CN114573576A - Preparation method of diketone compound and preparation method of imidazole derivative - Google Patents

Abstract

The invention provides a preparation method of a diketone compound and a preparation method of an imidazole derivative, belonging to the technical field of medicines. The preparation method of the diketone compound does not need to adopt chemicals such as zirconyl chloride which are seriously harmful to human bodies, and reduces the harm to the human bodies and the environment. Moreover, a large amount of acid is avoided in the preparation process, and a large amount of acidic wastewater is avoided, so that the wastewater treatment capacity is reduced, and the environmental pollution is reduced.

Description

Preparation method of diketone compound and preparation method of imidazole derivative

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method of a diketone compound and a preparation method of an imidazole derivative.

Background

Imidazolyl 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 two nitrogen atoms, has the characteristics of good electron transfer property and easy functionalization, and has wide biological activity in the imidazole derivatives. Illustratively, patent application CN103025731A discloses a compound represented by the following chemical formula I, which has the biological activity of inhibiting ALK5 and/or ALK4, can be used for inhibiting tumors and abnormal proliferative diseases, and has a prospect of becoming a novel antitumor drug.

Wherein R is₁₀A group such as an alkyl group having 1 to 6 carbon atoms; r₂₀Is F, Cl, Br, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and the like.

The diketone compound shown in the chemical formula II is a key intermediate for synthesizing the imidazole derivative shown in the chemical formula I.

In the prior art, the diketone compound shown in chemical formula II is synthesized by the method shown in the following synthetic scheme 1:

according to the synthesis steps, when the intermediate a-II is prepared, the raw material a-I, aniline and diphenyl phosphite ester are required to be subjected to the action of zirconyl chloride to obtain an N-P acetal intermediate b-II; zirconium oxychloride, which is highly harmful to the human body, is used in this step, and isopropyl alcohol is used. This not only causes serious contamination of the water, but also the isopropyl alcohol is easily left behind, which results in the final product not meeting the specification of isopropyl alcohol by ICH (International Conference on standardization of Technical Requirements for Registration of Pharmaceuticals for Human Use) (the residual amount of isopropyl alcohol does not exceed 0.5%). When the intermediate c-III is prepared, the intermediate b-II and the [1,2,4] triazole [1,5-a ] pyridine-6-formaldehyde are further coupled under an alkaline condition, and are hydrolyzed in an acid way to generate the monoketone, so that the intermediate c-III is obtained. In the step, a large amount of cesium carbonate is used, tetrahydrofuran and isopropanol are used as solvents, acid and alkali are required to be adjusted repeatedly in the post-treatment process, the process is complex, equipment is easy to damage in large-scale production, the amount of generated wastewater is large, and isopropanol is easy to remain, so that the final product does not meet the specification of ICH on isopropanol. In the process of preparing the diketone compound shown in chemical formula 2, DMSO (dimethyl sulfoxide) and HBr are used for oxidizing the intermediate c-III, and a large amount of HBr is used in the reaction, so that the equipment is greatly damaged, the wastewater treatment capacity is large, and the environmental pollution is serious.

The above information disclosed in this background section is only for enhancement of understanding of the background of the invention and therefore it may contain information that does not constitute prior art that is already known to a person of ordinary skill in the art.

Disclosure of Invention

The invention aims to provide a preparation method of a diketone compound and a preparation method of an imidazole derivative, which can reduce the environmental pollution of the imidazole derivative in the preparation process.

In order to achieve the purpose, the invention adopts the following technical scheme:

according to a first aspect of the present invention, there is provided a method for preparing a diketone compound, wherein the structural formula of the diketone compound is shown in chemical formula 2:

wherein each R is₁Independently selected from deuterium with carbon atom number, halogen group, cyano, alkyl with carbon atom number of 1-6, alkoxy with carbon atom number of 1-6 or halogenated alkyl with carbon atom number of 1-6;

the preparation method of the diketone compound comprises the following steps:

the first step,

Reacting a compound shown as a chemical formula P1, sulfur and bromoethane to generate a compound shown as a chemical formula P2;

step two,

Reacting the compound shown as the chemical formula P2 with the compound shown as the chemical formula P3 to generate the diketone compound shown as the chemical formula II.

According to a second aspect of the present invention, there is provided a method for preparing an imidazole derivative, wherein the imidazole derivative has a structure shown in chemical formula 1:

wherein R is₁Independently selected from deuterium, a halogen group, a cyano group, 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;

R₂fluorine, 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;

the preparation method of the imidazole derivative comprises the preparation method of the diketone compound.

According to the preparation method of the diketone compound and the preparation method of the imidazole derivative provided by the invention, when the diketone compound shown in the chemical formula 2 is prepared, chemicals which are seriously harmful to human bodies, such as zirconyl chloride, do not need to be adopted, and the harm of the dangerous chemicals to the human bodies and the environment can be reduced. Moreover, a large amount of acid is reduced in the preparation process, so that a large amount of acidic wastewater is avoided, the wastewater treatment capacity is reduced, and the environmental pollution is reduced.

Detailed Description

Example embodiments will now be described more fully. Example embodiments may, however, be embodied in many different forms and should not be construed as limited to the examples set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of example 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 provide a thorough understanding of embodiments of the invention.

The terms "first" and "second," etc. are used merely as labels, and are not limiting on the number of their objects.

In the present invention, "alkyl" may include straight chain alkyl groups, branched chain alkyl groups. The alkyl group may have a specified number of carbon atoms, for example, an alkyl group having 1 to 6 carbon atoms. In the present invention, numerical ranges such as "1 to 6" when used to define the number of carbon atoms refer to the respective integers in the given ranges; for example, the "alkyl group having 1 to 6 carbon atoms" refers to an alkyl group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. The alkyl group may be a lower alkyl group having 1 to 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) And the like.

In the present application, as a halogen group as a substituent, there is fluorine, chlorine, bromine or iodine.

In the present application, "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) And so on.

In the present application, "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like. In one embodiment, C₁-C₆The haloalkyl group containing a fluorine-substituted C₁-C₆An alkyl group; in another embodiment, C₁-C₄The haloalkyl group containing a fluorine-substituted C₁-C₄An alkyl group; in yet another embodiment, C₁-C₂The haloalkyl group containing a fluorine-substituted C₁-C₂An alkyl group.

The invention provides a preparation method of a diketone compound, wherein the structural formula of the diketone compound is shown as a chemical formula II:

wherein R is₁Selected from deuterium, halogen group, cyano group, alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms or haloalkyl group having 1 to 6 carbon atoms.

Alternatively, R₁Selected from methyl, ethyl, isopropyl, tert-butyl.

In the present application, the diketone compound represented by chemical formula 2 is selected from the following structures:

the preparation method of the diketone compound shown as the compound 2 comprises the following steps:

the first step,

Reacting the compound shown as the chemical formula P1, elemental sulfur and bromoethane to generate a compound shown as the chemical formula P2;

step two,

The compound shown as the chemical formula P2 and the compound shown as the chemical formula P3 are subjected to coupling reaction to generate the diketone compound shown as the chemical formula II.

According to the preparation method of the diketone compound provided by the invention, when the diketone compound shown in the chemical formula II is prepared, chemicals which are seriously harmful to human bodies, such as zirconyl chloride, do not need to be adopted, and the harm of the dangerous chemicals to the human bodies and the environment can be reduced. Moreover, a large amount of acid is avoided in the preparation process, and a large amount of acidic wastewater is avoided, so that the wastewater treatment capacity is reduced, and the environmental pollution is reduced.

Alternatively, in the first step, a reaction mixture of the compound shown in the chemical formula P1, elemental sulfur, bromoethane, a first base and a first solvent is reacted to generate the compound shown in the chemical formula P2. Therefore, in the step one, a large amount of acidic solution is avoided, and the reaction is carried out in an alkaline environment, so that the possible pollution caused by a large amount of acidic waste liquid is avoided. Moreover, the reaction product can not be salified due to the reaction under the alkaline condition, and the product can be directly separated by methods such as extraction and the like without adjusting the pH after the reaction is finished, so that the post-treatment process is reduced, the waste liquid amount is reduced, and the post-treatment process can be simplified.

Further optionally, in step one, the elemental sulfur is cyclooctylthio (S8).

Further alternatively, in step one, on a molar basis, a compound represented by formula P1: the elemental sulfur is 1 (1-2). Alternatively, a compound of formula P1, on a molar basis: the elemental sulfur is 1 (1.2-2). Alternatively, the compound of formula P1 on a molar basis: the elemental sulfur is 1 (1.5 to 1.8).

Further alternatively, in step one, on a molar basis, a compound represented by formula P1: and (1.2-2) bromine ethane. Alternatively, the compound of formula P6 on a molar basis: and (1.2-1.8) of bromoethane. Alternatively, the compound of formula P6 on a molar basis: bromoethane 1: 1.8.

Further optionally, in step one, the first base is an inorganic base or an alkali metal salt of a weak organic acid, and may be, for example, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate, sodium hydroxide, or other common inorganic bases or alkali metal salts of weak organic acids. On one hand, the organic base such as triethylamine, diisopropylethylamine, pyridine and the like can be avoided, the content of organic matters in the wastewater is reduced, and the environmental pollution is reduced. On the other hand, the inorganic base or the alkali metal salt of the weak organic acid not only causes less pollution to the environment than the organic base, but also reduces the pollution to the environment by generating and recycling solid waste in a concentration manner. Moreover, the alkali metal salts of the inorganic base or the organic weak acid have better solubility in the water phase, can be effectively separated from reaction products in the extraction process, and reduce the purification difficulty of the reaction products.

Optionally, in the first step, the first base is selected from one or more of potassium carbonate, sodium bicarbonate, potassium acetate, and sodium hydroxide, so as to ensure high solubility and low cost of the first base. Still further optionally, the first base is selected from one of sodium bicarbonate, potassium bicarbonate, or potassium acetate.

Further alternatively, in step one, on a molar basis, a compound represented by formula P1: first base ═ 1: (1-2). Alternatively, the compound of formula P1 on a molar basis: first base ═ 1: (1.6-2.0). Further alternatively, the compound of formula P1, on a molar basis: first base ═ 1: 2.0.

further optionally, in step one, the molar amount of the first base is not less than the molar amount of bromoethane.

Further optionally, in the first step, the first solvent is a mixture of a first organic solvent and water, wherein the first organic solvent includes one or more of an aromatic hydrocarbon solvent, an amide solvent, an ether solvent, and a nitrile solvent; wherein, by volume, the first organic solvent: water 1: (0.2-0.5). Thus, in this step one, a mixed solvent of an organic solvent and water may be used, and the product may be isolated by extraction after the reaction is completed.

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

Optionally, in the first step, the first organic solvent is selected from one of toluene, dimethylformamide, cyclopentyl methyl ether, dioxane, anisole and acetonitrile. Further optionally, the first organic solvent is toluene or anisole to improve reaction efficiency.

Optionally, in step one, the first organic solvent: water 1: 0.2.

alternatively, in step one, the molar amount of the compound represented by formula P1: volume of the first solvent was 1 mmol: (2-3) mL.

Further optionally, in the step one, the reaction system for preparing the compound shown in the chemical formula P2 further comprises a first phase transfer catalyst, so as to improve the reaction efficiency. That is, a mixture of the compound represented by chemical formula P1, elemental sulfur, bromoethane, the first base, the first phase transfer catalyst, and the first solvent is reacted to produce the compound represented by chemical formula P2.

Optionally, 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, TEBAC (benzyltriethylammonium chloride), TBAC (tetrabutylammonium chloride). Further optionally, the first phase transfer catalyst is tetrabutylammonium bromide.

Alternatively, in step one, on a molar basis, a compound represented by formula P1: first phase transfer catalyst ═ 1: (0.05-0.2). Further alternatively, the compound of formula P1, on a molar basis: first phase transfer catalyst ═ 1: 0.1.

further optionally, in the first step, a mixture containing the compound shown in the chemical formula P1, elemental sulfur, bromoethane, the first base and the first solvent is reacted at a temperature of 60 ℃ to 85 ℃, that is, the reaction temperature is 60 ℃ to 85 ℃. Optionally, the reaction temperature is from 70 ℃ to 85 ℃. Optionally, the reaction temperature is from 80 ℃ to 85 ℃.

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

Alternatively, in the second step, a mixture of the compound represented by the chemical formula P2, the compound represented by the chemical formula P3, a palladium catalyst, a second base and a second solvent is reacted to produce the diketone compound represented by the chemical formula 2. In the second step, compared with the preparation method in the prior art, the synthetic route avoids adopting a large amount of acidic solution, but the reaction is carried out in an alkaline environment, and the possible pollution caused by a large amount of acidic waste liquid is avoided. Moreover, because the reaction is carried out under the alkaline condition, the reaction product does not form salt, and the product can be directly separated by methods such as extraction and the like without adjusting the pH after the reaction is finished, so that the post-treatment process is reduced, the waste liquid amount is reduced, and the post-treatment process can be simplified.

Further alternatively, in step two, on a molar basis, a compound represented by formula P2: a compound represented by the formula P3 is 1 (1-1.2).

Further optionally, in step two, the palladium catalyst is selected from palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphonium palladium (II) or other divalent palladium catalysts. Alternatively, the palladium catalyst is di-tert-butyl- (4-dimethylaminophenyl) phosphonium palladium (II) dichloride (Pd 132).

Further alternatively, in step two, on a molar basis, a compound represented by formula P2: (0.005-0.01) of a palladium catalyst. Alternatively, the compound of formula P2 on a molar basis: palladium catalyst 1: 0.005.

Further optionally, in step two, the second base is an inorganic base or an alkali metal salt of an organic weak acid, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium acetate, and the like, which are commonly used. On one hand, the organic base such as triethylamine, diisopropylethylamine, pyridine and the like can be avoided, the content of organic matters in the wastewater is reduced, and the environmental pollution is reduced. On the other hand, the inorganic base or the alkali metal salt of the weak organic acid not only causes less pollution to the environment than the organic base, but also reduces the pollution to the environment by generating and recycling solid waste in a concentration manner. Moreover, the alkali metal salts of the inorganic base or the organic weak acid have better solubility in the water phase, can be effectively separated from reaction products in the extraction process, and reduce the purification difficulty of the reaction products.

Optionally, the second base is selected from one or more of potassium carbonate, sodium bicarbonate, potassium acetate, sodium hydroxide to ensure high solubility and low cost of the second base. Still further optionally, the second base is selected from one of sodium carbonate, potassium acetate, or potassium carbonate.

Further alternatively, the compound of formula P2, on a molar basis: second base ═ 1: (1-2). Alternatively, the compound of formula P2 on a molar basis: second base ═ 1: (1.5-2.0). Further alternatively, the compound of formula P2, on a molar basis: second base ═ 1: 2.0.

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 an alcohol solvent, an aromatic hydrocarbon solvent, an amide solvent, an ether solvent, and a nitrile solvent; wherein, by volume, the second organic solvent: water 1: (0.2-0.5). Thus, in the second step, a mixed solvent of an organic solvent and water is preferred, and the product can be isolated by direct extraction after the reaction is completed.

Wherein, the alcohol solvent includes, but is not limited to, C1-C4 lower alcohol such as methanol, ethanol, ethylene glycol, tert-butyl alcohol, etc. Aromatic hydrocarbon solvents include, but are not limited to, toluene, xylene, mesitylene, and the like. Amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and the like. Ether solvents include, but are not limited to, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, 1, 4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, ethylene glycol dimethyl ether, anisole, and the like. Nitrile solvents include, but are not limited to, acetonitrile, valeronitrile, and the like.

Optionally, the second organic solvent is selected from one or more of alcohol solvents, toluene, dimethylformamide, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran and acetonitrile. Further optionally, the second organic solvent is toluene to improve reaction efficiency.

Optionally, the second organic solvent: water 3: 1.

alternatively, the molar amount of the compound represented by formula P2: volume of the second solvent was 1 mmol: (3-5) mL.

Further optionally, in step two, a second phase transfer catalyst is also included in the mixture. That is, a mixture of the compound represented by chemical formula P2, the compound represented by chemical formula P3, a palladium catalyst, a second base, a second phase transfer catalyst, and a second solvent is reacted to produce the diketone compound represented by chemical formula 2.

Alternatively, the second phase transfer catalyst is selected from tetrabutylammonium bromide, 18-crown-6-ether, 15-crown-5-ether, TEBAC (benzyltriethylammonium chloride), TBAC (tetrabutylammonium chloride). Further optionally, the second phase transfer catalyst is tetrabutylammonium bromide.

Alternatively, the compound of formula P2 on a molar basis: second phase transfer catalyst ═ 1: (0.05-0.1). Further alternatively, the compound of formula P2, on a molar basis: second phase transfer catalyst ═ 1: 0.05.

further alternatively, a mixture comprising the compound of formula P2, the compound of formula P3, the palladium catalyst, the second base, and the second solvent is reacted at 60 ℃ to 80 ℃, i.e., at a reaction temperature of 60 ℃ to 80 ℃. Alternatively, the degree of reaction is from 65 ℃ to 75 ℃. Alternatively, the degree of reaction is from 65 ℃ to 70 ℃.

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

The invention also provides a preparation method of the imidazole derivative. The structure of the imidazole derivative is shown in a chemical formula 1:

wherein R is₁Independently selected from deuterium, a halogen group, a cyano group, 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; r₂Fluorine, 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;

alternatively, R in chemical formula 1₁Selected from fluoro, chloro, methyl, ethyl, isopropyl or tert-butyl.

Optionally, the imidazole derivative is selected from compounds shown as follows:

the preparation method of the imidazole derivative comprises the preparation method of the diketone compound. Therefore, the preparation method of the imidazole derivative has the same beneficial effects as the preparation method of the diketone compound, and the details are not repeated herein.

Optionally, the preparation method of the imidazole derivative further includes:

step three,

Reacting the compound shown in the chemical formula II, glyoxal dimethyl acetal and ammonium salt to generate a compound shown in a chemical formula P4;

step four:

the compound of the chemical formula P4 is formed into a compound of the chemical formula P5;

step five:

the compound of chemical formula P5 and the compound of chemical formula P6 react to produce the compound of chemical formula 1.

Alternatively, in step three, on a molar basis, a compound of formula II: glyoxal dimethyl acetal ═ 1: (2-2.5). Alternatively, the compound of formula II, on a molar basis: glyoxal dimethyl acetal ═ 1: 2.0.

alternatively, in step three, on a molar basis, a compound of formula II: ammonium salt 1: (2-2.5). Alternatively, the compound represented by chemical formula 2, in terms of molar amount: ammonium salt 1: 2.2.

optionally, in step three, the ammonium salt is selected from ammonium acetate, ammonium formate, ammonium chloride, ammonium bicarbonate or other ammonium salts.

In one embodiment of the invention, a mixture of the compound of formula II, glyoxal dimethyl acetal, an ammonium salt, and a third solvent is reacted to produce the compound of formula P4. Wherein the adding temperature of the glyoxal dimethyl acetal is-10 ℃ to 10 ℃. Optionally, the addition temperature is-5 ℃ to 5 ℃, optionally, the addition temperature is-5 ℃ to 0 ℃.

In another embodiment of the present invention, in step three, glyoxal dimethyl acetal may be added to a reaction solution of the compound represented by formula II and a third solvent at a first reaction temperature and reacted to completion at the first reaction temperature; then adding ammonium salt into the reaction system, and then reacting at a second reaction temperature to be complete to generate the compound shown as the chemical formula P4.

Optionally, the first reaction temperature is between-10 ℃ and 10 ℃. Further optionally, the first reaction temperature is between-5 ℃ and 5 ℃.

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

In another further embodiment, the second reaction temperature is from 15 ℃ to 35 ℃. Optionally, the second reaction temperature is 23 ℃ to 28 ℃.

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

Alternatively, the mass of the compound of formula II: volume of the third solvent is 1 g: (6-12) mL. Alternatively, the mass of the compound represented by chemical formula 2: volume of the third solvent is 1 g: (8-10) mL.

In one embodiment of the present invention, step four

In step four, optionally, the compound of formula P4 is reacted in a first acidic solvent. The first acidic solvent can be selected from acetic acid, diluted hydrochloric acid (1-3 mol/L), trifluoroacetic acid or other acidic solvents.

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

Alternatively, the mass of the compound of formula P4: volume of the first acidic solvent is 1 g: (2-5) mL. Further alternatively, the mass of the compound of formula P4: volume of the first acidic solvent is 1 g: (2-3) mL.

Alternatively, the reaction temperature of the compound represented by the chemical formula P4 in the first acidic solvent is 65 ℃ to 80 ℃. Further optionally, the reaction temperature is from 70 ℃ to 75 ℃.

Step five:

in step five, optionally, reacting a mixture of the compound of formula P5, the compound of formula P6, and a second acidic solvent at a third reaction temperature; then adding sodium triacetoxyborohydride into the reaction system and reacting at a fourth reaction temperature.

Further alternatively, the compound of formula P5, on a molar basis: a compound represented by the formula P6 ═ 1: (1-1.5).

Further optionally, the second acidic solvent comprises an acidic agent and a fourth solvent. Wherein the acidic reagent is selected from acetic acid, trifluoroacetic acid, benzenesulfonic acid or other acids.

Alternatively, the compound of formula P5 on a molar basis: acid reagent 1: (1-2). Further alternatively, the compound of formula P5, on a molar basis: acid reagent 1: (1-1.2).

Alternatively, the fourth solvent is selected from ether solvents, haloalkane solvents, such as tetrahydrofuran, methyltetrahydrofuran, dichloromethane, dichloroethane, and the like.

Alternatively, the mass of the compound of formula P5: volume of the fourth solvent is 1 g: (8-12) mL. Further optionally, the fourth solvent is dichloroethane, the mass of the compound represented by formula P5: volume of dichloroethane 1 g: 10 mL.

Optionally, the third reaction temperature is 40 ℃ to 80 ℃. Further optionally, the third reaction temperature is 60 ℃ to 70 ℃.

Optionally, the fourth reaction temperature is 35 ℃ to 50 ℃.

Alternatively, when sodium triacetoxyborohydride is added, the temperature of the reaction system may be lowered to-10 ℃ to 10 ℃ or to-5 ℃ to 5 ℃, and sodium triacetoxyborohydride is added in portions. After the addition of sodium triacetoxyborohydride, the temperature is raised to the fourth reaction temperature.

The invention relates to a synthesis method of a diketone compound, which is a key intermediate for preparing an active imidazole derivative with ALK5 inhibition effect. The active imidazole compound prepared according to the synthetic route of the invention can avoid using a high-risk reagent zirconium oxychloride, reduce the using amount of strong acid and strong base, simplify the post-treatment process, reduce the use of an environment-friendly solvent and reduce the environmental pollution. Therefore, the synthesis method has mild reaction conditions and reagent properties, simple and convenient post-treatment, easy purification, no need of column chromatography purification, and the whole process conforms to the requirement of green production and is more suitable for industrial production.

Detailed Description

In order to better illustrate the present invention and the effects obtained by the same, the following will describe in detail the preparation method of the diketone compound and the preparation method of the imidazole derivative of the present invention with reference to the examples. However, the embodiments according to the present specification may be modified into various other forms, and the scope of the present specification is not to be construed as being limited to the embodiments described below. The examples of this specification are provided to more fully describe the specification to those skilled in the art.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions claimed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. General reagents were purchased from Shang Wen Long chemical plant, Guangdong Guanghua chemical plant, Guangzhou chemical plant, Qingdao Tenglong chemical reagent Co., Ltd and Qingdao maritime chemical plant. The raw materials are from commercial sources, suppliers such as Shanghai Shengde medical science and technology, Inc., Shanghai Kangtu chemical, Inc., and the like.

The reaction is generally carried out under a positive pressure of nitrogen or argon or by placing a dry tube over the anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper. The glassware was dried.

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18, 2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase 5% -95%(CH with 0.1% formic acid)₃CN) in (H2O with 0.1% formic acid), by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

Hydrogen nuclear magnetic resonance spectroscopy: bruker 400MHz NMR instrument in CDCl at room temperature₃Or DMSO-d₆TMS (0ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet).

The first embodiment is as follows:

referring to scheme 2 below, compound 1 is prepared:

step 1): synthesis of intermediate 1-b

Under the protection of nitrogen, the raw material 1-a (7.56g, 50mmol), S8(19.2g, 75mmol), bromoethane (9.81g, 90mmol), NaHCO were added to the reaction flask in turn₃(8.4g, 100mmol), TBAB (1.62g,5mmol), toluene 100mL, water 20mL, stirring for 10min, heating to 80-85 ℃, reacting for 8h under heat preservation, extracting with toluene (100mL 2), washing the organic phase with water, separating, drying, concentrating the organic phase (50-60 ℃, minus 0.09 MPa-minus 0.08MPa) to dryness, and using 1 g: stirring 4mL of ethanol for 0.5h, filtering, pumping, drying a filter cake in a vacuum oven (50 ℃ and-0.08 MPa to-0.07 MPa) to obtain a 1-b intermediate (9.52g, the yield is 91%).

In this step, the present invention also verifies a plurality of different reaction conditions by parallel experiments to realize the step, such as adjusting the amount of the base, the kind and amount of the phase transfer catalyst, the kind of the solvent, and the like.

By verifying various reaction conditions, the alkali (sodium bicarbonate) in the step can also adopt common inorganic alkali such as potassium carbonate, sodium carbonate, potassium bicarbonate, potassium acetate and the like. Wherein the molar amount of the base: the molar amount of intermediate 1-a is 1: (1-2). When the base used is more basic, the amount thereof may be less. In the step, cheap and soluble inorganic alkali is mainly adopted, so that the pollution of the organic alkali to the environment is avoided, especially the discharge of waste water containing organic matters is reduced, and the environmental friendliness of the method is improved.

By verifying various reaction conditions, it was found that 18-crown-6-ether, 15-crown-5-ether, TEBAC (benzyltriethylammonium chloride), TBAC (tetrabutylammonium chloride) or other phase transfer catalysts can be used as the phase transfer catalyst (tetrabutylammonium bromide TBAB). Wherein, the molar weight of the phase transfer catalyst is as follows: the molar amount of the intermediate 1-b is (0.05 to 0.2): 1.

in step 1), when the reaction scale is large, the amount of the phase transfer catalyst can be reduced to save costs and reduce environmental pollution. Illustratively, when the mass of intermediate 1-b is greater than 1kg, the molar amount of phase transfer catalyst: the molar amount of the intermediate 1-a is (0.05 to 0.1): 1.

in the step 1), the reaction temperature is 60-85 ℃, and the reaction can be smoothly carried out; the reaction efficiency is higher when the reaction temperature is 70-85 ℃, and the reaction conversion rate is high when the temperature is high.

The reaction yields in the various reaction solvents were observed by parallel experiments. In order to adjust the solubility of the reaction raw materials, the raw materials have good compatibility and are more favorable for the reaction by screening the types of the organic solvents and the proportion of the organic solvents to water. Experiments show that the reaction yield is highest when a mixture of toluene and water is used as a solvent in the step. Detailed experimental results referring to table 1, a number of different reaction conditions and their yields are disclosed in table 1. In table 1, the difference between the respective reaction conditions is that the kind of the solvent is different, and other conditions (reaction raw material, substrate, amount, etc.) are kept the same.

Table 1: comparison of experimental results with different solvents

As can be seen from table 1, the yield is highest when a mixture of toluene and water is used as the solvent. Secondly, when a mixture of anisole and water is used as a solvent, this may be due to low reaction conversion due to poor material compatibility when a combination of a hydrophilic solvent and water is used. When a combination of ether and water is used as the solvent, the solvent of the ether is more polar than toluene, resulting in low reactivity thereof.

Step 2): synthesis of intermediates 1-d

Under the protection of nitrogen, 1-b (8.37g, 40mmol), raw material 1-c (10.29g, 42mmol) and Na were added in sequence to a reaction flask₂CO₃(8.48g, 80mmol), TBAB (0.65g,2mmol), toluene (90 mL), water (30 mL), stirring for 10min, adding Pd132(0.14g, 0.2mmol), heating to 65-70 ℃, and keeping the temperature for reaction for 5 h. Extracting with toluene (100 mL. multidot.2), washing the organic phase with water, separating, drying, concentrating the organic phase (50 ℃ -60 ℃, 0.07 MPa-0.08 MPa) to dryness, extracting with 1 g: heating 8mL of ethanol to 50-55 ℃, boiling and washing for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08 MPa-minus 0.07MPa) to obtain an intermediate 1-d (9.5g, yield 89%).

LC-MS(ESI,pos.ion)m/z:267.05[M+H]⁺；

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)。

The present invention also verifies a variety of different reaction conditions by parallel reactions to achieve step 2), such as adjusting the type and amount of base, the type and amount of phase transfer catalyst, the type of solvent, and the like.

By verifying various reaction conditions, the base (potassium carbonate) in the step 2) can also adopt common inorganic bases such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium acetate, sodium hydroxide and the like. Wherein, the intermediate 1-b: molar amount of base 1: (1-2). In the step, cheap and soluble inorganic alkali is mainly adopted, so that the pollution of the organic alkali to the environment is avoided, especially the discharge of waste water containing organic matters is reduced, and the environmental friendliness of the method is improved.

By verifying various different 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, TEAC (benzyltriethylammonium chloride), TBAC (tetrabutylammonium chloride) or other phase transfer catalysts. Wherein, the molar weight of the phase transfer catalyst is as follows: the molar amount of the intermediate 1-b is (0.05 to 0.1): 1.

in step 2), when the reaction scale is large, the amount of the phase transfer catalyst can be reduced to save costs and reduce environmental pollution. Illustratively, when the mass of intermediate 1-c is greater than 1kg, the molar amount of phase transfer catalyst: the molar amount of the intermediate 1-c is (0.05 to 0.07): 1.

in the step 2), the reaction temperature is 60-80 ℃, and the reaction can be smoothly carried out; the reaction efficiency is higher when the reaction temperature is 65-75 ℃, and the reaction conversion rate is higher when the temperature is high.

By verifying various reaction conditions, the yield of the reaction is highest when the mixture of toluene and water is used as a solvent in the step 2). Referring to table 2, a number of different reaction conditions and their yields are disclosed in table 2. In table 2, the difference between the reaction conditions is that the solvent is different in type, and the other conditions are the same.

Table 2: comparison of experimental results with different solvents

From the data in table 2, it follows: the yield of the mixed solvent of toluene and water is highest, and when the solubility of the raw materials in the selected solvent is poor, 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.

Step 3): synthesis of intermediates 1-e

Adding 80.0mL of intermediate 1-d (7.99g, 30mmol) methyl tert-butyl ether into a reaction bottle in sequence, stirring for 10min, cooling to-5-0 ℃, dropwise adding 60% glyoxal dimethyl acetal aqueous solution (9.05mL, 60mmol) into the system, and controlling the temperature at-5-0 ℃ in the dropwise adding process. After the dripping is finished, the reaction is carried out for 1h under the condition of heat preservation. Ammonium chloride (3.54g, 66mmol) was added in portions, after completion of addition, the reaction was carried out at room temperature for 5 hours, the pH was adjusted to 7 to 8 with a saturated sodium bicarbonate solution, extraction was carried out with dichloromethane (100.0mL × 2), the organic phase was washed with water, liquid separation and drying were carried out, the organic phase (40 ℃ to 50 ℃, 0.08MPa to-0.05 MPa) was concentrated to dryness, and the obtained solid product was purified with 1 g: heating 6mL of acetonitrile to 50-55 ℃, boiling and washing for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08 MPa-minus 0.07MPa) to obtain an intermediate 1-e (8.93g, yield 85%).

In step 3), ammonium chloride is used as an ammonia donor, and other ammonium salts may be used instead, for example, ammonium salts such as ammonium acetate, ammonium formate, and ammonium bicarbonate may be used instead. Wherein the molar amount of intermediates 1-d: molar amount of ammonium salt 1: (2-2.5).

In the step 3), the molar weight ratio of the glyoxal dimethyl acetal to the intermediate 1-d is (2-2.5): 1; in this step, the temperature of the dropwise addition of the glyoxal dimethylacetal solution is controlled at-10 ℃ to 10 ℃ or-5 ℃ to 5 ℃, and from the viewpoint of economy and improvement of the reaction conversion rate, it is preferably-5 ℃ to 0 ℃.

Step 4): synthesis of intermediates 1-f

Under the protection of nitrogen, sequentially adding an intermediate 1-e (7.01g, 20mmol) and 20mL of acetic acid into a reaction bottle, stirring for 10min, heating to 70-75 ℃, carrying out heat preservation reaction for 5h, concentrating the acetic acid under reduced pressure, adjusting the pH of the residue to 7-8 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane (100.0mL 2), washing an organic phase by using water, separating, drying, concentrating the organic phase (40-50 ℃, and-0.08-0.05 MPa) to dryness, and using 1g of a product: stirring 3mL of petroleum ether for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08 to minus 0.07MPa) to obtain an intermediate 1-f (5.78g, yield 95%).

¹H-NMR(DMSO-d₆，300MHz)δ(ppm)：14.18(s，1H)，9.79(s，1H)，9.56(s,1H)，8.55(s，1H)，7.98(d，1H,J＝9.4Hz)，7.89-7.73.(m,3H),7.24(s，1H)，2.51(s，3H)。

In the step 4), the reaction temperature is 65-80 ℃, and the reaction can be smoothly carried out; the reaction conversion rate is higher when the reaction temperature is 70-75 ℃.

And 5: synthesis of Compound 1

Under the protection of nitrogen, sequentially adding 1-f (9.12g, 30mmol) of intermediate and 45mL of dichloroethane into a reaction bottle, stirring for 10min, adding 1-g (5.0g, 45mmol) of raw materials and glacial acetic acid (2.16g, 36mmol), heating to 60-70 ℃, keeping the temperature for reaction for 3h, cooling the reaction system to-5 ℃, and adding NaBH (OAc) in batches₃(12.75, 60mmol), heating to 40-45 ℃ after adding, keeping the temperature for reaction for 20h, adjusting the pH value to 7-8 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane (150.0mL 2), washing an organic phase by using water, separating, drying, concentrating the organic phase (40-50 ℃ and-0.08 MPa-0.05 MPa) to dryness, and adding 1g of a product: stirring 6mL of ethanol for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃ and-0.08 MPa) to obtain a compound 1(9.8g, yield 82%).

LC-MS(ESI,pos.ion)m/z:400.15[M+H]⁺；

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)。

Example two:

compound 2 is prepared with reference to scheme 3 below:

step 1: synthesis of intermediate 2-a

Potassium hydroxide and iodobenzene diacetate (38.6g, 0.12mol) were added to a solution of 1- (6-tert-butylpyridin-2-yl) ethanone (17.7g, 0.1mol) in methanol (150mL) and stirred at room temperature for 12 hours. After removing the solvent by distillation under reduced pressure (30 ℃ C. -40 ℃ C., -0.09 MPa-0.08 MPa), 100mL of water was added to the obtained product, extraction was performed with dichloromethane (100mL 2), the organic phase was washed with a saturated aqueous solution of sodium carbonate, separated, dried, and the organic phase was concentrated to dryness (50 ℃ C. -60 ℃ C., -0.09 MPa-0.08 MPa) to obtain 2-a (15.1g, yield 78%).

Step 2: synthesis of intermediate 2-b

Under the protection of nitrogen, raw material 2-a (9.65g, 50mmol), S8(25.6g, 0.1mol), bromoethane (8.18g, 75mmol), K were added to a reaction flask in this order₂CO₃(6.9g, 50mmol), 18-crown-6 ether (2.64g, 10mmol), 100mL of toluene and 20mL of water, stirring for 10min, heating to 80-85 ℃, preserving heat for reaction for 8h, extracting with toluene (100.0mL 2), washing an organic phase with water, separating, drying, concentrating an organic phase (50-60 ℃, minus 0.09 MPa-minus 0.08MPa) to dryness, and using 1g of the product: stirring 3mL of ethanol for 0.5h, filtering, pumping, drying a filter cake in a vacuum oven (50 ℃ and-0.08 MPa to-0.07 MPa) to obtain a 2-b intermediate (10.06g, yield 80%).

And step 3: synthesis of intermediate 2-d

Under the protection of nitrogen, 2-b (7.53g, 30mmol), raw material 1-c (8.09g, 33mmol) and Na were added in sequence to a reaction flask₂CO₃(3.18g, 30mmol), 18-crown-6 ether (0.79g, 3mmol), toluene 100mL, water 30mL, stirring for 10min, adding palladium acetate (0.067g, 0.3mmol), heating to 70-75 ℃, and keeping the temperature for reaction for 5 h. Extracting with toluene (100mL x 2), washing the organic phase with water, separating, drying, concentrating the organic phase (50 ℃ -60 ℃, minus 0.09 MPa-minus 0.08MPa) to dryness, extracting with 1 g: heating 8mL of ethanol to 50-55 ℃, boiling and washing for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08 MPa-minus 0.07MPa) to obtain an intermediate 2-d (7.50g, yield 81%).

LC-MS(ESI,pos.ion)m/z:309.13[M+H]⁺；

¹H-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)。

And 4, step 4: synthesis of intermediate 2-e

Adding the intermediate 2-d (6.16g, 20mmol) and 50.0mL of tetrahydrofuran into a reaction bottle in sequence, stirring for 10min, cooling to-10 to-5 ℃, dropwise adding 60% glyoxal dimethyl acetal aqueous solution (7.55mL, 50mmol) into the system, and controlling the temperature of-10 to 0 ℃ in the dropwise adding process. After the dripping is finished, the reaction is carried out for 1h under the condition of heat preservation. Ammonium acetate (3.08g, 40mmol) is added in batches, after the addition is finished, the reaction is carried out for 5h at room temperature, the pH value is adjusted to 7-8 by saturated sodium carbonate solution, dichloromethane (100mL 2) is used for extraction, the organic phase is washed by water, liquid separation and drying are carried out, the organic phase (40 ℃ -50 ℃, minus 0.08 MPa-minus 0.05MPa) is concentrated to be dry, and the obtained solid product is obtained by using 1 g: heating 6mL of acetonitrile to 50-55 ℃, boiling and washing for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08 MPa-minus 0.07MPa) to obtain an intermediate 2-e (6.36g, yield 81%).

And 5: synthesis of intermediate 2-f

Under the protection of nitrogen, sequentially adding an intermediate 2-e (5.5g, 14mmol) and 22mL of hydrochloric acid into a reaction bottle, stirring for 10min, heating to 65-70 ℃, carrying out heat preservation reaction for 5h, concentrating the hydrochloric acid under reduced pressure, adjusting the pH of the residue to be 7-8 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane (100mL 2), washing an organic phase by using water, separating, drying, concentrating the organic phase (40-50 ℃, minus 0.08 MPa-minus 0.05MPa) to be dry, and using 1g of a product: stirring 3mL of petroleum ether for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃ and-0.08 MPa-0.05 MPa) to obtain an intermediate 2-f (4.23g, yield 87%).

Step 6: synthesis of Compound 2

Under the protection of nitrogen, sequentially adding the intermediate 2-f (4.16g, 12mmol) and 34mL of tetrahydrofuran into a reaction bottle, stirring for 10min, adding the raw materials 2-g (1.93g, 18mmol) and glacial acetic acid (0.72g, 12mmol), heating to 40-50 ℃, keeping the temperature for reaction for 3h, cooling the reaction system to-5 ℃, and adding NaBH (OAc) in batches₃(5.01g, 24mmol), heating to 35-40 ℃ after adding, keeping the temperature for reaction for 20h, adjusting the pH to 7-8 with saturated sodium bicarbonate solution, extracting with dichloromethane (100mL 2), washing the organic phase with water, separating, drying, concentrating the organic phase (40-50 ℃ and-0.08 MPa-0.05 MPa) to dryness, and adding 1g of: stirring 6mL of ethanol for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃ and-0.08 MPa) to obtain a compound 2(3.68g, yield 70%).

LC-MS(ESI,pos.ion)m/z:438.23[M+H]⁺；

¹H-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)。

Synthesis example 3: synthesis of Compound 3

Step 1: synthesis of intermediate 3-a

Potassium hydroxide and iodobenzene diacetate (38.6g, 0.12mol) were added to a solution of 1- (6-ethylpyridin-2-yl) ethanone (14.9g, 0.1mol) in methanol (150mL) and stirred at room temperature for 12 hours. After removing the solvent by distillation under reduced pressure (30 ℃ C. -40 ℃ C., -0.09 MPa-0.08 MPa), 100mL of water was added to the obtained product, extraction was performed with dichloromethane (100mL 2), the organic phase was washed with a saturated aqueous solution of sodium carbonate, separated, dried, and the organic phase was concentrated to dryness (50 ℃ C. -60 ℃ C., -0.09 MPa-0.08 MPa), yielding 3-a (11.9g, yield 72%).

Step 2: synthesis of intermediate 3-b

Under the protection of nitrogen, adding raw material 3-a (8.25g, 50mmol), S8(15.4g, 60mmol), bromoethane (6.5g, 60mmol), potassium acetate (7.84g, 80mmol), TEBA (5.70g, 2.5mmol), toluene 100mL and water 20mL in sequence into a reaction bottle, stirring for 10min, heating to 80-85 ℃, preserving heat for reaction for 8h, extracting with toluene (100.0mL 2), washing the organic phase with water, separating, drying, concentrating the organic phase (50-60 ℃, 0.09 MPa-0.08 MPa) to dryness, and adding the product 1 g: 3mL of ethanol is stirred for 0.5h, filtered, pumped and dried, and a filter cake is dried in a vacuum oven (50 ℃ and minus 0.08MPa to minus 0.07MPa) to obtain a 3-b intermediate (8.93g, the yield is 80%).

And step 3: synthesis of intermediate 3-d

Under the protection of nitrogen, 3-b (6.69g, 30mmol), raw material 1-c (8.09g, 33mmol) and NaHCO are added into a reaction bottle in sequence₃(5.04g, 60mmol), TEBA (0.68g, 3mmol), toluene 100mL, water 33mL, stirring for 10min, adding Pd132 (mmol), heating to 65-70 deg.C, and reacting for 5h under heat preservation. Extracting with toluene (100mL 2), washing the organic phase with water, separating, drying, concentrating the organic phase (50-60 deg.C, -0.09 MPa-0.08 MPa) to dryness, extracting with 1 g: heating 8mL of ethanol to 50-55 ℃, boiling and washing for 0.5h, filtering, and performing vacuum drying on a filter cake in a vacuum oven (50 ℃, minus 0.08 MPa-minus 0.0)7MPa) to afford intermediate 3-d (7.15g, 85% yield).

LC-MS(ESI,pos.ion)m/z:281.10[M+H]⁺；

¹H-NMR(CDCl₃，300MHz)δ(ppm)：9.16(s，1H)，8.44(s，1H)，8.17-8.15(d,1H)，8.05-8.03(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)。

And 4, step 4: synthesis of intermediate 3-e

Adding the intermediate 3-d (5.6g, 20mmol) and 67.0mL of anisole into a reaction bottle in sequence, stirring for 10min, cooling to 5-10 ℃, dropwise adding 60% glyoxal dimethyl acetal aqueous solution (6.63mL, 44mmol) into the system, and controlling the temperature to be 5-10 ℃ in the dropwise adding process. After the dripping is finished, the reaction is carried out for 1 hour under the condition of heat preservation. Adding potassium acetate (4.9g, 50mmol) in batches, reacting at room temperature for 5h after adding, adjusting the pH value to 7-8 by using a saturated sodium carbonate solution, extracting by using dichloromethane (100mL 2), washing an organic phase by using water, separating, drying, concentrating the organic phase (40-50 ℃, and-0.08 MPa-0.05 MPa) to be dry, and using 1g of a solid product to react with a solvent with the following weight percentage: heating 6mL of acetonitrile to 50-55 ℃, boiling and washing for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08 MPa-minus 0.07MPa) to obtain an intermediate 3-e (5.61g, yield 77%).

And 5: synthesis of intermediate 3-f

Under the protection of nitrogen, sequentially adding an intermediate 3-e (5.47g, 15mmol) and 11mL of trifluoroacetic acid into a reaction bottle, stirring for 10min, heating to 75-80 ℃, carrying out heat preservation reaction for 5h, concentrating the trifluoroacetic acid under reduced pressure, adjusting the pH of the residue to 7-8 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane (100mL 2), washing an organic phase by using water, separating, drying, concentrating the organic phase (40-50 ℃, and-0.08-0.05 MPa) to dryness, and using 1g of a product: stirring 3mL of petroleum ether for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃, minus 0.08MPa to minus 0.05MPa) to obtain an intermediate 3-f (4.11g, yield 86%).

And 6: synthesis of Compound 3

Under the protection of nitrogen, the intermediate 3-f (3.82g, 12mmol) and 45mL of dichloroethane were sequentially added to a reaction flask, stirred for 10min, and the starting material 3-g (2.30g, 18mmol), trifluoroacetic acid (2.74g, 24mmol) and L were addedThe temperature is between 70 and 80 ℃, the reaction is carried out for 3 hours under the condition of heat preservation, the temperature of a reaction system is reduced to between-5 and 5 ℃, NaBH (OAc) is added in batches₃(5.09g, 24mmol), heating to 40-50 ℃ after adding, keeping the temperature for reaction for 20h, adjusting the pH to 7-8 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane (100.0mL 2), washing an organic phase by using water, separating, drying, concentrating the organic phase (40-50 ℃ and-0.08 MPa-0.05 MPa) to dryness, and adding 1g of a product: stirring 6mL of ethanol for 0.5h, filtering, and drying a filter cake in a vacuum oven (50 ℃ and-0.08 MPa) to obtain a compound 3(3.39g, yield 66%).

LC-MS(ESI,pos.ion)m/z:430.15[M+H]⁺；

¹H-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)。

Compound activity assay

The inhibition of ALK5 kinase phosphorylation by the compounds prepared by the synthesis method of the present invention was evaluated according to the following assay method.

The ALK5 protein was expressed as a human recombinant GST-fusion protein in Sr9 insect cells using a baculovirus expression system. The expressed protein was purified by GSH-Sepharose (Sigma-Aldrich) affinity chromatography. In 96-well Flashplates from PerkinElmer (Boston, MA, USA)^TMThe kinase assay was performed in a reaction volume of 50. mu.L. The reaction cocktail reagent was added in four steps, in the following order: 20 μ L assay buffer (standard buffer), 5 μ L aqueous ATP, 5 μ L of 10% DMSO solution containing test compound, 10 μ L GSK3(14-27) (200ng)/10 μ L ALK5 solution (1ng) (premix). The reaction cocktail reagent contained 60mM HEPES-NaOH, pH 7.5, 3mM MgCl₂、3mM MnCl₂、3μM Na₃VO₄、1.2mM DTT、50μg/mL PEG₂₀₀₀₀、1μM[γ-³³P]-ATP (approx.2.5 x 10)⁵cpm per well), 200 ng/10. mu.L of GSK3(14-27) and 1 ng/10. mu.L of ALK 5. The reaction cocktail reagents were incubated at 30 ℃ for 60 min. With 50. mu.L of 2% (v/v) H₃PO₄The reaction was stopped, and the plate was aspirated through 200. mu.L of 0.9%(w/v) NaCl washes twice. The assay was performed using a Beckman Coulter Biomek 2000 automated system. Measurement with a microplate scintillation counter (Microbeta, Wallac)³³P_iIn "cpm"). IC (integrated circuit)₅₀Defined as the concentration of compound that inhibits 50% of the enzyme activity under the conditions tested.

IC of Compounds 1 to 4 synthesized in examples₅₀The values are shown in the following table.

According to the test results in the table, ALK5 kinase inhibition IC of the compounds 1-3 of the present application₅₀Are all less than 0.1 mu M, and have higher ALK5 kinase inhibitory activity.

It should be understood that the present application is not limited in its application to the embodiments set forth in the present specification. The application is capable of other embodiments and of being practiced and carried out in various ways. The foregoing variations and modifications are within the scope of the present application. It will be understood that the application disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text. All of these different combinations constitute a number of alternative aspects of the present application. The embodiments described in this specification illustrate preferred embodiments known to the implementation of the present application and will enable those skilled in the art to make and use the present application.

Claims (12)

1. A preparation method of a diketone compound is characterized in that the structural formula of the diketone compound is shown in chemical formula 2:

wherein R is₁Selected from deuterium, halogen group, cyano group, alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms or halogeno group having 1 to 6 carbon atomsAn alkyl group;

the preparation method of the diketone compound comprises the following steps:

the first step,

Reacting the compound shown as the chemical formula P1, elemental sulfur and bromoethane to generate a compound shown as the chemical formula P2;

step two,

The compound shown as the chemical formula P2 and the compound shown as the chemical formula P3 are subjected to coupling reaction to generate the diketone compound shown as the chemical formula II.

2. The method of claim 1, wherein in step one, the reaction mixture of the compound represented by formula P1, elemental sulfur, bromoethane, the first base, and the first solvent is reacted to form the compound represented by formula P2.

3. The method for preparing the diketone compound according to claim 2, wherein the first solvent is a mixture of a first organic solvent and water, wherein the first organic solvent comprises one or more of an aromatic hydrocarbon solvent, an amide solvent, an ether solvent, and a nitrile solvent; wherein, by volume, the first organic solvent: water 1: (0.2-0.5).

4. The method according to claim 3, wherein the first organic solvent is one selected from toluene, dimethylformamide, cyclopentyl methyl ether, 1, 4-dioxane, anisole and acetonitrile.

5. The method for preparing the diketone compound according to claim 2, wherein the reaction mixture further comprises a first phase transfer catalyst selected from the group consisting of tetrabutylammonium bromide, 18-crown-6-ether, 15-crown-5-ether, benzyltriethylammonium chloride, and tetrabutylammonium chloride.

6. The method of claim 1, wherein in step two, the compound of formula P2, the compound of formula P3, the palladium catalyst, the second base, and the second solvent are reacted to form the diketone compound of formula II.

7. The method for preparing the diketone compound according to claim 6, wherein the second solvent is a mixture of a second organic solvent and water, wherein the second organic solvent comprises one or more of an alcohol solvent, an aromatic hydrocarbon solvent, an amide solvent, an ether solvent, and a nitrile solvent; wherein, by volume, the second organic solvent: water 1: (0.2-0.5).

8. The method according to claim 7, wherein the second organic solvent is selected from toluene, lower alcohol solvents of C1-C4, DMF, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, and acetonitrile.

9. The method according to claim 6, wherein in step two, 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.

10. The preparation method of the imidazole derivative is characterized in that the structure of the imidazole derivative is shown as a chemical formula 1:

wherein R is₁Selected from deuterium, a halogen group, a cyano group, 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;

R₂selected from fluorine, chlorine, bromine, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or halogenated alkyl with 1-6 carbon atoms;

the process for producing the imidazole derivative includes the process for producing the diketone compound according to any one of claims 1 to 10.

11. The method for preparing imidazole derivatives according to claim 11, further comprising:

step three,

Reacting the compound shown in the chemical formula II, glyoxal dimethyl acetal and ammonium salt to generate a compound shown in a chemical formula P4;

step four:

the compound shown as the chemical formula P4 generates a compound shown as the chemical formula P5;

step five:

the compound of chemical formula P5 and the compound of chemical formula P6 react to produce the compound of chemical formula 1.

12. The process for the preparation of imidazole derivatives according to claim 11, selected from the group consisting of the compounds shown below: