

[0065] The present application also provides a preparation method of the nitryl pyrazine compound in the above technical solution, which includes the following steps: mixing the pyrazine compound in the above technical solution, nitromethane and a first organic solvent, and performing addition reaction to obtain the nitryl pyrazine compound.

[0066] In the present application, the molar ratio of the pyrazine compound to nitromethane can be 1:1-20, and in specific embodiments, can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20.

[0067] In the present application, the first organic solvent can include one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, toluene, diethyl ether, isopropyl ether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide (DMAc), dimethyl sulfoxide, sulfolane, and N-methyl pyrrolidone. In the present application, the use amount ratio of the pyrazine compound to the first solvent can be 1 mol:0.5-5 L, and in specific embodiments, can be 1 mol:0.5 L, 1 mol:1 L, 1 mol:1.25 L, 1 mol:1.3 L, 1 mol:1.4 L, 1 mol:1.5 L, 1 mol:2 L, 1 mol:3 L, 1 mol:4 L, or 1 mol:5 L.

[0068] In the present application, the temperature of the addition reaction can be -30-100℃, and in specific embodiments, can be -30℃, -20℃, -10℃, -5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, or 100℃; the time of the addition reaction can be 1-20 h, and in specific embodiments, can be 1 h, 2 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, or 20 h.

[0069] After the addition reaction is completed, the present application can further include spin-drying the obtained addition reaction solution to obtain the nitro pyrazine compound, or the addition reaction solution obtained by the addition reaction is directly used for the next step without treatment.

[0070] The present application also provides the use of the pyrazine compound or the nitro pyrazine compound in the preparation of an intermediate of upatinib.

[0071] The present application also provides a preparation method of an intermediate of upatinib, including the following steps: mixing the nitro pyrazine compound, an alkaline reagent, and a second organic solvent to perform an intramolecular cyclization-aromatization reaction to obtain an intermediate of upatinib having a structure shown in formula II.

[0072]

[0073] wherein X is halogen, in particular fluorine, chlorine, bromine or iodine.

[0074] In the present application, the basic reagent can include one or more of nitrogen-containing organic base, alkali metal hydroxide, alkali metal carbonate, alkali metal alcoholate and alkali metal hydride; the nitrogen-containing organic base can include one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine (DMAP), in particular DBU and / or diisopropylethylamine; the alkali metal hydroxide can include one or more of sodium hydroxide, potassium hydroxide and cesium hydroxide, in particular sodium hydroxide; the alkali metal carbonate can include one or more of sodium carbonate, potassium carbonate and cesium carbonate, in particular sodium carbonate; the alkali metal alcoholate can include one or more of sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium tert-butoxide, cesium methoxide and cesium tert-butoxide; the alkali metal hydride can include one or more of sodium hydride, potassium hydride and cesium hydride.

[0075] In the present application, the molar ratio of the nitro-pyrazine compound to the basic reagent can be 1:1-5, in particular 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

[0076] In the present application, the second organic solvent can include one or more of dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, sulfolane, N-methyl pyrrolidone, toluene, diethyl ether, isopropyl ether, acetonitrile, 1,4-dioxane, THF, dichloromethane, chloroform, ethyl acetate, isopropyl acetate and acetone, in particular DMSO and / or DMF.

[0077] In the present application, the temperature of the intramolecular cyclization-aromatization reaction can be 0-180℃, in particular 0℃, 10℃, 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 85℃, 90℃, 100℃, 110℃, 120℃, 130℃, 40℃, 150℃, 160℃, 170℃ or 180℃; the time of the intramolecular cyclization-aromatization reaction can be 1-20h, in particular 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h or 20h.

[0078] After the intramolecular cyclization-aromatization reaction is completed, the application can further comprise: cooling the obtained intramolecular cyclization-aromatization reaction solution to room temperature, pouring into water, adding an acid to adjust the pH to neutral, precipitating a solid, filtering, and drying the obtained solid component after water washing to obtain an upatin intermediate having a structure shown in Formula II. In the application, the acid can comprise hydrochloric acid and / or sulfuric acid.

[0079] In order to further illustrate the application, the pyrazine compounds provided by the application, the preparation method and application thereof, the preparation method of the nitryl pyrazine compounds, the preparation method and application thereof, and the preparation method of the upatin intermediate are described in detail below in combination with examples, but they cannot be understood as limiting the protection scope of the application.

[0080] Example 1

[0081] Preparation of a compound (pyrazine compound) having a structure shown in Formula IV-1

[0082]

[0083] 100 mmol of compound V-1 and 150 mL of water were added, and hydrochloric acid was added to adjust the pH to 1; an ice water bath was used to cool to 0-10℃, and 8.7 g of formaldehyde aqueous solution (38% mass fraction, 110 mmol) was added dropwise; after the addition was completed, the ice water bath was removed, and the solution was stirred at room temperature for 30 min, and then the temperature was increased to 60℃ and reacted for 2 h; after cooling to 0-10℃, potassium carbonate was added to adjust the pH to 8, and a large amount of solid was precipitated, which was filtered, and the obtained solid component was washed with 50 mL of water and dried under vacuum to constant weight to obtain a compound having a structure shown in Formula IV-1 (yellow solid, 26.0 g, yield 98%, purity 99%).

[0084] Figure 1 The hydrogen spectrum of the compound having a structure shown in Formula IV-1 is as follows, 1 H-NMR (400M, DMSO-d6): 8.29 (1H, s), 7.32 (1H, t), 5.02 (1H, t). It can be seen that the compound having a structure shown in Formula IV-1 is successfully prepared.

[0085] Example 2

[0086] Preparation of a compound (pyrazine compound) having a structure shown in Formula IV-1

[0087]

[0088] Add 100 mmol of compound V-1 and 200 mL of methanol, adjust pH to 2 with sulfuric acid; cool to 0-10°C in an ice water bath, drop 10.3 g of formaldehyde aqueous solution (38% mass fraction, 130 mmol); after adding, remove the ice water bath, stir at room temperature for 30 min, then warm to 70°C and react for 2 h; spin off the methanol, add 200 mL of water, cool to 0-10°C, adjust pH to 8 with potassium carbonate, and a large amount of solid is precipitated, filter, wash the obtained solid component with 50 mL of water, and dry to constant weight in vacuum to obtain a compound with the structure shown in formula IV-1 (yellow solid, 25.4 g, yield 96%, purity 97%, hydrogen spectrum identical with Figure 1

[0089] Example 3

[0090] Preparation of a compound with the structure shown in formula IV-2 (pyrazine compound)

[0091]

[0092] Add 100 mmol of compound V-1 and 200 mL of methanol, adjust pH to 2 with sulfuric acid; cool to 0-10°C in an ice water bath, drop 10.3 g of formaldehyde aqueous solution (38% mass fraction, 130 mmol); after adding, remove the ice water bath, stir at room temperature for 30 min, then warm to 70°C and react for 2 h; spin off the methanol, add 200 mL of water, cool to 0-10°C, adjust pH to 8 with potassium carbonate, and a large amount of solid is precipitated, filter, wash the obtained solid component with 50 mL of water, and dry to constant weight in vacuum to obtain a compound with the structure shown in formula IV-1 (yellow solid, 25.4 g, yield 96%, purity 97%, hydrogen spectrum identical with

[0093] Figure 2 The hydrogen spectrum of the compound with the structure shown in formula IV-2 is as follows, 1 H-NMR (400M, DMSO-d6): 8.23 (1H, s), 7.52 (1H, t), 5.04 (1H, t). It can be seen that the compound with the structure shown in formula IV-2 is successfully prepared.

[0094] Example 4

[0095] Preparation of a compound with the structure shown in formula IV-2 (pyrazine compound)

[0096]

[0097] ​Add 100 mmol of compound V-2 and 180 mL of tetrahydrofuran, adjust the pH to 3 with trifluoroacetic acid; cool to 0-10°C in an ice water bath, drop 11.8 g of formaldehyde aqueous solution (38% mass fraction, 150 mmol); after adding, remove the ice water bath, stir at room temperature for 30 min, then warm to 70°C and react for 3 h; spin off the tetrahydrofuran, add 200 mL of water, cool to 0-10°C, adjust the pH to 8 with potassium carbonate, and a large amount of solid is precipitated, filter, wash the obtained solid component with 50 mL of water, and dry to constant weight in a vacuum to obtain a compound with the structure shown in formula IV-2 (yellow solid, 16.5 g, yield 94%, purity 97%, and the hydrogen spectrum is the same as that shown in formula IV-2). Figure 2

[0098] Example 5

[0099] Preparation of a compound with the structure shown in formula III-1 (nitro pyrazine compound) and formula II-1 (upatinib intermediate)

[0100]

[0101] Add 40 mmol of a compound with the structure shown in formula IV-1, 60 mmol of nitromethane, and 50 mL of dichloromethane, stir at room temperature for 1 h, spin dry, to obtain a compound with the structure shown in formula III-1 as a yellow solid; then add 50 mL of DMSO and 100 mmol of DBU, warm to 80°C and react for 6 h; cool to room temperature, pour into 300 mL of water, adjust the pH to neutral with hydrochloric acid, and a large amount of solid is precipitated, filter, wash the obtained solid component with 20 mL of water, and dry to obtain an upatinib intermediate with the structure shown in formula II-1 (yellow solid, 7.3 g, yield 92%, purity 97%).

[0102] Figure 3 The hydrogen spectrum of the upatinib intermediate with the structure shown in formula II-1 is as follows, 1 H-NMR (400M, DMSO-d6): 12.38 (1H, s), 8.37 (1H, s), 7.99 (1H, d), 6.65 (1H, d). It can be seen that the upatinib intermediate with the structure shown in formula II-1 is successfully prepared.

[0103] Example 6

[0104] Preparation of a compound with the structure shown in formula III-1 (nitro pyrazine compound) and formula II-1 (upatinib intermediate)

[0105]

[0106] ​To 40 mmol of a compound having the structure of Formula IV-1, 80 mmol of nitromethane, and 50 mL of ethyl acetate, 10 °C stirring reaction for 2 h, rotary evaporation under reduced pressure to obtain a yellow solid compound having the structure of Formula III-1; then add 80 mL of DMAc and 120 mmol of sodium carbonate powder, heated to 90 °C for 5 h; cool to room temperature, pour into 400 mL of water, adjust pH to neutral with hydrochloric acid, a large amount of solid precipitated, filter, the resulting solid component with 20 mL of water, dried to obtain the upatinib intermediate having the structure of Formula II-1 (yellow solid, 6.9 g, yield 87%, purity 96%, hydrogen spectrum is the same as Figure 3

[0107] Example 7

[0108] Preparation of compounds having the structure of Formula III-2 (nitro pyrazine compound) and Formula II-2 (upatinib intermediate)

[0109]

[0110] To 40 mmol of a compound having the structure of Formula IV-2, 50 mmol of nitromethane, and 60 mL of acetonitrile, 30 °C stirring reaction for 1 h; then add 100 mmol of sodium hydroxide, heated to 85 °C for 5 h; rotary evaporation under reduced pressure to remove acetonitrile, add 100 mL of water, adjust pH to neutral with hydrochloric acid, a large amount of solid precipitated, filter, the resulting solid component with 20 mL of water, dried to obtain the upatinib intermediate having the structure of Formula II-2 (yellow solid, 5.9 g, yield 96%, purity 97%).

[0111] Figure 4 The hydrogen spectrum of the upatinib intermediate having the structure of Formula II-2 is as follows, 1 H-NMR (400M, DMSO-d6): 12.36 (1H, s), 8.33 (1H, s), 8.01 (1H, d), 6.65 (1H, d).

[0112] Example 8

[0113] Preparation of compounds having the structure of Formula III-2 (nitro pyrazine compound) and Formula II-2 (upatinib intermediate)

[0114]

[0115] ​Add 40 mmol of compound having the structure of Formula IV-2, 100 mmol of nitromethane and 50 mL of isopropyl ether, stir the reaction at room temperature for 2 h, distill to dryness under reduced pressure to obtain a compound having the structure of Formula III-2 in the form of a yellow solid; then add 80 mL of 1,4-dioxane and 19.4 g of diisopropylethylamine (150 mmol), warm to 100 °C and react for 3 h; spin off the solvent, add 100 mL of water, adjust the pH to neutral with hydrochloric acid, precipitate a large amount of solid, filter, wash the resulting solid fraction with 20 mL of water and then slurry with 50 mL of heptane; filter again, dry the resulting solid under vacuum to obtain an upatin intermediate having the structure of Formula II-2 (yellow solid, 5.4 g, yield 88%, purity 96%).

[0116] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered within the scope of protection of the present application.

Claims

1. A method for preparing an intermediate of utpatinib, characterized in that, Includes the following steps: The pyrazine compound of Formula IV, nitromethane, and a first organic solvent are mixed and subjected to an addition reaction to obtain the nitropyrazine compound of Formula III; the first organic solvent includes one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, toluene, diethyl ether, isopropyl ether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane, and N-methylpyrrolidone. The nitropyrazine compound of Formula III, a basic reagent, and a second organic solvent are mixed and subjected to an intramolecular cyclization-aromatization reaction to obtain an utpatinib intermediate having the structure shown in Formula II; the second organic solvent includes one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, sulfolane, N-methylpyrrolidone, toluene, diethyl ether, isopropyl ether, acetonitrile, 1,4-dioxane, THF, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, and acetone; the basic reagent includes one or more of nitrogen-containing organic bases, alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, and alkali metal hydrides. The pyrazine compounds of Formula IV have the following structures The nitropyrazine compounds described in Formula III have the following structures. The utpatinib intermediate with the structure shown in Formula II has the following structure Where X is a halogen.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the nitropyrazine compound to the basic reagent is 1:1~5; The intramolecular cyclization-aromatization reaction is carried out at a temperature of 0~180℃ for a time of 1~20h.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the pyrazine compound to nitromethane is 1:1 to 20; The addition reaction is carried out at a temperature of -30 to 100°C for a duration of 1 to 20 hours.

4. The preparation method according to claim 1, characterized in that, The preparation method of the pyrazine compounds of Formula IV includes the following steps: The compound shown in Formula V, an aqueous formaldehyde solution, an acid, and a solvent are mixed, and the resulting mixture is subjected to a condensation reaction to obtain the pyrazine compound shown in Formula IV. The compound shown in Formula V has the following structure .

5. The preparation method according to claim 4, characterized in that, The molar ratio of the compound shown in Formula V to formaldehyde in the aqueous formaldehyde solution is 1:1~10; The acid includes one or more of hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, formic acid, and phosphoric acid; The pH value of the mixture is 0~6; The solvent includes one or more of water, lower alcohols, tetrahydrofuran, acetonitrile, dimethylformamide, and dimethyl sulfoxide.

6. The preparation method according to claim 4 or 5, characterized in that, The condensation reaction is carried out at a temperature of 0~100℃ for a time of 0.5~10h.

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