Pyrazine compound and preparation method and application thereof, nitropyrazine compound and preparation method and application thereof, and preparation method of upatinib intermediate

Abstract

The invention provides a pyrazine compound and a preparation method and application thereof, a nitropyrazine compound and a preparation method and application thereof, and a preparation method of an upatinib intermediate, and relates to the technical field of medicine synthesis. The pyrazine compound with the structure as shown in the formula IV and nitromethane are subjected to an addition reaction to obtain a nitropyrazine compound with the structure as shown in the formula III, and then the upatinib intermediate with the structure as shown in the formula II can be obtained through an intramolecular cyclization-aromatization reaction in the presence of an alkaline reagent. Compared with the prior art, an expensive metal catalyst (such as a palladium catalyst) and other expensive silicon reagents do not need to be used, only the formaldehyde aqueous solution and nitromethane which are low in price and easy to obtain are used, and the production cost of the upatinib intermediate is greatly reduced; moreover, compared with the use of acetaldehyde gas, the formaldehyde aqueous solution is used, so that the operation is simpler and more convenient, and industrial production is more facilitated. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a pyrazine compound and a preparation method and application thereof, a nitropyrazine compound and a preparation method and application thereof, and a preparation method of an upadacitinib intermediate. Background Art

[0002] Upadacitinib (CAS: 1310726-60-3, structural formula as shown in Formula I) is a small molecule oral targeted drug developed by AbbVie, a leading international biopharmaceutical company. It has been approved for the treatment of atopic dermatitis (AD), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in adults and adolescents aged 12 and above, becoming the selective JAK1 inhibitor with the most indications in my country. In clinical trials for the treatment of various autoimmune diseases and inflammatory diseases, Upadacitinib has shown good efficacy.

[0003]

[0004] At present, the preparation method of upadacitinib mainly comprises: compound II-1 is subjected to protection and aromatic nucleophilic substitution reaction to obtain compound E, which is then subjected to substitution, ring closure and deprotection with compound D to generate compound A, and finally a urea condensation reaction is carried out to prepare upadacitinib. The reaction route is as follows:

[0005]

[0006] From the above reaction route, it can be seen that compound II-1 is one of the key intermediates of upadacitinib. There are three main methods for preparing compound II-1: routes 1 to 3.

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

[0008]

[0009] Route 2: Compound V-1 and acetaldehyde react directly under the action of palladium catalyst to obtain compound II-1. Although this route is simple and has only one step reaction, it also has obvious disadvantages. Not only does it require the use of acetaldehyde gas, which is inconvenient to operate, but the palladium catalyst is expensive and the industrial production cost is high.

[0010]

[0011] Route 3: Compound V-1 and compound L (2-methyl-3-butyn-2-ol) are coupled under the combined catalysis of palladium catalyst and copper catalyst to generate compound K, and then a strong base is used to close the ring 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 expensive palladium catalyst, resulting in high production cost.

[0012]

[0013] Therefore, it is urgent to develop a method for preparing upadacitinib intermediate II-1 with low production cost. Summary of the invention

[0014] In view of this, the object of the present invention is to provide a pyrazine compound and a preparation method and application thereof, a nitropyrazine compound and a preparation method and application thereof, and a preparation method of an upadacitinib intermediate. The pyrazine compound having a structure shown in formula IV and the nitropyrazine compound having a structure shown in formula III provided by the present invention are used as intermediates to prepare an upadacitinib intermediate having a structure shown in formula II, and the production cost of the upadacitinib intermediate is low, the product yield is high, and the operation is simple.

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

[0016] The present invention provides a pyrazine compound having a structure shown in Formula IV:

[0017]

[0018] Wherein, X is a halogen.

[0019] The present invention also provides a method for preparing the pyrazine compound described in the above technical solution, comprising the following steps:

[0020] Mixing compound V, formaldehyde aqueous solution, acid and solvent, and subjecting the obtained mixed solution to a condensation reaction to obtain the pyrazine compound;

[0021]

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

[0023] The formaldehyde is used in the form of a formaldehyde aqueous solution, the mass concentration of the formaldehyde aqueous solution is 1 to 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 to 6;

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

[0027] Preferably, the condensation reaction temperature is 0 to 100° C. and the time is 0.5 to 10 h.

[0028] The present invention also provides a nitropyrazine compound having a structure shown in Formula III:

[0029]

[0030] Wherein, X is a halogen.

[0031] The present invention also provides a method for preparing the nitropyrazine compound described in the above technical solution, comprising the following steps: mixing the pyrazine compound described in the above technical solution, nitromethane and a first organic solvent, and performing an addition reaction to obtain the nitropyrazine compound.

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

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

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

[0035] The present invention also provides use of the pyrazine compound described in the above technical solution or the nitropyrazine compound described in the above technical solution in the preparation of upadacitinib intermediates.

[0036] The present invention also provides a method for preparing an upadacitinib intermediate, comprising the following steps: mixing the nitropyrazine compound, an alkaline reagent and a second organic solvent described in the above technical scheme, and performing an intramolecular cyclization-aromatization reaction to obtain an upadacitinib intermediate having a structure shown in formula II;

[0037]

[0038] Wherein, X is a halogen.

[0039] Preferably, the alkaline agent 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 nitropyrazine compound to the alkaline agent is 1:1 to 5;

[0041] The second organic solvent includes one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, sulfolane, N-methylpyrrolidone, toluene, 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 to 180° C., and the time is 1 to 20 hours.

[0043] The pyrazine compound having a structure shown in Formula IV provided by the present invention is subjected to an addition reaction with nitromethane to obtain a nitropyrazine compound having a structure shown in Formula III, and then an upadacitinib intermediate having a structure shown in Formula II is obtained by an intramolecular cyclization-aromatization reaction in the presence of an alkaline reagent. The upadacitinib intermediate having a structure shown in Formula II is prepared using the pyrazine compound having a structure shown in Formula IV provided by the present invention and the nitropyrazine compound having a structure shown in Formula III as intermediates. Compared with the prior art, the present invention does not need to use expensive metal catalysts (such as palladium catalysts) and other expensive silicon reagents, and only uses cheap and readily available formaldehyde aqueous solution and nitromethane, which greatly reduces the production cost of the upadacitinib intermediate; moreover, compared with the use of acetaldehyde gas, the present invention uses formaldehyde aqueous solution, which is simpler to operate and more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0045] Figure 2 is a hydrogen spectrum of a compound having a structure shown in formula IV-2;

[0046] Figure 3 is a hydrogen spectrum of the upadacitinib intermediate having the structure shown in formula II-1;

[0047] Figure 4 It is a hydrogen spectrum of the upadacitinib intermediate having the structure shown in formula II-2. DETAILED DESCRIPTION

[0048] The present invention provides a pyrazine compound having a structure shown in Formula IV:

[0049]

[0050] Wherein, X is a halogen, and in a specific embodiment, it can be fluorine, chlorine, bromine or iodine.

[0051] The present invention also provides a method for preparing the pyrazine compound described in the above technical solution, comprising the following steps: mixing compound V, formaldehyde aqueous solution, acid and solvent, and subjecting the obtained mixed solution to a condensation reaction to obtain the pyrazine compound;

[0052]

[0053] Wherein, X is a halogen, and in a specific embodiment, it can be fluorine, chlorine, bromine or iodine.

[0054] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0055] In the present invention, the molar ratio of the compound V to formaldehyde in the formaldehyde aqueous solution can be 1:1-10, and in specific embodiments 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.

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

[0057] In the present invention, the acid may 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, and in a specific embodiment, it may be hydrochloric acid. In the present invention, the pH value of the mixed solution may be 0 to 6, and in a specific embodiment, it may be 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6.

[0058] In the present invention, the solvent may include one or more of water, lower alcohol, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), and in a specific embodiment, it may be water; the lower alcohol may include one or more of methanol, ethanol and isopropanol. In the present invention, the amount ratio of the compound V to the solvent may be 1 mol: 0.5 to 5 L, and in a specific embodiment, it may 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.

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

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

[0061] After completing the condensation reaction, the present invention may further include post-treatment, which may include: adding water, cooling to 0-10°C, adding an alkaline agent to adjust the pH value to 7-12 (in a specific embodiment, it may be 7, 8, 9, 10, 11 or 12), precipitating a solid, filtering, washing the obtained solid component with water and drying to obtain the pyrazine compound. In the present invention, the alkaline agent may include an alkali metal carbonate and / or an alkali metal hydroxide, which may be one or more of potassium carbonate, sodium carbonate, KOH and NaOH in a specific embodiment. In the present invention, the drying may include vacuum drying, and the present invention has no special restrictions on the conditions for the drying, and drying to constant weight is sufficient.

[0062] The present invention also provides a nitropyrazine compound having a structure shown in Formula III:

[0063]

[0064] Wherein, X is a halogen, and in a specific embodiment, it can be fluorine, chlorine, bromine or iodine.

[0065] The present invention also provides a method for preparing the nitropyrazine compound described in the above technical solution, comprising the following steps: mixing the pyrazine compound described in the above technical solution, nitromethane and a first organic solvent, and performing an addition reaction to obtain the nitropyrazine compound.

[0066] In the present invention, 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 invention, the first organic solvent may include one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, toluene, ether, isopropyl ether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide (DMAc), dimethyl sulfoxide, cyclopentane and N-methylpyrrolidone. In the present invention, the amount ratio of the pyrazine compound to the first solvent may be 1 mol: 0.5 to 5 L, and in a specific embodiment may 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 invention, the temperature of the addition reaction can be -30 to 100°C, and in specific embodiments can be -30°C, -20°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the time of the addition reaction can be 1 to 20h, and in specific embodiments can be 1h, 2h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h or 20h.

[0069] After the addition reaction is completed, the present invention may further include spinning the obtained addition reaction liquid to dryness to obtain the nitropyrazine compound, or the addition reaction liquid obtained by the addition reaction is directly used in the next reaction without being treated.

[0070] The present invention also provides use of the pyrazine compound described in the above technical solution or the nitropyrazine compound described in the above technical solution in the preparation of upadacitinib intermediates.

[0071] The present invention also provides a method for preparing an upadacitinib intermediate, comprising the following steps: mixing the nitropyrazine compound, an alkaline reagent and a second organic solvent described in the above technical scheme, and performing an intramolecular cyclization-aromatization reaction to obtain an upadacitinib intermediate having a structure shown in formula II;

[0072]

[0073] Wherein, X is a halogen, and in a specific embodiment, it can be fluorine, chlorine, bromine or iodine.

[0074] In the present invention, the alkaline reagent may include 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; the nitrogen-containing organic base may include one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine (DMAP), and in a specific embodiment, may be DBU and / or diisopropylethylamine; the alkali metal hydroxide may include one or more of sodium hydroxide, potassium hydroxide and cesium hydroxide, and in a specific embodiment, may be sodium hydroxide; the alkali metal carbonate may include one or more of sodium carbonate, potassium carbonate and cesium carbonate, and in a specific embodiment, may be sodium carbonate; the alkali metal alcoholate may 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 may include one or more of sodium hydride, potassium hydride and cesium hydride.

[0075] In the present invention, the molar ratio of the nitropyrazine compound to the alkaline agent can be 1:1-5, and in specific embodiments can be 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 invention, the second organic solvent may include one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, sulfolane, N-methylpyrrolidone, toluene, ether, isopropyl ether, acetonitrile, 1,4-dioxane, THF, dichloromethane, chloroform, ethyl acetate, isopropyl acetate and acetone, and in a specific embodiment may be DMSO and / or DMF.

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

[0078] After completing the intramolecular cyclization-aromatization reaction, the present invention may further include: cooling the obtained intramolecular cyclization-aromatization reaction solution to room temperature, pouring it into water, adding acid to adjust the pH to neutral, precipitating solids, filtering, washing the obtained solid components with water and then drying them to obtain an upadacitinib intermediate having a structure shown in Formula II. In the present invention, the acid may include hydrochloric acid and / or sulfuric acid.

[0079] To further illustrate the present invention, the pyrazine compounds and preparation methods and uses thereof, the nitropyrazine compounds and preparation methods and uses thereof, and the preparation method of upadacitinib intermediates provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0080] Example 1

[0081] Preparation of the compound represented by the structure of formula IV-1 (pyrazine compound)

[0082]

[0083] Add 100 mmol of compound V-1 and 150 mL of water, and adjust the pH to 1 with hydrochloric acid; cool to 0-10°C in an ice-water bath, and add dropwise 8.7 g of formaldehyde aqueous solution (38% mass fraction, 110 mmol); remove the ice-water bath after the addition, stir at room temperature for 30 minutes, and then raise the temperature to 60°C to react for 2 hours; cool to 0-10°C, adjust the pH to 8 with potassium carbonate, a large amount of solid precipitated, filter, wash the obtained solid component with 50 mL of water, and vacuum dry to constant weight to obtain a compound with the structure shown in formula IV-1 (yellow solid, 26.0 g, yield 98%, purity 99%).

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

[0085] Example 2

[0086] Preparation of the compound represented by the structure of formula IV-1 (pyrazine compound)

[0087]

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

[0089] Example 3

[0090] Preparation of the compound represented by the structure of formula IV-2 (pyrazine compound)

[0091]

[0092] Add 100 mmol of compound V-2 and 120 mL of ethanol, and adjust the pH to 1 with methanesulfonic acid; cool to 0-10°C in an ice-water bath, and add dropwise 9.5 g of formaldehyde aqueous solution (38% mass fraction, 120 mmol); remove the ice-water bath after addition, stir at room temperature for 30 minutes, and then heat to 50°C for reaction for 3 hours; spin off the ethanol, add 200 mL of water, cool to 0-10°C, adjust the pH to 8 with potassium carbonate, precipitate a large amount of solid, filter, wash the obtained solid component with 50 mL of water, and vacuum dry to obtain a compound with the structure shown in formula IV-2 (yellow solid, 16.7 g, yield 95%, purity 98%).

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

[0094] Example 4

[0095] Preparation of the compound of 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, and add 11.8 g of formaldehyde aqueous solution (38% mass fraction, 150 mmol) dropwise; remove the ice-water bath after the addition, stir at room temperature for 30 minutes, then heat to 70°C and react for 3 hours; spin off the tetrahydrofuran, add 200 mL of water, cool to 0-10°C, adjust the pH to 8 with potassium carbonate, precipitate a large amount of solid, filter, wash the obtained solid component with 50 mL of water, and vacuum dry to constant weight to obtain a compound of the structure shown in formula IV-2 (yellow solid, 16.5 g, yield 94%, purity 97%, hydrogen spectrum and Figure 2 same).

[0098] Example 5

[0099] Preparation of compounds having structures represented by formula III-1 (nitropyrazine compounds) and formula II-1 (upadacitinib intermediates)

[0100]

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

[0102] Figure 3 is a hydrogen spectrum of the upadacitinib intermediate having the structure shown in formula II-1, 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 present invention successfully prepared the upadacitinib intermediate having the structure shown in formula II-1.

[0103] Example 6

[0104] Preparation of compounds having structures represented by formula III-1 (nitropyrazine compounds) and formula II-1 (upadacitinib intermediates)

[0105]

[0106] 40 mmol of a compound having a structure shown in formula IV-1, 80 mmol of nitromethane and 50 mL of ethyl acetate were added, the reaction was stirred at 10 ° C for 2 h, and the mixture was dried under reduced pressure to obtain a yellow solid compound having a structure shown in formula III-1; then 80 mL of DMAc and 120 mmol of sodium carbonate powder were added, the temperature was raised to 90 ° C for reaction for 5 h; cooled to room temperature, poured into 400 mL of water, the pH was adjusted to neutral with hydrochloric acid, a large amount of solid was precipitated, filtered, and the obtained solid component was washed with 20 mL of water and dried to obtain an upadacitinib intermediate having a structure shown in formula II-1 (yellow solid, 6.9 g, yield 87%, purity 96%, hydrogen spectrum and Figure 3 same).

[0107] Example 7

[0108] Preparation of compounds having structures shown in formula III-2 (nitropyrazine compounds) and formula II-2 (upadacitinib intermediates)

[0109]

[0110] Add 40mmol of a compound having a structure shown in formula IV-2, 50mmol of nitromethane and 60mL of acetonitrile, and stir the reaction at 30°C for 1h; then add 100mmol of sodium hydroxide, raise the temperature to 85°C and react for 5h; remove the acetonitrile by distillation under reduced pressure, add 100mL of water, adjust the pH to neutral with hydrochloric acid, precipitate a large amount of solid, filter, wash the obtained solid component with 20mL of water, and dry to obtain an upadacitinib intermediate having a structure shown in formula II-2 (yellow solid, 5.9g, yield 96%, purity 97%).

[0111] Figure 4 is a hydrogen spectrum of the upadacitinib intermediate having the structure shown in formula II-2, 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 structures shown in formula III-2 (nitropyrazine compounds) and formula II-2 (upadacitinib intermediates)

[0114]

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

[0116] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pyrazine compound, characterized in that: It has the structure shown in Formula IV: Wherein, X is a halogen.

2. The method for preparing the pyrazine compound according to claim 1, characterized in that: The following steps are involved: Mixing compound V, formaldehyde aqueous solution, acid and solvent, and subjecting the obtained mixed solution to a condensation reaction to obtain the pyrazine compound; 3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound V to the formaldehyde in the formaldehyde aqueous 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 mixed solution is 0 to 6; The solvent includes one or more of water, lower alcohol, tetrahydrofuran, acetonitrile, dimethylformamide and dimethyl sulfoxide.

4. The preparation method according to claim 2 or 3, characterized in that: The condensation reaction temperature is 0 to 100° C. and the reaction time is 0.5 to 10 hours.

5. A nitropyrazine compound, characterized in that: It has the structure shown in formula III: Wherein, X is a halogen.

6. The method for preparing the nitropyrazine compound according to claim 5, comprising the following steps: The pyrazine compound according to claim 1, nitromethane and a first organic solvent are mixed and subjected to an addition reaction to obtain the nitropyrazine compound.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the pyrazine compound to nitromethane is 1:1 to 20; The first organic solvent comprises one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetone, toluene, ether, isopropyl ether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane and N-methylpyrrolidone; The temperature of the addition reaction is -30 to 100° C., and the time is 1 to 20 hours.

8. Use of the pyrazine compound according to claim 1 or the nitropyrazine compound according to claim 5 in the preparation of an upadacitinib intermediate.

9. A method for preparing an upadacitinib intermediate, characterized in that: The following steps are involved: Mixing the nitropyrazine compound according to claim 5, an alkaline reagent and a second organic solvent, and performing an intramolecular cyclization-aromatization reaction to obtain an upadacitinib intermediate having a structure shown in Formula II; Wherein, X is a halogen.

10. The preparation method according to claim 9, characterized in that: The alkaline reagent includes 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; The molar ratio of the nitropyrazine compound to the alkaline agent is 1:1 to 5; The second organic solvent includes one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, sulfolane, N-methylpyrrolidone, toluene, ether, isopropyl ether, acetonitrile, 1,4-dioxane, THF, dichloromethane, chloroform, ethyl acetate, isopropyl acetate and acetone; The temperature of the intramolecular cyclization-aromatization reaction is 0 to 180° C., and the time is 1 to 20 hours.

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