Preparation methods of diketone compounds and imidazole derivatives

Abstract

This disclosure provides a method for preparing diketone compounds and an imidazole derivative, belonging to the field of pharmaceutical technology. The method for preparing diketone compounds eliminates the need for chemicals such as zirconium oxychloride, which are seriously harmful to humans, thus reducing harm to human health and the environment. Furthermore, the preparation process avoids the large-scale use of acids, preventing the generation of large amounts of acidic wastewater, thereby reducing wastewater treatment volume and environmental pollution.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing diketone compounds and an imidazole derivative. Background Technology

[0002] The imidazole group is a component of histidine, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA) purines in organisms. The hydrogen atom in the imidazole ring can migrate between the two nitrogen atoms, exhibiting good electron transfer and easy functionalization, resulting in a wide range of biological activities in imidazole derivatives. For example, patent application CN103025731A discloses a compound represented by chemical formula I, which exhibits biological activity inhibiting ALK5 and / or ALK4, and can be used to inhibit tumors and abnormal proliferative diseases, showing promise as a novel antitumor drug.

[0003]

[0004] Where R 10 It is an alkyl group or other group having 1 to 6 carbon atoms; R 20 It can be F, Cl, Br, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, etc.

[0005] The diketone compounds represented by chemical formula II are key intermediates for the synthesis of imidazole derivatives represented by chemical formula I.

[0006]

[0007] In the prior art, the diketone compounds represented by chemical formula II are synthesized using the method shown in synthetic route 1 below:

[0008]

[0009] According to the above synthetic steps, in preparing chemical formula II, the raw material aI needs to be reacted with aniline and diphenyl phosphite under the action of zirconium oxychloride to obtain NP acetal intermediate b-II. This step requires the use of zirconium oxychloride, which is highly hazardous to human health, and isopropanol. This not only causes serious water pollution, but isopropanol residues are also likely to remain, resulting in the final product not meeting the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) requirements for isopropanol (isopropanol residue not exceeding 0.5%). In preparing intermediate c-III, intermediate b-II needs to be further coupled with [1,2,4]triazole[1,5-a]pyridine-6-carboxaldehyde under alkaline conditions, followed by acidic hydrolysis to generate a monoketone, thus obtaining intermediate c-III. This step requires the use of large amounts of cesium carbonate and tetrahydrofuran and isopropanol as solvents. The post-treatment process necessitates repeated adjustments of the acid-base balance, making the process complex and prone to damaging equipment in large-scale production. It also generates a large volume of wastewater, and the presence of residual isopropanol can lead to the final product failing to meet ICH regulations regarding isopropanol. In the preparation of the diketone compounds shown in Formula 2, DMSO (dimethyl sulfoxide) and HBr are used to oxidize intermediate c-III. The large amount of HBr used in the reaction not only causes significant damage to equipment but also generates substantial wastewater, resulting in severe environmental pollution.

[0010] The information disclosed in the background section is only for enhancing the understanding of the background of the present invention, and therefore may include information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0011] The purpose of this invention is to provide a method for preparing diketone compounds and imidazole derivatives, thereby reducing environmental pollution during the preparation of imidazole derivatives.

[0012] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0013] According to a first aspect of the present invention, a method for preparing a diketone compound is provided, wherein the diketone compound has the structural formula shown in Chemical Formula 2:

[0014]

[0015] Each R1 is independently selected from deuterium, halogen group, cyano, alkyl group with 1 to 6 carbon atoms, alkoxy group with 1 to 6 carbon atoms, or haloalkyl group with 1 to 6 carbon atoms.

[0016] The preparation method of the diketone compound includes:

[0017] Step 1

[0018]

[0019] The compound represented by chemical formula P1 reacts with sulfur and bromoethane to produce the compound represented by chemical formula P2.

[0020] Step Two

[0021]

[0022] The compound represented by chemical formula P2 reacts with the compound represented by chemical formula P3 to produce a diketone compound represented by chemical formula II.

[0023] According to a second aspect of the present invention, a method for preparing an imidazole derivative is provided, wherein the structure of the imidazole derivative is shown in Chemical Formula 1:

[0024]

[0025] R1 is independently selected from deuterium, halogen group, cyano, alkyl group with 1 to 6 carbon atoms, alkoxy group with 1 to 6 carbon atoms, or haloalkyl group with 1 to 6 carbon atoms.

[0026] R2 is fluorine, chlorine, bromine, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms;

[0027] The preparation method of the imidazole derivative includes the preparation method of the above-mentioned diketone compounds.

[0028] According to the preparation methods of diketone compounds and imidazole derivatives provided by the present invention, the preparation of diketone compounds represented by Formula 2 does not require the use of chemicals such as zirconium oxychloride, which are seriously harmful to humans, thus reducing the harm of these hazardous materials to human health and the environment. Furthermore, the preparation process reduces the large-scale use of acid, avoiding the generation of large amounts of acidic wastewater, thereby reducing wastewater treatment volume and environmental pollution. Detailed Implementation

[0030] The exemplary embodiments will now be described more fully. However, these exemplary embodiments can be implemented in many forms and should not be construed as limited to the examples set forth herein; rather, they are provided so that the invention will be more comprehensive and complete, and will fully convey the concept of the exemplary embodiments to those skilled in the art. The described features may be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided to give a full understanding of embodiments of the invention.

[0031] The terms "first" and "second" are used only as markers and are not a limitation on the number of objects.

[0032] In this invention, "alkyl" can include straight-chain alkyl and branched-chain alkyl. An alkyl group can have a specified number of carbon atoms, for example, an alkyl group having 1 to 6 carbon atoms. In this invention, numerical ranges such as "1 to 6" used to define the number of carbon atoms refer to integers within a given range; for example, "alkyl group having 1 to 6 carbon atoms" means an alkyl group that can contain 1, 2, 3, 4, 5, or 6 carbon atoms. An alkyl group can be a lower alkyl group having 1 to 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atoms.

[0033] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), etc.

[0034] In this application, the halogen group used as a substituent is fluorine, chlorine, bromine, or iodine.

[0035] In this application, "alkoxy" means an alkyl group attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and so on.

[0036] In this application, "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, and examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc. In one embodiment, the C1-C6 haloalkyl comprises a fluorinated C1-C6 alkyl group; in another embodiment, the C1-C4 haloalkyl comprises a fluorinated C1-C4 alkyl group; and in yet another embodiment, the C1-C2 haloalkyl comprises a fluorinated C1-C2 alkyl group.

[0037] This invention provides a method for preparing a diketone compound, the structural formula of which is shown in Chemical Formula II:

[0038]

[0039] R1 is selected from deuterium, halogen groups, cyano groups, alkyl groups with 1 to 6 carbon atoms, alkoxy groups with 1 to 6 carbon atoms, or haloalkyl groups with 1 to 6 carbon atoms.

[0040] Optionally, R1 is selected from methyl, ethyl, isopropyl, and tert-butyl.

[0041] In this application, the diketone compounds represented by Chemical Formula 2 are selected from the structures shown below:

[0042]

[0043] The preparation method of the diketone compound, as shown in compound 2, includes the following steps:

[0044] Step 1

[0045]

[0046] The compound represented by chemical formula P1, elemental sulfur, and bromoethane react to produce the compound represented by chemical formula P2.

[0047] Step Two

[0048]

[0049] The compound represented by chemical formula P2 and the compound represented by chemical formula P3 undergo a coupling reaction to generate a diketone compound represented by chemical formula II.

[0050] According to the method for preparing diketone compounds provided by the present invention, the preparation of diketone compounds represented by chemical formula II does not require the use of chemicals such as zirconium oxychloride, which are seriously harmful to humans, thus reducing the harm of these hazardous materials to human health and the environment. Furthermore, the preparation process avoids the large-scale use of acids, preventing the generation of large amounts of acidic wastewater, thereby reducing wastewater treatment volume and environmental pollution.

[0051] Optionally, in step one, the reaction mixture of the compound represented by chemical formula P1, elemental sulfur, bromoethane, the first base, and the first solvent reacts to generate the compound represented by chemical formula P2. Thus, in step one, the use of a large amount of acidic solution is avoided; instead, the reaction occurs in an alkaline environment, preventing potential pollution from large amounts of acidic wastewater. Furthermore, because the reaction occurs under alkaline conditions, the reaction products do not form salts. After the reaction, the products can be directly separated by extraction or other methods without adjusting the pH, reducing post-processing steps and wastewater volume, and simplifying the post-processing procedure.

[0052] Alternatively, in step one, the elemental sulfur is cyclooctasulfide (S8).

[0053] Further optionally, in step one, the ratio of the compound represented by chemical formula P1 to elemental sulfur is 1:(1-2) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P1 to elemental sulfur is 1:(1.2-2) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P1 to elemental sulfur is 1:(1.5-1.8) in molar amounts.

[0054] Further optionally, in step one, the ratio of the compound represented by chemical formula P1 to bromoethane is 1:(1.2-2) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P6 to bromoethane is 1:(1.2-1.8) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P6 to bromoethane is 1:1.8 in molar amounts.

[0055] Optionally, in step one, the first base is an alkali metal salt of an inorganic base or a weak organic acid, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate, sodium hydroxide, or other commonly used alkali metal salts of inorganic bases or weak organic acids. On the one hand, this avoids the use of organic bases, such as triethylamine, diisopropylethylamine, pyridine, etc., reducing the organic matter content in the wastewater and minimizing environmental pollution. On the other hand, alkali metal salts of inorganic bases or weak organic acids not only cause less environmental pollution than organic bases, but also reduce environmental pollution by generating and recovering solid waste through concentration. Furthermore, these alkali metal salts of inorganic bases or weak organic acids have better solubility in the aqueous phase, allowing for effective separation from the reaction products during extraction and reducing the difficulty of purifying the reaction products.

[0056] Optionally, in step one, the first alkali is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium acetate, and sodium hydroxide to ensure that the first alkali has high solubility and low cost. More specifically, the first alkali is selected from one of sodium bicarbonate, potassium bicarbonate, or potassium acetate.

[0057] Further optionally, in step one, the ratio of the compound represented by chemical formula P1 to the first base is 1:(1-2) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P1 to the first base is 1:(1.6-2.0) in molar amounts. Further optionally, the ratio of the compound represented by chemical formula P1 to the first base is 1:2.0 in molar amounts.

[0058] Further optionally, in step one, the molar amount of the first base is not less than the molar amount of bromoethane.

[0059] Further optionally, in step one, the first solvent is a mixture of a first organic solvent and water, wherein the first organic solvent includes one or more of aromatic hydrocarbon solvents, amide solvents, ether solvents, and nitrile solvents; wherein, by volume, the ratio of the first organic solvent to water is 1:(0.2~0.5). Thus, in this step one, a mixed solvent of organic solvent and water can be used, and the product can be separated by extraction after the reaction is completed.

[0060] More specifically, in step one, aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mesitylene. Amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. Ether solvents include, but are not limited to, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, and anisole. Nitrile solvents include, but are not limited to, acetonitrile and valerate.

[0061] Optionally, in step one, the first organic solvent is selected from toluene, dimethylformamide, cyclopentyl methyl ether, dioxane, anisole, and acetonitrile. More preferably, the first organic solvent is toluene or anisole to improve reaction efficiency.

[0062] Optionally, in step one, the ratio of the first organic solvent to water is 1:0.2 by volume.

[0063] Optionally, in step one, the molar amount of the compound represented by chemical formula P1: the volume of the first solvent = 1 mmol: (2-3) mL.

[0064] Optionally, in step one, the reaction system for preparing the compound represented by chemical formula P2 further includes a first phase transfer catalyst to improve reaction efficiency. That is, a mixture of the compound represented by chemical formula P1, elemental sulfur, bromoethane, a first base, a first phase transfer catalyst, and a first solvent reacts to produce the compound represented by chemical formula P2.

[0065] Optionally, in step one, the reaction mixture further includes a first phase transfer catalyst, which is selected from tetrabutylammonium bromide, 18-crown-6-ether, 15-crown-5-ether, TEBAC (benzyltriethylammonium chloride), and TBAC (tetrabutylammonium chloride). More preferably, the first phase transfer catalyst is tetrabutylammonium bromide.

[0066] Optionally, in step one, the molar ratio of the compound represented by chemical formula P1 to the first phase transfer catalyst is 1:(0.05~0.2). Further optionally, the molar ratio of the compound represented by chemical formula P1 to the first phase transfer catalyst is 1:0.1.

[0067] Further optionally, in step one, the mixture comprising the compound represented by chemical formula P1, elemental sulfur, bromoethane, a first base, and a first solvent is reacted at 60°C to 85°C, i.e., the reaction temperature is 60°C to 85°C. Alternatively, the reaction temperature is 70°C to 85°C. Alternatively, the reaction temperature is 80°C to 85°C.

[0068] In a more specific embodiment of the present invention, in step one, the reaction system is a mixture of the compound represented by chemical formula P1, elemental sulfur, bromoethane, a first base, a first phase transfer catalyst, and a first solvent, wherein, in molar amounts, the ratio of the compound represented by chemical formula P6: elemental sulfur: bromoethane: first base: first phase transfer catalyst = 1:1.5:1.8:2:0.1; the first solvent includes toluene and water, wherein the volume ratio of toluene to water is 10:2.

[0069] Optionally, in step two, the mixture of the compound represented by chemical formula P2, the compound represented by chemical formula P3, the palladium catalyst, the second base, and the second solvent reacts to generate the diketone compound represented by chemical formula 2. In step two, this synthetic route avoids the use of large amounts of acidic solutions compared to existing preparation methods, instead reacting in an alkaline environment, thus avoiding potential pollution from large amounts of acidic wastewater. Furthermore, because the reaction occurs under alkaline conditions, the reaction products do not form salts. After the reaction, the products can be directly separated by extraction or other methods without adjusting the pH, reducing post-processing steps and wastewater volume, and simplifying the post-processing procedure.

[0070] Further optionally, in step two, the ratio of the compound represented by chemical formula P2 to the compound represented by chemical formula P3 is 1:(1 to 1.2) in molar amounts.

[0071] Further optionally, in step two, the palladium catalyst is selected from palladium acetate, palladium chloride, tetra(triphenylphosphine)palladium, dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine (II), or other divalent palladium catalysts. Optionally, the palladium catalyst is dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine (II) (Pd132).

[0072] Further optionally, in step two, the ratio of the compound represented by chemical formula P2 to the palladium catalyst is 1:(0.005~0.01) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P2 to the palladium catalyst is 1:0.005 in molar amounts.

[0073] Optionally, in step two, the second base is an alkali metal salt of an inorganic base or a weak organic acid, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium acetate, and other commonly used inorganic bases or weak organic acid alkali metal salts. On the one hand, this avoids the use of organic bases, such as triethylamine, diisopropylethylamine, pyridine, etc., reducing the organic matter content in the wastewater and minimizing environmental pollution. On the other hand, alkali metal salts of inorganic bases or weak organic acids not only cause less environmental pollution than organic bases, but also reduce environmental pollution by generating and recovering solid waste through concentration. Furthermore, these alkali metal salts of inorganic bases or weak organic acids have better solubility in the aqueous phase, allowing for effective separation from the reaction products during extraction and reducing the difficulty of purifying the reaction products.

[0074] Optionally, the second alkali is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium acetate, and sodium hydroxide to ensure that the second alkali has high solubility and low cost. More preferably, the second alkali is selected from one of sodium carbonate, potassium acetate, or potassium carbonate.

[0075] Further optionally, the ratio of the compound represented by chemical formula P2 to the second base is 1:(1-2) in molar amounts. Alternatively, the ratio of the compound represented by chemical formula P2 to the second base is 1:(1.5-2.0) in molar amounts. Further optionally, the ratio of the compound represented by chemical formula P2 to the second base is 1:2.0 in molar amounts.

[0076] Further optionally, the second solvent is a mixture of a second organic solvent and water, wherein the second organic solvent includes one or more of alcohol solvents, aromatic hydrocarbon solvents, amide solvents, ether solvents, and nitrile solvents; wherein, by volume, the ratio of the second organic solvent to water is 1:(0.2-0.5). Thus, in this second step, a mixture of organic solvent and water is preferred, allowing for direct extraction and separation of the product after the reaction is complete.

[0077] Among them, alcohol solvents include, but are not limited to, lower C1-C4 alcohols such as methanol, ethanol, ethylene glycol, and tert-butanol. Aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, and mesitylene. Amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. Ether solvents include, but are not limited to, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, and anisole. Nitrile solvents include, but are not limited to, acetonitrile and valerate.

[0078] Optionally, the second organic solvent is selected from one or more of the following solvents: alcohols, toluene, dimethylformamide, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, and acetonitrile. More preferably, the second organic solvent is toluene to improve reaction efficiency.

[0079] Optionally, the ratio of the second organic solvent to water is 3:1 by volume.

[0080] Optionally, the molar amount of the compound represented by chemical formula P2: the volume of the second solvent = 1 mmol: (3-5) mL.

[0081] Further optionally, in step two, the mixture further includes a second phase transfer catalyst. That is, the mixture of the compound represented by chemical formula P2, the compound represented by chemical formula P3, the palladium catalyst, the second base, the second phase transfer catalyst, and the second solvent reacts to generate a diketone compound represented by chemical formula 2.

[0082] Optionally, the second phase transfer catalyst is selected from tetrabutylammonium bromide, 18-crown-6-ether, 15-crown-5-ether, TEBAC (benzyltriethylammonium chloride), and TBAC (tetrabutylammonium chloride). More preferably, the second phase transfer catalyst is tetrabutylammonium bromide.

[0083] Optionally, the ratio of the compound represented by chemical formula P2 to the second phase transfer catalyst is 1:(0.05–0.1) in molar amounts. Further optionally, the ratio of the compound represented by chemical formula P2 to the second phase transfer catalyst is 1:0.05 in molar amounts.

[0084] Further optionally, the mixture comprising the compound represented by chemical formula P2, the compound represented by chemical formula P3, the palladium catalyst, the second base, and the second solvent is reacted at 60°C to 80°C, i.e., the reaction temperature is 60°C to 80°C. Alternatively, the reaction temperature is 65°C to 75°C. Alternatively, the reaction temperature is 65°C to 70°C.

[0085] In one embodiment of the present invention, the reaction system is a mixture of a compound represented by chemical formula P2, a compound represented by chemical formula P3, a palladium catalyst, a second base, a second phase transfer catalyst, and a second solvent. The molar ratio of the compound represented by chemical formula P2 to the compound represented by chemical formula P3 is 1:1.05:0.005:2:0.05. The second solvent comprises toluene and water, wherein the volume ratio of toluene to water is 3:1.

[0086] This invention also provides a method for preparing an imidazole derivative. The structure of the imidazole derivative is shown in Chemical Formula 1:

[0087]

[0088] R1 is independently selected from deuterium, halogen group, cyano, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, or haloalkyl with 1 to 6 carbon atoms; R2 is fluorine, chlorine, bromine, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, or haloalkyl with 1 to 6 carbon atoms.

[0089] Optionally, R1 in Formula 1 is selected from fluorine, chlorine, methyl, ethyl, isopropyl or tert-butyl.

[0090] Optionally, the imidazole derivative is selected from the following compounds:

[0091]

[0092] The method for preparing the imidazole derivative described in this application includes the method for preparing the diketone compounds described above. Therefore, the method for preparing the imidazole derivative has the same beneficial effects as the method for preparing the diketone compounds described above, and will not be repeated here.

[0093] Optionally, the method for preparing the imidazole derivative further includes:

[0094] Step 3

[0095]

[0096] The compound shown in chemical formula II, glyoxal dimethyl acetal, and ammonium salt react to produce the compound shown in chemical formula P4;

[0097] Step Four:

[0098]

[0099] The compound with chemical formula P4 produces the compound with chemical formula P5;

[0100] Step 5:

[0101]

[0102] The compound represented by chemical formula P5 reacts with the compound represented by chemical formula P6 to produce the compound represented by chemical formula 1.

[0103] Optionally, in step three, the ratio of the compound represented by formula II to glyoxal dimethyl acetal is 1:(2-2.5) in molar amounts. Optionally, the ratio of the compound represented by formula II to glyoxal dimethyl acetal is 1:2.0 in molar amounts.

[0104] Optionally, in step three, the ratio of the compound represented by chemical formula II to the ammonium salt is 1:(2-2.5) in molar amounts. Optionally, the ratio of the compound represented by chemical formula 2 to the ammonium salt is 1:2.2 in molar amounts.

[0105] Optionally, in step three, the ammonium salt is selected from ammonium acetate, ammonium formate, ammonium chloride, ammonium bicarbonate, or other ammonium salts.

[0106] In one embodiment of the present invention, a mixture of the compound represented by chemical formula II, glyoxal dimethyl acetal, ammonium salt, and a third solvent reacts to generate the compound represented by chemical formula P4. The glyoxal dimethyl acetal is added at a temperature of -10°C to 10°C. Optionally, the addition temperature is -5°C to 5°C, or alternatively, -5°C to 0°C.

[0107] In another embodiment of the present invention, in step three, glyoxal dimethyl acetal can be added to the reaction solution formed by the compound of chemical formula II and the third solvent at a first reaction temperature, and the reaction can be carried out to completion at the first reaction temperature; then an ammonium salt can be added to the reaction system, and the reaction can be carried out to completion at a second reaction temperature to generate the compound of chemical formula P4.

[0108] Optionally, the first reaction temperature is -10℃ to 10℃. More preferably, the first reaction temperature is -5℃ to 5℃.

[0109] In a further embodiment, the second reaction temperature is the ambient temperature.

[0110] In another further embodiment, the second reaction temperature is 15°C to 35°C. Alternatively, the second reaction temperature is 23°C to 28°C.

[0111] Optionally, the third solvent is selected from acetonitrile, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, or anisole.

[0112] Optionally, the mass of the compound represented by chemical formula II : volume of the third solvent = 1 g : (6-12) mL. Optionally, the mass of the compound represented by chemical formula 2 : volume of the third solvent = 1 g : (8-10) mL.

[0113] In one embodiment of the present invention, step four

[0114]

[0115] In step four, optionally, the compound represented by chemical formula P4 is reacted in a first acidic solvent. The first acidic solvent may be selected from acetic acid, dilute hydrochloric acid (1–3 mol / L), trifluoroacetic acid, or other acidic solvents.

[0116] Optionally, the dilute hydrochloric acid is an aqueous solution of hydrochloric acid with a concentration of 2–3 mol / L.

[0117] Optionally, the mass of the compound represented by chemical formula P4 is equal to the volume of the first acidic solvent, with a ratio of 1 g to (2-5) mL. Further optionally, the mass of the compound represented by chemical formula P4 is equal to the volume of the first acidic solvent, with a ratio of 1 g to (2-3) mL.

[0118] Optionally, when the compound represented by chemical formula P4 reacts in the first acidic solvent, the reaction temperature is 65°C to 80°C. More preferably, the reaction temperature is 70°C to 75°C.

[0119] Step 5:

[0120]

[0121] In step five, optionally, the compound represented by chemical formula P5, the compound represented by chemical formula P6, and the mixture of the second acidic solvent are reacted at a third reaction temperature; then sodium triacetoxyborohydride is added to the reaction system and reacted at a fourth reaction temperature.

[0122] Further alternatively, in molar quantities, the ratio of the compound represented by chemical formula P5 to the compound represented by chemical formula P6 is 1:(1 to 1.5).

[0123] Optionally, the second acidic solvent includes an acidic reagent and a fourth solvent. The acidic reagent is selected from acetic acid, trifluoroacetic acid, benzenesulfonic acid, or other acids.

[0124] Optionally, the ratio of the compound represented by chemical formula P5 to the acidic reagent is 1:(1-2) in molar amounts. Further optionally, the ratio of the compound represented by chemical formula P5 to the acidic reagent is 1:(1-1.2) in molar amounts.

[0125] Optionally, the fourth solvent is selected from ether solvents and haloalkane solvents, such as tetrahydrofuran, methyltetrahydrofuran, dichloromethane, dichloroethane, etc.

[0126] Optionally, the mass of the compound represented by chemical formula P5 : volume of the fourth solvent = 1 g : (8-12) mL. Further optionally, the fourth solvent is dichloroethane, and the mass of the compound represented by chemical formula P5 : volume of dichloroethane = 1 g : 10 mL.

[0127] Optionally, the third reaction temperature is 40℃~80℃. More preferably, the third reaction temperature is 60℃~70℃.

[0128] Optionally, the fourth reaction temperature is 35℃~50℃.

[0129] Optionally, when adding sodium triacetoxyborohydride, the temperature of the reaction system can be lowered to -10℃ to 10℃ or to -5℃ to 5℃, and the sodium triacetoxyborohydride can be added in batches. After the sodium triacetoxyborohydride is added, the temperature is then raised to the fourth reaction temperature.

[0130] This invention relates to a method for synthesizing diketone compounds, which are key intermediates for preparing active imidazole derivatives with ALK5 inhibitory activity. The synthetic route of this invention avoids the use of highly hazardous reagents such as zirconium oxychloride, reduces the amount of strong acids and bases used, simplifies post-processing, and reduces the use of environmentally unfriendly solvents, thus reducing environmental pollution. Therefore, the synthetic method of this application has relatively mild reaction conditions and reagent properties, simple post-processing, and is easy to purify, eliminating the need for column chromatography purification. The entire process meets the requirements of green production and is more suitable for industrial production. Detailed Implementation

[0131] To better illustrate the present invention and its effects, the preparation methods of the diketone compounds and imidazole derivatives of the present invention will be described in detail below with reference to embodiments. However, the embodiments according to this specification can be modified into various other forms, and the scope of this specification is not to be construed as limited to the embodiments described below. The embodiments are provided to describe this specification more completely to those skilled in the art.

[0132] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare many other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions claimed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0133] In the examples described below, all temperatures are specified in Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant. Raw materials were sourced commercially from suppliers such as Shanghai Shengde Pharmaceutical Technology Co., Ltd., and Shanghai Kangtuo Chemical Co., Ltd.

[0134] The reaction is generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified), and the reaction flasks are all sealed with suitable rubber stoppers. All glassware is dried.

[0135] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1×30mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid), electrospray ionization (ESI) at 210 nm / 254 nm, and UV detection.

[0136] 1H NMR spectroscopy: Bruker 400MHz NMR spectrometer, room temperature, using CDCl3 or DMSO-d6 as solvent (in ppm), with TMS (0 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet).

[0137] Example 1:

[0138] Compound 1 was prepared according to the following synthetic route 2:

[0139]

[0140] Step 1): Synthesis of intermediate 1-b

[0141] Under nitrogen protection, starting material 1-a (7.56 g, 50 mmol), S8 (19.2 g, 75 mmol), bromoethane (9.81 g, 90 mmol), NaHCO3 (8.4 g, 100 mmol), TBAB (1.62 g, 5 mmol), 100 mL toluene, and 20 mL water were added sequentially to a reaction flask. The mixture was stirred for 10 min, heated to 80℃~85℃, and maintained at this temperature for 8 h. The mixture was then extracted with toluene (100 mL * 2), the organic phase was washed with water, separated, dried, and concentrated to dryness at 50℃~60℃, -0.09 MPa~-0.08 MPa. The product was stirred with 1 g: 4 mL ethanol for 0.5 h, filtered, dried under vacuum, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa~-0.07 MPa) to obtain intermediate 1-b (9.52 g, yield 91%).

[0142] In this step, the present invention also verifies the implementation of this step by parallel experiments under various different reaction conditions, such as adjusting the amount of base, the type of base, the type and amount of phase transfer catalyst, and the type of solvent.

[0143] By verifying various reaction conditions, it was found that the base (sodium bicarbonate) in this step can also be commonly used inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, and potassium acetate. The molar ratio of the base to the intermediate 1-a is 1:(1-2). The stronger the basicity of the base used, the less of it needs to be used. In this step, the present invention mainly uses inexpensive and easily soluble inorganic bases to avoid environmental pollution caused by organic bases, especially reducing wastewater discharge containing organic matter and improving the environmental friendliness of the method.

[0144] By verifying various reaction conditions, it was found that the phase transfer catalyst (tetrabutylammonium bromide TBAB) can also be 18-crown-6-ether, 15-crown-5-ether, TEBAC (benzyltriethylammonium chloride), TBAC (tetrabutylammonium chloride), or other phase transfer catalysts. The molar ratio of the phase transfer catalyst to the molar ratio of intermediate 1-b is (0.05–0.2):1.

[0145] In step 1), when the reaction scale is large, the amount of phase transfer catalyst can be reduced to save costs and reduce environmental pollution. For example, when the mass of intermediate 1-b is greater than 1 kg, the molar amount of phase transfer catalyst: the molar amount of intermediate 1-a = (0.05~0.1):1.

[0146] In step 1), the reaction can proceed smoothly at temperatures ranging from 60℃ to 85℃; the reaction efficiency is higher at temperatures ranging from 70℃ to 85℃, and the reaction conversion rate is faster at higher temperatures.

[0147] The reaction yield was observed through parallel experiments using various different reaction solvents. To adjust the solubility of the reactants, the types of organic solvents and the ratio of organic solvent to water were screened, with better compatibility between the reactants being more conducive to the reaction. Experiments revealed that a mixture of toluene and water yielded the highest reaction rate in this step. Detailed experimental results are shown in Table 1, which discloses several different reaction conditions and their yields. The differences between the various reaction conditions in Table 1 lie in the type of solvent; other conditions (reactants, substrates, and amounts, etc.) remain consistent.

[0148] Table 1: Comparison of experimental results with different solvents

[0149]

[0150] As shown in Table 1, the highest yield was achieved when a mixture of toluene and water was used as the solvent. The second highest yield was achieved when a mixture of anisole and water was used. This is likely because the poor compatibility of the materials, resulting in low reaction conversion, is due to the combination of a hydrophilic solvent and water. When a combination of ether and water was used as the solvent, the ether solvent is more polar than toluene, leading to lower reactivity.

[0151] Step 2): Synthesize intermediate 1-d

[0152] Under nitrogen protection, 1-b (8.37 g, 40 mmol), starting material 1-c (10.29 g, 42 mmol), Na2CO3 (8.48 g, 80 mmol), TBAB (0.65 g, 2 mmol), toluene (90 mL), and water (30 mL) were added sequentially to the reaction flask. The mixture was stirred for 10 min, and then Pd132 (0.14 g, 0.2 mmol) was added. The temperature was raised to 65℃~70℃ and the reaction was maintained at this temperature for 5 h. Extracted with toluene (100 mL * 2), the organic phase was washed with water, separated, dried, and concentrated to dryness (50℃~60℃, -0.07MPa~-0.08MPa). It was then boiled and washed with ethanol at 1 g: 8 mL at 50℃~55℃ for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08MPa~-0.07MPa) to obtain intermediate 1-d (9.5 g, yield 89%).

[0153] LC-MS(ESI,pos.ion)m / z:267.05[M+H] + ;

[0154] 1H-NMR (CDCl3, 300MHz) δ (ppm): 9.14 (s, 1H), 8.46 (s, 1H), 8.18-8.15 (d, 1H), 8.04-8.01 (d, 1H), 7.88-7.83 (m, 2H), 7.43-7.40 (d, 1H), 2.53 (s, 3H).

[0155] The present invention also verified the implementation of step 2) by parallel reactions under various different reaction conditions, such as adjusting the type and amount of base, the type and amount of phase transfer catalyst, and the type of solvent.

[0156] By verifying various reaction conditions, it was found that the base (potassium carbonate) in step 2) can also be commonly used inorganic bases such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium acetate, and sodium hydroxide. Specifically, the molar ratio of intermediate 1-b to the base is 1:(1-2). In this step, the present invention primarily uses inexpensive and easily soluble inorganic bases to avoid environmental pollution from organic bases, especially reducing wastewater discharge containing organic matter and improving the environmental friendliness of the method.

[0157] By verifying various reaction conditions, it was found that the phase transfer catalyst (tetrabutylammonium bromide) in step 2) can also be 18-crown-6-ether, 15-crown-5-ether, TEBAC (benzyltriethylammonium chloride), TBAC (tetrabutylammonium chloride), or other phase transfer catalysts. The molar ratio of the phase transfer catalyst to the molar ratio of intermediate 1-b is (0.05–0.1):1.

[0158] In step 2), when the reaction scale is large, the amount of phase transfer catalyst can be reduced to save costs and reduce environmental pollution. For example, when the mass of intermediate 1-c is greater than 1 kg, the molar amount of phase transfer catalyst: molar amount of intermediate 1-c = (0.05~0.07):1.

[0159] In step 2), the reaction can proceed smoothly at temperatures ranging from 60℃ to 80℃; the reaction efficiency is higher at temperatures ranging from 65℃ to 75℃, and the conversion rate is higher at higher temperatures.

[0160] By verifying various reaction conditions, the highest reaction yield was achieved when a mixture of toluene and water was used as the solvent in step 2). See Table 2, which discloses several different reaction conditions and their yields. The difference between the various reaction conditions in Table 2 lies in the type of solvent; all other conditions are the same.

[0161] Table 2: Comparison of experimental results with different solvents

[0162]

[0163]

[0164] The data in Table 2 show that the mixed solvent of toluene and water yields the highest results. When the raw material has poor solubility in the selected solvent, the reaction conversion rate is low. In addition, when the boiling point of the solvent is low, the reaction system temperature is low and the reaction activity is low.

[0165] Step 3): Synthesize intermediate 1-e

[0166] Add 80.0 mL of intermediate 1-d (7.99 g, 30 mmol) methyl tert-butyl ether sequentially to the reaction flask, stir for 10 min, cool to -5℃ to 0℃, and then add dropwise 9.05 mL (60 mmol) of 60% glyoxal dimethyl acetal aqueous solution to the system, maintaining the temperature between -5℃ and 0℃ during the addition process. After the addition is complete, maintain the temperature for 1 h. Ammonium chloride (3.54 g, 66 mmol) was added in batches. After the addition was complete, the reaction was carried out at room temperature for 5 h. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (100.0 mL * 2). The organic phase was washed with water, separated, dried, and concentrated to dryness (40℃-50℃, -0.08 MPa to -0.05 MPa). The obtained solid product was boiled and washed with acetonitrile (1 g: 6 mL) at 50℃-55℃ for 0.5 h. The mixture was filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa to -0.07 MPa) to obtain intermediate 1-e (8.93 g, yield 85%).

[0167] In step 3), ammonium chloride serves as the ammonia donor, but other ammonium salts can be used as substitutes, such as ammonium acetate, ammonium formate, and ammonium bicarbonate. The molar ratio of intermediate 1-d to the molar ratio of the ammonium salt is 1:(2-2.5).

[0168] In step 3), the molar ratio of glyoxal dimethyl acetal to intermediate 1-d is (2-2.5):1; in this step, the temperature is controlled at -10℃ to 10℃ or -5℃ to 5℃ during the dropwise addition of the glyoxal dimethyl acetal solution. From the perspective of economy and improving reaction conversion rate, -5℃ to 0℃ is preferred.

[0169] Step 4): Synthesize intermediate 1-f

[0170] Under nitrogen protection, intermediate 1-e (7.01 g, 20 mmol) and acetic acid (20 mL) were added sequentially to the reaction flask. The mixture was stirred for 10 min, heated to 70℃~75℃, and kept at this temperature for 5 h. The acetic acid was concentrated under reduced pressure. The pH of the residue was adjusted to 7~8 with saturated sodium bicarbonate solution. The residue was extracted with dichloromethane (100.0 mL * 2). The organic phase was washed with water, separated, and dried. The organic phase was concentrated to dryness (40℃~50℃, -0.08 MPa~-0.05 MPa). The product was stirred with 1 g: 3 mL petroleum ether for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08~-0.07 MPa) to obtain intermediate 1-f (5.78 g, yield 95%).

[0171] 1 H-NMR (DMSO-d6, 300MHz) δ (ppm): 14.18 (s, 1H), 9.79 (s, 1H), 9.56 (s, 1H), 8.5 5 (s, 1H), 7.98 (d, 1H, J=9.4Hz), 7.89-7.73. (m, 3H), 7.24 (s, 1H), 2.51 (s, 3H).

[0172] In step 4), the reaction can proceed smoothly at a temperature of 65℃ to 80℃; the conversion rate is higher when the reaction temperature is 70℃ to 75℃.

[0173] Step 5: Synthesize compound 1

[0174] Under nitrogen protection, intermediate 1-f (9.12 g, 30 mmol) and 45 mL of dichloroethane were added sequentially to the reaction flask. After stirring for 10 min, starting material 1-f (5.0 g, 45 mmol) and glacial acetic acid (2.16 g, 36 mmol) were added. The temperature was raised to 60℃~70℃ and the reaction was maintained for 3 h. The reaction system was then cooled to -5℃~5℃, and NaBH(OAc)3 (12.75 g, 60 mmol) was added in portions. After the addition was complete, the temperature was raised to 40℃. The reaction was carried out at ~45℃ for 20 h. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (150.0 mL * 2). The organic phase was washed with water, separated, dried, and concentrated to dryness at 40℃-50℃, -0.08 MPa to -0.05 MPa. The product was stirred with 1 g: 6 mL ethanol for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa) to obtain compound 1 (9.8 g, yield 82%).

[0175] LC-MS(ESI,pos.ion)m / z:400.15[M+H] + ;

[0176] 1H-NMR (CDCl3, 300MHz) δ (ppm): 8.97 (s, 1H), 8.37 (s, 1H), 7.87-7.64 (m, 2H), 7.47 (t, 1H, J=7. 8Hz), 7.25 (d, 1H, J=7.9Hz), 7.15-6.94 (m, 2H), 6.56-6.29 (m, 3H), 4.49 (s, 2H), 2.48 (s, 3H).

[0177] Example 2:

[0178] Compound 2 was prepared following synthetic route 3:

[0179]

[0180] Step 1: Synthesis of intermediate 2-a

[0181] Potassium hydroxide and diacetic acid iodobenzene (38.6 g, 0.12 mol) were added to a methanol (150 mL) solution of 1-(6-tert-butylpyridin-2-yl)acetone (17.7 g, 0.1 mol), and the mixture was stirred at room temperature for 12 hours. The solvent was removed by vacuum distillation (30 °C–40 °C, -0.09 MPa–-0.08 MPa). 100 mL of water was added to the product, and the mixture was extracted with dichloromethane (100 mL x 2). The organic phase was washed with a saturated sodium carbonate aqueous solution, separated, dried, and concentrated to dryness (50 °C–60 °C, -0.09 MPa–-0.08 MPa) to give 2-a (15.1 g, 78% yield).

[0182] Step 2: Synthesis of intermediate 2-b

[0183] Under nitrogen protection, the following reactants were added sequentially to the reaction flask: 2-a (9.65 g, 50 mmol), S8 (25.6 g, 0.1 mol), bromoethane (8.18 g, 75 mmol), K2CO3 (6.9 g, 50 mmol), 18-crown-6 ether (2.64 g, 10 mmol), 100 mL toluene, and 20 mL water. The mixture was stirred for 10 min, heated to 80℃~85℃, and maintained at this temperature for the reaction. Extracted with toluene (100.0 mL * 2) for 8 h, the organic phase was washed with water, separated, dried, and concentrated to dryness (50℃~60℃, -0.09MPa~-0.08MPa). The product was stirred with 1 g: 3 mL ethanol for 0.5 h, filtered, dried under vacuum, and the filter cake was dried in a vacuum oven (50℃, -0.08MPa~-0.07MPa) to obtain 2-b intermediate (10.06 g, yield 80%).

[0184] Step 3: Synthesis of intermediate 2-d

[0185] Under nitrogen protection, 2-b (7.53 g, 30 mmol), starting material 1-c (8.09 g, 33 mmol), Na2CO3 (3.18 g, 30 mmol), 18-crown-6 ether (0.79 g, 3 mmol), 100 mL toluene, and 30 mL water were added sequentially to the reaction flask. The mixture was stirred for 10 min, and palladium acetate (0.067 g, 0.3 mmol) was added. The temperature was raised to 70 °C–75 °C, and the reaction was maintained at this temperature for 5 h. Extracted with toluene (100 mL * 2), the organic phase was washed with water, separated, dried, and concentrated to dryness (50℃~60℃, -0.09MPa~-0.08MPa). It was then boiled and washed with 1 g: 8 mL ethanol at 50℃~55℃ for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08MPa~-0.07MPa) to obtain intermediate 2-d (7.50 g, yield 81%).

[0186] LC-MS(ESI,pos.ion)m / z:309.13[M+H] + ;

[0187] 1 H-NMR (CDCl3, 300MHz) δ (ppm): 9.15 (s, 1H), 8.47 (s, 1H), 8.18-8.15 (d, 1H), 8.03-7.99 (d, 1H), 7.86-7.82 (m, 2H), 7.42-7.39 (d, 1H), 2.54 (s, 9H).

[0188] Step 4: Synthesis of intermediate 2-e

[0189] Add intermediate 2-d (6.16 g, 20 mmol) and tetrahydrofuran (50.0 mL) sequentially to the reaction flask, stir for 10 min, cool to -10℃ to -5℃, and then add 60% glyoxal dimethyl acetal aqueous solution (7.55 mL, 50 mmol) dropwise to the system, maintaining the temperature between -10℃ and 0℃ during the addition process. After the addition is complete, maintain the temperature for 1 h. Ammonium acetate (3.08 g, 40 mmol) was added in batches. After the addition was complete, the reaction was carried out at room temperature for 5 h. The pH was adjusted to 7-8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (100 mL * 2). The organic phase was washed with water, separated, dried, and concentrated to dryness (40℃-50℃, -0.08 MPa to -0.05 MPa). The obtained solid product was boiled and washed with acetonitrile (1 g: 6 mL) at 50℃-55℃ for 0.5 h. The mixture was filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa to -0.07 MPa) to obtain intermediate 2-e (6.36 g, yield 81%).

[0190] Step 5: Synthesis of intermediate 2-f

[0191] Under nitrogen protection, intermediate 2-e (5.5 g, 14 mmol) and 22 mL of hydrochloric acid were added sequentially to the reaction flask. The mixture was stirred for 10 min, heated to 65℃~70℃, and kept at this temperature for 5 h. The hydrochloric acid was concentrated under reduced pressure. The pH of the residue was adjusted to 7~8 with saturated sodium bicarbonate solution. The residue was extracted with dichloromethane (100 mL * 2). The organic phase was washed with water, separated, and dried. The organic phase was concentrated to dryness (40℃~50℃, -0.08 MPa~-0.05 MPa). The product was stirred with 1 g: 3 mL petroleum ether for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa~-0.05 MPa) to obtain intermediate 2-f (4.23 g, yield 87%).

[0192] Step 6: Synthesis of Compound 2

[0193] Under nitrogen protection, intermediate 2-f (4.16 g, 12 mmol) and tetrahydrofuran (34 mL) were added sequentially to the reaction flask. The mixture was stirred for 10 min, followed by the addition of starting material 2-f (1.93 g, 18 mmol) and glacial acetic acid (0.72 g, 12 mmol). The temperature was raised to 40℃–50℃ and maintained for 3 h. The reaction system was then cooled to -5℃–5℃, and NaBH(OAc)3 (5.01 g, 24 mmol) was added in portions. After the addition was complete, the temperature was raised to 3℃. The reaction was carried out at 5℃~40℃ for 20h. The pH was adjusted to 7~8 with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (100mL*2). The organic phase was washed with water, separated, dried, and concentrated to dryness at 40℃~50℃, -0.08MPa~-0.05MPa. The product was stirred with 1g:6mL ethanol for 0.5h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08MPa) to obtain compound 2 (3.68g, yield 70%).

[0194] LC-MS(ESI,pos.ion)m / z:438.23[M+H] + ;

[0195] 1 H-NMR (CDCl3, 300MHz) δ (ppm): 8.95 (s, 1H), 8.34 (s, 1H), 7.86-7.67 (m, 2H), 7.48 (t, 1H, J = 7.8Hz), 7.25 (d, 1H, J=7.9Hz), 7.19-6.99 (m, 2H), 6.59-6.30 (m, 3H), 4.51 (s, 2H), 2.53 (s, 9H), 2.35 (s, 3H).

[0196] Synthesis Example 3: Synthesis of Compound 3

[0197]

[0198] Step 1: Synthesis of intermediate 3-a

[0199] Potassium hydroxide and diacetic acid iodobenzene (38.6 g, 0.12 mol) were added to a methanol (150 mL) solution of 1-(6-ethylpyridin-2-yl)acetone (14.9 g, 0.1 mol), and the mixture was stirred at room temperature for 12 hours. After removing the solvent by vacuum distillation (30 °C–40 °C, -0.09 MPa–-0.08 MPa), 100 mL of water was added to the product, and the mixture was extracted with dichloromethane (100 mL * 2). The organic phase was washed with a saturated sodium carbonate aqueous solution, separated, dried, and concentrated to dryness (50 °C–60 °C, -0.09 MPa–-0.08 MPa) to give 3-a (11.9 g, yield 72%).

[0200] Step 2: Synthesis of intermediate 3-b

[0201] Under nitrogen protection, the following ingredients were added sequentially to a reaction flask: 3-a (8.25 g, 50 mmol), S8 (15.4 g, 60 mmol), bromoethane (6.5 g, 60 mmol), potassium acetate (7.84 g, 80 mmol), TEBA (5.70 g, 2.5 mmol), 100 mL toluene, and 20 mL water. The mixture was stirred for 10 min, heated to 80 °C–85 °C, and maintained at this temperature for 8 h. The mixture was then extracted with toluene (100.0 mL * 2), the organic phase was washed with water, separated, dried, and concentrated to dryness at 50 °C–60 °C, -0.09 MPa–-0.08 MPa. The product was stirred with 1 g: 3 mL ethanol for 0.5 h, filtered, dried under vacuum, and the filter cake was dried in a vacuum oven at 50 °C, -0.08 MPa–-0.07 MPa to obtain the 3-b intermediate (8.93 g, yield 80%).

[0202] Step 3: Synthesis of intermediate 3-d

[0203] Under nitrogen protection, 3-b (6.69 g, 30 mmol), starting material 1-c (8.09 g, 33 mmol), NaHCO3 (5.04 g, 60 mmol), TEBA (0.68 g, 3 mmol), 100 mL toluene, and 33 mL water were added sequentially to the reaction flask. The mixture was stirred for 10 min, then Pd132 was added, and the temperature was raised to 65℃~70℃ and maintained for 5 h. The mixture was extracted with toluene (100 mL * 2), the organic phase was washed with water, separated, dried, and concentrated to dryness (50℃~60℃, -0.09 MPa~-0.08 MPa). The mixture was then boiled with 1 g: 8 mL ethanol at 50℃~55℃ for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa~-0.07 MPa) to obtain intermediate 3-d (7.15 g, yield 85%).

[0204] LC-MS(ESI,pos.ion)m / z:281.10[M+H] + ;

[0205] 1 H-NMR (CDCl3, 300MHz) δ (ppm): 9.16 (s, 1H), 8.44 (s, 1H), 8.17-8.15 (d, 1H), 8.05-8.0 3(d,1H), 7.87-7.82(m,2H), 7.44-7.40(d,1H), 3.75-3.71(m,2H), 2.55-2.52(m,3H).

[0206] Step 4: Synthesis of intermediate 3-e

[0207] Add intermediate 3-d (5.6 g, 20 mmol) and anisole (67.0 mL) sequentially to the reaction flask, stir for 10 min, cool to 5℃~10℃, and then add 60% glyoxal dimethyl acetal aqueous solution (6.63 mL, 44 mmol) dropwise to the system, maintaining the temperature at 5℃~10℃ during the addition. After the addition is complete, maintain the temperature for 1 h. Potassium acetate (4.9 g, 50 mmol) was added in batches. After the addition was complete, the reaction was carried out at room temperature for 5 h. The pH was adjusted to 7-8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (100 mL * 2). The organic phase was washed with water, separated, dried, and concentrated to dryness (40℃-50℃, -0.08 MPa to -0.05 MPa). The obtained solid product was boiled and washed with acetonitrile (1 g: 6 mL) at 50℃-55℃ for 0.5 h. The mixture was filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa to -0.07 MPa) to obtain intermediate 3-e (5.61 g, yield 77%).

[0208] Step 5: Synthesis of intermediate 3-f

[0209] Under nitrogen protection, intermediate 3-e (5.47 g, 15 mmol) and 11 mL of trifluoroacetic acid were added sequentially to the reaction flask. The mixture was stirred for 10 min, heated to 75℃~80℃, and kept at this temperature for 5 h. The trifluoroacetic acid was concentrated under reduced pressure. The pH of the residue was adjusted to 7~8 with saturated sodium bicarbonate solution. The residue was extracted with dichloromethane (100 mL * 2). The organic phase was washed with water, separated, and dried. The organic phase was concentrated to dryness (40℃~50℃, -0.08 MPa~-0.05 MPa). The product was stirred with 1 g: 3 mL petroleum ether for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa~-0.05 MPa) to obtain intermediate 3-f (4.11 g, yield 86%).

[0210] Step 6: Synthesis of Compound 3

[0211] Under nitrogen protection, intermediate 3-f (3.82 g, 12 mmol) and 45 mL of dichloroethane were added sequentially to the reaction flask. After stirring for 10 min, starting material 3-f (2.30 g, 18 mmol) and trifluoroacetic acid (2.74 g, 24 mmol) were added. The temperature was raised to 70℃~80℃ and the reaction was maintained for 3 h. The reaction system was then cooled to -5℃~5℃, and NaBH(OAc)3 (5.09 g, 24 mmol) was added in portions. After the addition was complete, the temperature was raised to 40℃. The reaction was carried out at 50℃ for 20 h. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The product was extracted with dichloromethane (100.0 mL * 2). The organic phase was washed with water, separated, dried, and concentrated to dryness at 40℃-50℃, -0.08 MPa to -0.05 MPa. The product was stirred with 1 g: 6 mL ethanol for 0.5 h, filtered, and the filter cake was dried in a vacuum oven (50℃, -0.08 MPa) to obtain compound 3 (3.39 g, yield 66%).

[0212] LC-MS(ESI,pos.ion)m / z:430.15[M+H] + ;

[0213] 1 H-NMR (CDCl3, 300MHz) δ (ppm): 8.95 (s, 1H), 8.38 (s, 1H), 7.88-7.64 (m, 2H), 7.43 (t, 1H, J=7.8Hz), 7.27 ( d, 1H, J=7.9Hz), 7.18-6.94 (m, 2H), 6.56-6.30 (m, 3H), 4.50 (s, 2H), 3.78-3.62 (m, 2H), 2.55-2.43 (t, 3H).

[0214] Compound activity testing

[0215] The inhibitory effect of the compounds prepared by the synthetic method of the present invention on ALK5 kinase phosphorylation was evaluated according to the following assay methods.

[0216] The ALK5 protein was expressed as a recombinant human GST fusion protein in Sr9 insect cells using a baculovirus expression system. The expressed protein was purified by GSH-agarose (Sigma-Aldrich) affinity chromatography. The protein was processed in 96-well FlashPlates from PerkinElmer (Boston, MA, USA). TMThe kinase assay was performed using a 50 μL reaction volume. The reaction cocktail reagent was added in four steps, in the following order: 20 μL assay buffer (standard buffer), 5 μL ATP aqueous solution, 5 μL DMSO solution containing 10% of the test compound, and 10 μL GSK3(14-27) (200 ng) / 10 μL ALK5 solution (1 ng) (premixed). The reaction cocktail reagent contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na3VO4, 1.2 mM MTT, and 50 μg / mL PEG. 20000 1 μM [γ- 33 P]-ATP (approximately 2.5 x 10⁻⁶) 5 The reaction cocktail consisted of 200 ng / 10 μL GSK3 (14-27) and 1 ng / 10 μL ALK5. The reaction mixture was incubated at 30 °C for 60 min. The reaction was terminated with 50 μL of 2% (v / v) H3PO4. The plate was aspirated, and 200 μL of 0.9% H3PO4 was added.

[0217] Wash twice with (w / v) NaCl. Measured using a Beckman Coulter Biomek 2000 automated system. Measured using a microplate scintillation counter (Microbeta, Wallac). 33 P i The combination of (in "cpm"). IC 50 Defined as the concentration of a compound that inhibits 50% of enzyme activity under experimental conditions.

[0218] IC50 of compounds 1 to 4 synthesized in the examples 50 The values ​​are shown in the table below.

[0219]

[0220] Based on the test results in the table above, compounds 1-3 of this application exhibit an IC5 inhibitory effect on ALK5 kinase. 50 All values ​​are less than 0.1 μM, indicating high ALK5 kinase inhibitory activity.

[0221] It should be understood that this application is not limited to the embodiments listed in this specification. This application can have other embodiments and can be implemented and performed in various ways. The foregoing variations and modifications fall within the scope of this application. It should be understood that the disclosure and definition of this application extend to all alternative combinations of two or more individual features mentioned or apparent herein. All these different combinations constitute multiple alternative aspects of this application. The embodiments described in this specification illustrate preferred embodiments known for implementing this application and will enable those skilled in the art to utilize this application.

Claims

1. A method for preparing a diketone compound, characterized by, The structure of the diketone compound is shown in Chemical Formula 2: R1 is selected from deuterium, a halogen group, a cyano group, an alkyl group with 1-6 carbon atoms, an alkoxy group with 1-6 carbon atoms, or a haloalkyl group with 1-6 carbon atoms; The preparation method of the diketone compound comprises the following steps: Step one, In step one, a reaction mixture of a compound shown in Chemical Formula P1, elemental sulfur, bromoethane, a first base, and a first solvent is reacted to generate a compound shown in Chemical Formula P2; Step two, In step two, a mixture of the compound shown in Chemical Formula P2, a compound shown in Chemical Formula P3, a palladium catalyst, a second base, and a second solvent is reacted to generate the diketone compound shown in Chemical Formula II; the mixture further comprises a second phase transfer catalyst selected from tetrabutylammonium bromide, 18-crown-6-ether, 15-crown-5-ether, benzyltriethylammonium chloride, and tetrabutylammonium chloride.

2. The method of claim 1, wherein the compound is represented by the following formula 1 : ###0001### Formula 1 The first solvent is a mixture of a first organic solvent and water, wherein the first organic solvent is one or more of an aromatic hydrocarbon solvent, an amide solvent, an ether solvent, and a nitrile solvent; the first organic solvent: water = 1:(0.2-0.5) by volume.

3. The method of claim 2, wherein the compound is represented by the following formula 1 : ###0001### Formula 1 The first organic solvent is selected from toluene, dimethylformamide, cyclopentyl methyl ether, 1,4-dioxane, anisole, and acetonitrile.

4. The method of claim 1, wherein the compound is represented by the following formula: ###0002### 2 In step one, the reaction mixture further comprises a first phase transfer catalyst selected from tetrabutylammonium bromide, 18-crown-6-ether, 15-crown-5-ether, benzyltriethylammonium chloride, and tetrabutylammonium chloride.

5. The method of claim 1, wherein the compound is represented by the following formula: ###0002### 5 The second solvent is a mixture of a second organic solvent and water, wherein the second organic solvent is one or more of an alcohol solvent, an aromatic hydrocarbon solvent, an amide solvent, an ether solvent, and a nitrile solvent; the second organic solvent: water = 1:(0.2-0.5) by volume.

6. The method of claim 5, wherein the compound is represented by the following formula: ###0002### 6 The second organic solvent is selected from toluene, a C1-C4 lower alcohol solvent, DMF, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, and acetonitrile.

7. A method of preparing an imidazole derivative, characterized by, The structure of the imidazole derivative is shown in Chemical Formula 1: R1 is selected from deuterium, a halogen group, a cyano group, an alkyl group with 1-6 carbon atoms, an alkoxy group with 1-6 carbon atoms, or a haloalkyl group with 1-6 carbon atoms; R2 is selected from fluorine, chlorine, bromine, an alkyl group with 1-6 carbon atoms, an alkoxy group with 1-6 carbon atoms, or a haloalkyl group with 1-6 carbon atoms; The preparation method of the imidazole derivative comprises the preparation method of the diketone compound according to any one of claims 1-6.

8. The method for preparing imidazole derivatives according to claim 7, characterized in that, The preparation method of the imidazole derivative further comprises: Step three, The compound shown in Chemical Formula II, glyoxal dimethyl acetal, and an ammonium salt are reacted to generate a compound shown in Chemical Formula P4; Step four: The compound shown in Chemical Formula P4 is converted into a compound shown in Chemical Formula P5; Step five: The compound shown in Chemical Formula P5 and a compound shown in Chemical Formula P6 are reacted to generate the compound shown in Chemical Formula 1.

9. Process for the preparation of imidazole derivatives according to claim 8, selected from the group consisting of the following compounds: ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###

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