Preparation method of pyrazole bipyridazine compound

Abstract

The invention relates to a preparation method of a pyrazole bipyridazine compound, which comprises the following steps: (1) reacting a compound A with a compound B to obtain a compound C; wherein R1 is selected from a C1-C12 straight chain or branched chain alkyl group or a C3-C8 cycloalkyl group, and R2 is selected from hydrogen or a C1-C12 straight chain or branched chain alkyl group; (2) when R2 is C1-C12 linear chain or branched chain alkyl, the compound C is subjected to a hydrolysis reaction to obtain a compound C-1; reacting the compound C-1 with hydrazine to obtain a compound D; when R2 is hydrogen, the compound C reacts with hydrazine to obtain a compound D; and (3) reacting the compound D with a chlorination reagent to obtain a compound E. The preparation method provided by the invention mainly adopts a conventional reaction, avoids a Grignard ultralow-temperature reaction or a noble metal catalytic reaction, and is mild in reaction condition, low in comprehensive cost, easy in reaction implementation and beneficial to industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for preparing pyrazole-linked pyridazine compounds. Background Art

[0002] Pyrazole-linked pyridazine compounds are an important part of drug structures. WO2014032498A1 reported the application of a series of pyrazole-linked pyridazine compounds as highly selective anti-cancer c-Met inhibitors (such as formula A), CN115872976A reported the application of a series of pyrazole-linked pyridazine compounds as PARP-1 and c-Met dual inhibitors (such as formula B), and WO2008051808A2 reported that a series of pyrazole-linked pyridazines can regulate protein kinases for anti-cancer purposes (such as formula C). When synthesizing such pyrazole-linked pyridazine compounds, the following pyrazole-linked pyridazine intermediate (such as formula D) is usually used. How to better prepare the compound of formula D is a very meaningful topic.

[0003]

[0004] WO2014032498A1 reported a method (as shown in the following formula), in which pyrazole borate is converted into a pyrazole-linked pyridazine compound under the catalysis of a ligand palladium complex with 3,5-dichloropyridazine. Through literature retrieval, it is found that the synthesis methods adopted by most literatures, such as Journal of Medicinal chemistry (2024), 67(6), 4916 - 4935, CN115872976A, WO2008155378A1, etc., are all the same as this method, that is, the conversion is achieved through Suzuki coupling reaction. The disadvantage of this method is that the costs of the used materials pyrazole borate and the catalyst palladium ligand complex are relatively high, and due to different substituents required for the project, there are no mature varieties supplied in the market. Therefore, pyrazole borate usually needs to be prepared by oneself. When preparing, either cryogenic Grignard reaction or noble metal-catalyzed reaction is required, and the cost of preparing pyrazole borate is also relatively high, the implementation conditions are relatively harsh, which also increases the difficulty of large-scale production.

[0005]

[0006] Therefore, providing a method for preparing pyrazole-linked pyridazine compounds with simple reaction, mild conditions and low comprehensive cost is of great significance for industrial production. Summary of the Invention

[0007] To solve the above technical problems, the present invention provides a method for preparing pyrazole-linked pyridazine compounds. The preparation method provided by the present invention mainly uses conventional reactions, avoiding Grignard ultra-low temperature reactions or noble metal-catalyzed reactions. The reaction conditions are mild, the comprehensive cost is low, the reaction is easy to implement, and it is conducive to industrial production.

[0008] To achieve this purpose, the present invention adopts the following technical solutions:

[0009] The present invention provides a method for preparing pyrazole-linked pyridazine compounds, and the preparation method includes the following steps:

[0010] (1) Compound A reacts with compound B to obtain compound C; the reaction formula is as follows:

[0011]

[0012] Among them, R1 is selected from C1-C12 (such as C1, C2, C4, C6, C8, C10, C12, etc.) straight-chain or branched-chain alkyl groups or C3-C8 (such as C3, C4, C5, C6, C7, C8) cycloalkyl groups, and R2 is selected from hydrogen or C1-C12 straight-chain or branched-chain alkyl groups (such as C1, C2, C4, C6, C8, C10, C12, etc.);

[0013] (2) When R2 is a C1-C12 straight-chain or branched-chain alkyl group, compound C first undergoes a hydrolysis reaction to obtain compound C-1; compound C-1 reacts with hydrazine to obtain compound D; the reaction formula is as follows:

[0014]

[0015] When R2 is hydrogen, compound C reacts with hydrazine to obtain compound D; the reaction formula is as follows:

[0016]

[0017] (3) Compound D reacts with a chlorinating reagent to obtain compound E, and the reaction formula is as follows:

[0018]

[0019] In the present invention, the hydrazine includes hydrazine hydrate or hydrazine salt, such as any one or a combination of at least two of hydrazine hydrate, hydrazine hydrochloride, hydrazine nitrate, or hydrazine sulfate.

[0020] The preparation method provided by the present invention mainly uses conventional reactions, avoiding Grignard ultra-low temperature reactions or noble metal-catalyzed reactions. The reaction conditions are mild, the comprehensive cost is low, the reaction is easy to implement, and it is conducive to industrial production.

[0021] Preferably, in step (1), when R2 is a C1-C12 linear or branched alkyl group, the molar ratio of compound A to compound B is 1:(1 - 2) (for example, it can be 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, etc.), and preferably 1:(1 - 1.2).

[0022] Preferably, in step (1), when R2 is a C1-C12 linear or branched alkyl group, the reaction is carried out in the presence of an acid.

[0023] Preferably, the acid includes any one or a combination of at least two of p-toluenesulfonic acid, benzenesulfonic acid, or methanesulfonic acid.

[0024] Preferably, the molar ratio of compound A to the acid is 1:(0.02 - 0.2) (for example, it can be 1:0.02, 1:0.05, 1:0.08, 1:0.1, 1:0.12, 1:0.15, 1:0.18, 1:0.2, etc.), and preferably 1:(0.1 - 0.15).

[0025] Preferably, in step (1), when R2 is a C1-C12 linear or branched alkyl group, the reaction is carried out in the presence of a solvent.

[0026] Preferably, the solvent includes any one or a combination of at least two of toluene, xylene, or benzene.

[0027] Preferably, in step (1), when R2 is a C1-C12 linear or branched alkyl group, the reaction temperature is 100 - 120 °C (for example, it can be 100 °C, 105 °C, 110 °C, 120 °C, etc.), and the reaction time is 12 - 32 h (for example, it can be 12 h, 14 h, 16 h, 18 h, 20 h, 28 h, 32 h, etc.).

[0028] Preferably, in step (1), when R2 is a C1-C12 linear or branched alkyl group, the reaction further includes a post-treatment step.

[0029] Preferably, the post-treatment includes: adding water to the reaction system and stirring, and obtaining compound C by filtration.

[0030] Preferably, in step (1), when R2 is hydrogen, the molar ratio of compound A to compound B is 1:(1 - 2) (for example, it can be 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, etc.), and preferably 1:(1 - 1.1).

[0031] Preferably, in step (1), when R2 is hydrogen, the reaction is carried out in the presence of a base.

[0032] Preferably, the base includes any one or a combination of at least two of potassium hydroxide, sodium hydroxide, or lithium hydroxide.

[0033] Preferably, the molar ratio of compound A to the base is 1:(1 - 3) (for example, it can be 1:1, 1:1.5, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, etc.), and preferably 1:(1 - 1.5).

[0034] Preferably, in step (1) when R2 is hydrogen, the reaction is carried out in the presence of a solvent.

[0035] Preferably, the solvent includes water.

[0036] Preferably, in step (1) when R2 is hydrogen, the material mixing method of the reaction includes: mixing compound B and the solvent, adding the base and compound A in sequence, and then reacting to obtain compound C.

[0037] Preferably, the addition temperatures of the base and compound A are each independently 0 - 10°C (for example, it can be 0°C, 2°C, 4°C, 6°C, 8°C, 10°C, etc.).

[0038] Preferably, in step (1) when R2 is hydrogen, the temperature of the reaction is 20 - 30°C (for example, it can be 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, etc.), and the reaction time is 12 - 20 h (for example, it can be 12 h, 14 h, 16 h, 18 h, 20 h, etc.).

[0039] Preferably, in step (1) when R2 is hydrogen, the reaction further includes a post - treatment step.

[0040] Preferably, the post - treatment includes: adding acid to the reaction system to adjust the pH to 7.5 - 8.5 (for example, it can be 7.5, 7.8, 8, 8.2, 8.5, etc.), then extracting, adding acid to the aqueous phase to adjust the pH to 4 - 5 (for example, it can be 4, 4.2, 4.4, 4.6, 4.8, 5, etc.) to obtain a solution of compound C.

[0041] Preferably, the acid includes glacial acetic acid.

[0042] Preferably, the solvent used for extraction includes dichloromethane.

[0043] Preferably, in step (2) when R2 is a C1 - C12 straight - chain or branched - chain alkyl group, the hydrolysis reaction is carried out in the presence of a base.

[0044] Preferably, the base includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0045] Preferably, the molar ratio of compound C to the base is 1:(1 - 3) (for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.).

[0046] Preferably, when R2 is a C1-C12 straight-chain or branched-chain alkyl group in step (2), the hydrolysis reaction is carried out in the presence of a solvent.

[0047] Preferably, the solvent includes water.

[0048] Preferably, when R2 is a C1-C12 straight-chain or branched-chain alkyl group in step (2), the temperature of the hydrolysis reaction is 0-10 °C (such as 0 °C, 2 °C, 4 °C, 6 °C, 8 °C, 10 °C, etc.), and the time of the hydrolysis reaction is 0.5-1.5 h (such as 0.5 h, 0.8 h, 1 h, 1.2 h, 1.5 h, etc.).

[0049] Preferably, when R2 is a C1-C12 straight-chain or branched-chain alkyl group in step (2), the hydrolysis reaction is followed by a post-treatment step.

[0050] Preferably, the post-treatment includes: adding an acid to the reaction system to adjust the pH to 2-5 (such as 2, 2.5, 3, 3.5, 4, 4.5, 5, etc.) to obtain a solution of compound C-1.

[0051] Preferably, the acid includes glacial acetic acid.

[0052] Preferably, when R2 is a C1-C12 straight-chain or branched-chain alkyl group in step (2), the molar ratio of compound C to hydrazine is 1:(1-4) (such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.), preferably 1:(1-1.5).

[0053] Preferably, when R2 is a C1-C12 straight-chain or branched-chain alkyl group in step (2), the temperature of the reaction between compound C-1 and hydrazine is 80-100 °C (such as 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, etc.), and the time is 12-20 h (such as 12 h, 14 h, 16 h, 18 h, 20 h, etc.).

[0054] Preferably, when R2 is hydrogen in step (2), the molar ratio of compound C to hydrazine is 1:(1-4) (such as 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.), preferably 1:(1-2).

[0055] Preferably, when R2 is hydrogen in step (2), the temperature of the reaction between compound C and hydrazine is 80-100 °C (such as 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, etc.), and the time is 12-20 h (such as 12 h, 14 h, 16 h, 18 h, 20 h, etc.).

[0056] Preferably, the chlorinating reagent in step (3) includes any one or a combination of at least two of phosphorus oxychloride, thionyl chloride, or phosphorus pentachloride.

[0057] Preferably, the molar ratio of compound D to the chlorinating reagent in step (3) is 1:(1 - 3) (for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.), and preferably 1:(1.5 - 2).

[0058] Preferably, the reaction in step (3) is carried out in the presence of a base.

[0059] Preferably, the base includes any one or a combination of at least two of diisopropylethylamine, triethylamine, or 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU).

[0060] Preferably, the molar ratio of compound D to the base is 1:(1 - 3) (for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.), and preferably 1:(2 - 2.5).

[0061] Preferably, the reaction in step (3) is carried out in the presence of a solvent.

[0062] Preferably, the solvent includes any one or a combination of at least two of acetonitrile, tetrahydrofuran, toluene, or ethylene glycol dimethyl ether.

[0063] Preferably, the material mixing method of the reaction in step (3) includes: mixing compound D and the solvent, sequentially adding the chlorinating reagent and the base, and then reacting to obtain compound E.

[0064] Preferably, the addition temperature of the chlorinating reagent is 5 - 10°C (for example, it can be 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, etc.).

[0065] Preferably, the addition temperature of the base is 10 - 20°C (for example, it can be 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, etc.).

[0066] Preferably, the temperature of the reaction in step (3) is 50 - 90°C (for example, it can be 50°C, 60°C, 70°C, 80°C, 90°C, etc.), and the reaction time is 8 - 16 h (for example, it can be 8 h, 10 h, 12 h, 14 h, 16 h, etc.).

[0067] Preferably, the reaction in step (3) further includes a post - treatment step.

[0068] Preferably, the post - treatment includes: mixing the reaction system with water, and after extraction, washing, drying, decolorization, concentration, and recrystallization, obtaining compound E.

[0069] Preferably, the solvent used for recrystallization includes acetonitrile.

[0070] Preferably, the preparation method includes the following steps:

[0071] (1) Mix compound A, compound B, an acid and a solvent, and react at 100 - 120 °C for 12 - 20 h to obtain compound C; the molar ratio of compound A, compound B and the acid is 1:(1 - 2):(0.02 - 0.2); wherein, R1 is selected from C1 - C12 straight-chain or branched-chain alkyl or C3 - C8 cycloalkyl, and R2 is C1 - C12 straight-chain or branched-chain alkyl;

[0072] Alternatively, mix compound B and a solvent, add a base and compound A in sequence at 0 - 10 °C, then react at 20 - 30 °C for 12 - 20 h, add an acid to the reaction system to adjust the pH to 7.5 - 8.5, then perform extraction, add an acid to the aqueous phase to adjust the pH to 4 - 5 to obtain a solution of compound C; the molar ratio of compound A, compound B and the base is 1:(1 - 2):(1 - 3); wherein, R1 is C1 - C12 straight-chain or branched-chain alkyl and R2 is hydrogen;

[0073] (2) When R2 is C1 - C12 straight-chain or branched-chain alkyl, mix compound C, a base and a solvent, and perform hydrolysis reaction at 0 - 10 °C for 0.5 - 1.5 h, add an acid to the reaction system to adjust the pH to 2 - 5 to obtain a solution of compound C-1; mix the solution of compound C-1 and hydrazine, and react at 80 - 100 °C for 12 - 20 h to obtain compound D; the molar ratio of compound C and hydrazine is 1:(1 - 4);

[0074] When R2 is hydrogen, mix the solution of compound C and hydrazine, and react at 80 - 100 °C for 12 - 20 h to obtain compound D; the molar ratio of compound C and hydrazine is 1:(1 - 4);

[0075] (3) Mix compound D and a solvent, add a chlorinating reagent at 5 - 10 °C, add a base at 10 - 20 °C, then react at 50 - 90 °C for 8 - 16 h, mix the reaction system and water, and obtain compound E after extraction, washing, drying, decolorization, concentration and recrystallization; the molar ratio of compound D, the chlorinating reagent and the base is 1:(1 - 3):(1 - 3).

[0076] Compared with the prior art, the present invention has at least the following beneficial effects:

[0077] The preparation method provided by the present invention mainly uses conventional reactions, avoiding Grignard ultra-low temperature reactions or noble metal-catalyzed reactions. The reaction conditions are mild, the comprehensive cost is low, the reaction is easy to implement, and it is beneficial to industrial production. Detailed implementation manners

[0078] To facilitate the understanding of the present invention, the following examples are listed. Those skilled in the art should understand that the said examples are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0079] Example 1

[0080] This example provides a preparation method of pyrazole - linked pyridazine compounds, and the reaction formula is as follows:

[0081]

[0082] Synthesis of C1:

[0083] Glyoxylic acid (50% aqueous solution) (148 g, 0.1 mol) was diluted with 296 g of water. Under an ice - water bath, potassium hydroxide (5.6 g, 0.1 mol) was added, and the temperature was controlled at 5°C. Then potassium hydroxide (11.2 g, 0.2 mol) was added. After stirring until completely dissolved and clear, 1 - (1 - methyl - 1H - pyrazol - 4 - yl) - ethanone (A1, 12.4 g, 0.1 mol) was added dropwise while controlling the temperature at 5°C. After addition, the temperature was naturally raised to 25°C, and stirring was continued for 16 h. The temperature was lowered by an ice - water bath, acetic acid was added to adjust the pH to 8, 100 g of dichloromethane was added, and after stirring and separating the liquid, the organic phase was separated. The aqueous phase was further adjusted to pH = 4 with acetic acid to obtain 4 - (1 - methyl - 1H - pyrazol - 4 - yl) - 4 - oxo - 2 - butenoic acid (C1), which was directly used in the next step without purification.

[0084] Synthesis of D1:

[0085] Hydrazine hydrate (80% aqueous solution) (15.6 g, 0.25 mol) was added to the above - mentioned system of C1, and the reaction was refluxed for 16 h. After cooling to 25°C, filtration and drying were carried out to obtain yellow solid 6 - (1 - methyl - 1H - pyrazol - 4 - yl)pyridazin - 3(2H) - one (D1, 14.1 g, yield 80%).

[0086] Compound D1: MS(ESI+): 177.2;

[0087] 1 H NMR(400 MHz, d6 - DMSO), δ 3.90(s, 3H), 6.95(d, J = 9.8 Hz, 1H), 7.78(d, J = 9.8 Hz, 1H), 7.88(s, 1H), 8.22(s, 1H), 12.92(s, 1H).

[0088] Synthesis of E1:

[0089] D1 (17.6 g, 0.1 mol) was added to 170 mL of acetonitrile, stirred until dissolved, cooled to 5 °C, phosphorus oxychloride (22.7 g, 0.15 mol) was added dropwise, the temperature was controlled at 15 °C, then diisopropylethylamine (19.4 g, 0.15 mol) was added, the temperature was raised to 70 °C and stirring was continued for 12 h. The reaction solution was poured into ice water, extracted with dichloromethane, separated, washed with saturated sodium bicarbonate solution until weakly alkaline, dried over sodium sulfate, decolorized with activated carbon, filtered by suction, concentrated, recrystallized with acetonitrile again, filtered, and dried to obtain a yellow solid 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (E1, 17.1 g, yield 88%).

[0090] Compound E1: MS(ESI+): 195.2;

[0091] 1 1H NMR (400 MHz, d6-DMSO), δ 3.94 (s, 3H), 7.89 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 9.0 Hz, 1H), 8.16 (s, 1H), 8.50 (s, 1H).

[0092] Example 2

[0093] This example provides a method for preparing a pyrazole-linked pyridazine compound, and the reaction formula is as follows:

[0094]

[0095] Synthesis of C2:

[0096] 1-(1-Methyl-1H-pyrazol-4-yl)-ethanone (A1, 12.4 g, 0.1 mol), ethyl glyoxylate (12.2 g, 0.12 mol), p-toluenesulfonic acid (3.8 g, 0.02 mol), and 124 mL of toluene were added to a reaction flask, heated under reflux for 16 h, cooled to 25 °C, a solid precipitated, 100 mL of water was added and stirred for 30 min, filtered, and dried to obtain a white solid ethyl 4-(1-methyl-1H-pyrazol-4-yl)-4-oxo-2-butenoate (C2).

[0097] Compound C2:

[0098] MS(ESI+): 209.2;

[0099] 11H NMR (400 MHz, d6-DMSO), δ 1.35 (t, J = 7.2 Hz, 3H), 3.98 (s, 3H), 4.29 (q, J = 7.2 Hz, 2H), 6.90 (d, J = 15.6 Hz, 1H), 7.55 (d, J = 15.6 Hz, 1H), 8.00 (s, 1H), 8.02 (s, 1H).

[0100] Synthesis of D1:

[0101] Add C2 (20.8 g, 0.1 mol) to the reaction flask, add 208 mL of water, and under an ice-water bath, add sodium hydroxide (4.8 g, 0.12 mol). After 1 h, add glacial acetic acid (9 g, 0.15 mol) to obtain compound C2-1. Add hydrazine hydrate (80% aqueous solution) (15.6 g, 0.25 mol) to the system, reflux for 16 h, cool to 25 °C, filter, and dry to obtain the yellow solid 6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (D1, 13.2 g, yield 75%).

[0102] Synthesis of E1:

[0103] Add D1 (17.6 g, 0.1 mol) to 170 mL of acetonitrile, stir to dissolve, cool to 5 °C, dropwise add phosphorus oxychloride (22.7 g, 0.15 mol), control the temperature at 15 °C, then add diisopropylethylamine (19.4 g, 0.15 mol), heat to 80 °C and continue stirring for 16 h. Pour the reaction solution into ice water, extract with dichloromethane, separate, wash with saturated sodium bicarbonate solution until weakly alkaline, dry with sodium sulfate, decolorize with activated carbon, filter, concentrate, recrystallize with acetonitrile, filter, and dry to obtain the yellow solid 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (E1, 17.1 g, yield 88%).

[0104] Example 3

[0105] This example provides a preparation method of pyrazole-linked pyridazine compounds. The reaction formula refers to Example 1, and the difference from Example 1 is only that the synthesis method of E1 is different:

[0106] Synthesis of E1:

[0107]

[0108] D1 (17.6 g, 0.1 mol) was added to 170 mL of ethylene glycol dimethyl ether, stirred until dissolved, cooled to 5 °C, and thionyl chloride (23.8 g, 0.2 mol) was added dropwise. The temperature was controlled at 25 °C, then triethylamine (20.2 g, 0.2 mol) was added, and the temperature was raised to 80 °C and stirred for 12 h. The reaction solution was poured into ice water, extracted with ethyl acetate, separated, washed with saturated sodium bicarbonate solution until weakly alkaline, dried over sodium sulfate, decolorized with activated carbon, filtered by suction, concentrated, recrystallized with acetonitrile, filtered, and dried to obtain 16.5 g of a yellow solid, 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (E1), with a yield of 85%.

[0109] Example 4

[0110] This example provides a method for preparing pyrazole-linked pyridazine compounds, and the reaction formula is as follows:

[0111]

[0112] Synthesis of C2a:

[0113] 1-(1-Cyclopropyl-1H-pyrazol-4-yl)-ethanone (A2, 15.0 g, 0.1 mol), ethyl glyoxylate (12.2 g, 0.12 mol), benzenesulfonic acid (3.16 g, 0.02 mol), and 124 mL of toluene were added to a reaction flask, heated to reflux for 26 h, cooled to 25 °C, and a solid precipitated. 100 mL of water was added and stirred for 30 min, then filtered and dried to obtain 4-(1-cyclopropyl-1H-pyrazol-4-yl)-4-oxo-2-butenoic acid ethyl ester (C2a) as a white solid.

[0114] Compound C2a:

[0115] MS(ESI+): 235.2.

[0116] Synthesis of D2:

[0117] C2a (23.4 g, 0.1 mol) was added to a reaction flask, 208 mL of water was added, and under an ice-water bath, potassium hydroxide (6.73 g, 0.12 mol) was added. After 2 h, glacial acetic acid (9 g, 0.15 mol) was added to obtain compound C2b; hydrazine hydrate (80% aqueous solution) (15.6 g, 0.25 mol) was added to the system, and the mixture was refluxed for 26 h, cooled to 25 °C, filtered, and dried to obtain 16.2 g of a yellow solid, 6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (D2), with a yield of 80%.

[0118] Compound D2:

[0119] MS(ESI+): 203.2.

[0120] Synthesis of E2:

[0121] Add D2 (20.2 g, 0.1 mol) to 200 mL of toluene, stir to dissolve, cool down to 5 °C, dropwise add phosphorus oxychloride (45.4 g, 0.3 mol), control the temperature at 45 °C, then add DBU (45.6 g, 0.3 mol), heat up to 100 °C and continue stirring for 16 h. Pour the reaction solution into ice water, extract with ethyl acetate, separate the layers, wash with saturated sodium bicarbonate solution until weakly alkaline, dry with sodium sulfate, decolorize with activated carbon, filter by suction, concentrate, and then recrystallize with acetonitrile, filter, and dry to obtain 17.2 g of yellow solid 3-chloro-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridazine (E2), with a yield of 78%.

[0122] Compound E2:

[0123] MS(ESI+): 221.1;

[0124] 1 H NMR(400 MHz, d6-DMSO), δ 1.19–0.89 (m, 4H), 3.91–3.75 (m, 1H), 7.88 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 8.13 (s, 1H), 8.58 (s, 1H).

[0125] Example 5

[0126] This example provides a preparation method of pyrazole-linked pyridazine compounds, and the reaction formula is as follows:

[0127]

[0128] Synthesis of C3a:

[0129] Add 1-(1-isopropyl-1H-pyrazol-4-yl)-ethanone (A2, 15.2 g, 0.1 mol), ethyl glyoxylate (12.2 g, 0.2 mol), methanesulfonic acid (1.92 g, 0.02 mol), and 150 mL of toluene to the reaction flask, heat under reflux for 26 h, cool down to 25 °C, and a solid precipitates. Add 100 mL of water, stir for 30 min, filter, and dry to obtain white solid ethyl 4-(1-isopropyl-1H-pyrazol-4-yl)-4-oxo-2-butenoate (C3a).

[0130] Compound C3a:

[0131] MS(ESI+): 237.2.

[0132] Synthesis of D3:

[0133] Add C3a (23.6 g, 0.1 mol) to a reaction flask, add 236 mL of water, and under an ice-water bath, add lithium hydroxide (2.88 g, 0.12 mol). After 2 h, add glacial acetic acid (9 g, 0.15 mol) to obtain compound C3b; add hydrazine hydrate (80% aqueous solution) (15.6 g, 0.25 mol) to the system, reflux for 26 h, cool to 25 °C, filter and dry to obtain the yellow solid 6-(1-isopropyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one (D3, 15.9 g, yield 78%).

[0134] Compound D3:

[0135] MS(ESI+): 205.1.

[0136] Synthesis of E3:

[0137] Add D3 (20.4 g, 0.1 mol) to 200 mL of acetonitrile, stir to dissolve, cool to 5 °C, dropwise add phosphorus oxychloride (45.4 g, 0.3 mol), control the temperature at 45 °C, then add DBU (45.6 g, 0.3 mol), heat to 100 °C and continue stirring for 16 h. Pour the reaction solution into ice water, extract with ethyl acetate, separate, wash with saturated sodium bicarbonate solution until weakly alkaline, dry over sodium sulfate, decolorize with activated carbon, filter, concentrate, and then recrystallize with acetonitrile, filter and dry to obtain the yellow solid 3-chloro-6-(1-isopropyl-1H-pyrazol-4-yl)pyridazine (E3, 19.8 g, yield 89%).

[0138] Compound E3:

[0139] MS(ESI+): 223.1.

[0140] The applicant declares that the above is only the specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A method for preparing a pyrazole-linked pyridazine compound, characterized in that, The preparation method comprises the following steps: (1) Compound A and Compound B react to obtain Compound C; the reaction formula is as follows: Wherein, R1 is selected from C1-C12 straight-chain or branched-chain alkyl or C3-C8 cycloalkyl, and R2 is selected from hydrogen or C1-C12 straight-chain or branched-chain alkyl; (2) When R2 is C1-C12 straight-chain or branched-chain alkyl, Compound C first undergoes a hydrolysis reaction to obtain Compound C-1; Compound C-1 and hydrazine react to obtain Compound D; the reaction formula is as follows: When R2 is hydrogen, Compound C and hydrazine react to obtain Compound D; the reaction formula is as follows: (3) Compound D and a chlorinating reagent react to obtain Compound E, the reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that, In step (1), when R2 is C1-C12 straight-chain or branched-chain alkyl, the molar ratio of Compound A to Compound B is 1:(1-2); Preferably, in step (1), when R2 is C1-C12 straight-chain or branched-chain alkyl, the reaction is carried out in the presence of an acid; Preferably, the acid includes any one or a combination of at least two of p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid; Preferably, the molar ratio of Compound A to the acid is 1:(0.02-0.2); Preferably, in step (1), when R2 is C1-C12 straight-chain or branched-chain alkyl, the reaction is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of toluene, xylene or benzene.

3. The preparation method according to claim 1 or 2, characterized in that, In step (1), when R2 is C1-C12 straight-chain or branched-chain alkyl, the reaction temperature is 100-120 °C, and the reaction time is 12-32 h; Preferably, in step (1), when R2 is C1-C12 straight-chain or branched-chain alkyl, the reaction further includes a post-treatment step; Preferably, the post-treatment includes: adding water to the reaction system and stirring, and filtering to obtain Compound C.

4. The preparation method according to any one of claims 1-3, characterized in that, In step (1), when R2 is hydrogen, the molar ratio of Compound A to Compound B is 1:(1-2); Preferably, in step (1), when R2 is hydrogen, the reaction is carried out in the presence of a base; Preferably, the base includes any one or a combination of at least two of potassium hydroxide, sodium hydroxide or lithium hydroxide; Preferably, the molar ratio of Compound A to the base is 1:(1-3); Preferably, in step (1), when R2 is hydrogen, the reaction is carried out in the presence of a solvent; Preferably, the solvent includes water.

5. The preparation method according to any one of claims 1-4, characterized in that, In step (1), when R2 is hydrogen, the material mixing method of the reaction includes: mixing Compound B and the solvent, sequentially adding the base and Compound A, and then reacting to obtain Compound C; Preferably, the addition temperature of the base and Compound A is independently 0-10 °C; Preferably, in step (1), when R2 is hydrogen, the reaction temperature is 20-30 °C, and the reaction time is 12-20 h; Preferably, in step (1), when R2 is hydrogen, the reaction further includes a post-treatment step; Preferably, the post-treatment includes: adding acid to the reaction system to adjust the pH to 7.5-8.5, then extracting, adding acid to the aqueous phase to adjust the pH to 4-5 to obtain a solution of Compound C.

6. The preparation method according to any one of claims 1-5, characterized in that, Step (2) When R2 is a C1-C12 straight-chain or branched-chain alkyl group, the hydrolysis reaction is carried out in the presence of a base; Preferably, the base includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, or lithium hydroxide; Preferably, the molar ratio of compound C to the base is 1:(1-3); Preferably, in step (2) when R2 is a C1-C12 straight-chain or branched-chain alkyl group, the hydrolysis reaction is carried out in the presence of a solvent; Preferably, the solvent includes water.

7. The preparation method according to any one of claims 1-6, characterized in that, In step (2) when R2 is a C1-C12 straight-chain or branched-chain alkyl group, the temperature of the hydrolysis reaction is 0-10 °C, and the time of the hydrolysis reaction is 0.5-1.5 h; Preferably, in step (2) when R2 is a C1-C12 straight-chain or branched-chain alkyl group, the hydrolysis reaction further includes a post-treatment step; Preferably, the post-treatment includes: adding an acid to the reaction system to adjust the pH to 2-5 to obtain a solution of compound C-1; Preferably, in step (2) when R2 is a C1-C12 straight-chain or branched-chain alkyl group, the molar ratio of compound C to hydrazine is 1:(1-4); Preferably, in step (2) when R2 is a C1-C12 straight-chain or branched-chain alkyl group, the temperature of the reaction between compound C-1 and hydrazine is 80-100 °C, and the time is 12-20 h.

8. The preparation method according to any one of claims 1-7, characterized in that, In step (2) when R2 is hydrogen, the molar ratio of compound C to hydrazine is 1:(1-4); Preferably, in step (2) when R2 is hydrogen, the temperature of the reaction between compound C and hydrazine is 80-100 °C, and the time is 12-20 h.

9. The preparation method according to any one of claims 1-8, characterized in that, Step (3) The chlorinating reagent includes any one or a combination of at least two of phosphorus oxychloride, thionyl chloride, or phosphorus pentachloride; Preferably, in step (3), the molar ratio of compound D to the chlorinating reagent is 1:(1-3); Preferably, in step (3), the reaction is carried out in the presence of a base; Preferably, the base includes any one or a combination of at least two of diisopropylethylamine, triethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; Preferably, the molar ratio of compound D to the base is 1:(1-3); Preferably, in step (3), the reaction is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of acetonitrile, tetrahydrofuran, toluene, or ethylene glycol dimethyl ether.

10. The preparation method according to any one of claims 1-9, characterized in that, The material mixing method of the reaction in step (3) includes: mixing compound D and the solvent, sequentially adding the chlorinating reagent and the base, and then reacting to obtain compound E; Preferably, the addition temperature of the chlorinating reagent is 5-10 °C; Preferably, the addition temperature of the base is 10-20 °C; Preferably, in step (3), the temperature of the reaction is 50-90 °C, and the time of the reaction is 8-16 h; Preferably, in step (3), the reaction further includes a post-treatment step; Preferably, the post-treatment includes: mixing the reaction system with water, and after extraction, washing, drying, decolorization, concentration, and recrystallization, compound E is obtained.

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