An N-aryl substituted imidate ester compound, a preparation method and use thereof

Abstract

The present application relates to a kind of N-aryl substituted imine ester compound and its preparation method and purposes, and the method for obtaining N-aryl substituted imine ester compound by the reaction of aromatic amine and ortho ester is disclosed, then with hydroxylamine or amine reaction, the preparation method of the compound containing benzimidazole structure.This method is used for the preparation of the key intermediate benzimidazole or double benzimidazole of telmisartan, can avoid some problems existing in prior art, such as the safety of nitration reaction itself and the disposal of nitration waste liquid, the phosphorus-containing waste liquid caused by using polyphosphoric acid and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, specifically relating to an N-aryl substituted imine ester compound, its preparation method, and its uses. Background Technology

[0002] Telmisartan is the active ingredient in a medication for treating hypertension. Benzimidazole (VI-2) and bisbenzimidazole (VI-1) are key intermediates in the preparation of telmisartan. Patent (EP502314) reports a method for first preparing a monobenzimidazole intermediate (VI-2) from aniline (VIII-3) through acylation, nitration, reduction, and hydrolysis, followed by polyphosphate cyclization to obtain the bisbenzimidazole intermediate (VI-1). The route is as follows:

[0003]

[0004] This method has some problems, such as the safety of the nitration reaction itself, the disposal of nitration waste liquid, and the phosphorus-containing waste liquid caused by the use of polyphosphoric acid.

[0005] Therefore, developing synthetic methods for the key intermediates of telmisartan, benzimidazole (VI-2) and bisbenzimidazole (VI-1), which are safe, environmentally friendly, green and sustainable, remains of great significance. Summary of the Invention

[0006] One object of this invention is to provide N-aryl substituted imine ester compounds represented by Formula III.

[0007] Another object of this invention is to provide a method for preparing N-aryl substituted imine ester compounds represented by Formula III.

[0008] Another object of this invention is to provide the use of N-aryl substituted imine esters of Formula III to prepare benzimidazole compound VI.

[0009] According to one embodiment of the present invention, a type III based N-aryl substituted imine ester compound, its salt or solvate thereof is provided:

[0010]

[0011] Where R is selected from

[0012] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0013] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0014] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0015] Wherein, the salt of the compound shown in Formula III is selected from inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate;

[0016] Solvates of the compounds shown in Formula III include hydrates, alcohols, dichloromethane compounds, methyl ether compounds, and toluene compounds.

[0017] According to another embodiment of the present invention, a class of compounds of formula III-a based on N-aryl substituted imine esters, their salts, or solvates thereof is provided:

[0018]

[0019] Where R is selected from

[0020] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0021] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0022] Wherein, the salt of the compound shown in Formula III-a is selected from inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate.

[0023] Solvates of compounds represented by formula III-a, such as hydrates, alcohols, dichloromethane compounds, tertiary methyl ether compounds, and toluene compounds.

[0024] According to another embodiment of the present invention, a method for preparing the compound of formula I, its salt or solvate thereof, by reacting it with the compound of formula II to obtain the compound of formula III is provided:

[0025]

[0026] Where R is selected from

[0027] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0028] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0029] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0030] In one embodiment, the compound of Formula I, its salt, or its solvate reacts with the compound of Formula II under acidic or non-acidic conditions to obtain the compound of Formula III.

[0031] Specifically, in the range of 0 to 100°C, the compound shown in Formula I, its salt or its solvate, and the compound shown in Formula II are added to a solvent. The reaction is carried out for 1 to 3 hours in the presence or absence of acid. After the compound shown in Formula I, its salt or its solvate are completely converted, the solvent is removed and the compound shown in Formula III is obtained.

[0032] Preferably, the molar ratio of the compound of formula I, its salt or solvate, to the compound of formula II is 1:0.8-1:10, more preferably 1:1-1:1.5;

[0033] Preferably, the compound of Formula I, its salt or its solvate, reacts with the compound of Formula II in the range of 10 to 80°C, more preferably in the range of 40 to 60°C.

[0034] The solvent is selected from C1-C6 alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons, such as toluene, xylene, and chlorobenzene; or esters, such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents, such as acetonitrile and dichloromethane; or combinations of the above solvents; preferably methanol, ethanol, toluene, xylene, isopropyl acetate, ethyl acetate, anisole, acetonitrile, and dichloromethane, more preferably ethanol, toluene, acetonitrile, and anisole.

[0035] The acid is selected from one or a combination of organic acids, inorganic acids, or Lewis acids; wherein the organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pentylamino acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or a combination thereof; wherein the inorganic acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, or a combination thereof; wherein the Lewis acid is selected from aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride, zinc chloride, or a combination thereof; preferably acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid, more preferably acetic acid or p-toluenesulfonic acid.

[0036] According to another embodiment of the present invention, a method for preparing the compound of formula I, its salt or solvate thereof, by reacting it with the compound of formula II-a to obtain the compound of formula III-a is provided:

[0037]

[0038] Where R is selected from

[0039] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0040] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0041] In one embodiment, the compound of formula I, its salt or its solvate, reacts with the compound of formula II-a under acidic or non-acidic conditions to obtain the compound of formula III-a.

[0042] Specifically, in the range of 0 to 100°C, the compound shown in Formula I, its salt or its solvate, and the compound shown in Formula II-a are added to a solvent and reacted for 1 to 3 hours in the presence or absence of acid. After the compound shown in Formula I, its salt or its solvate are completely converted, the solvent is removed by concentration to obtain the compound shown in Formula III-a.

[0043] Preferably, the molar ratio of the compound of formula I, its salt or solvate, to the compound of formula II-a is 1:0.8-1:10, more preferably 1:1-1:1.5;

[0044] Preferably, the compound of Formula I, its salt or its solvate reacts with the compound of Formula II-a in the range of 10 to 80°C, more preferably in the range of 40 to 60°C.

[0045] The solvent is selected from C1-C6 alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons, such as toluene, xylene, and chlorobenzene; or esters, such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers, such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents, such as acetonitrile and dichloromethane; or combinations of the above solvents; preferably methanol, ethanol, toluene, xylene, isopropyl acetate, ethyl acetate, anisole, acetonitrile, and dichloromethane, more preferably ethanol, toluene, acetonitrile, and anisole.

[0046] The acid is selected from one or a combination of organic acids, inorganic acids, or Lewis acids; wherein the organic acid is selected from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pentylamino acid, oxalic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or a combination thereof; wherein the inorganic acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, perchloric acid, or a combination thereof; wherein the Lewis acid is selected from aluminum trichloride, magnesium chloride, magnesium bromide, tin tetrachloride, titanium tetrachloride, zinc chloride, or a combination thereof; preferably acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid, more preferably acetic acid or p-toluenesulfonic acid.

[0047] According to another embodiment of the present invention, a use is provided for the compound of Formula III in preparing the compound of Formula IV:

[0048]

[0049] Where R is selected from

[0050] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0051] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0052] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0053] In one embodiment, the compound of Formula III, its salt or solvate thereof, reacts with hydroxylamine to give the compound of Formula IV;

[0054] Specifically, in the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours, and a solid is precipitated. The solid is filtered, washed, and dried to obtain the compound of formula IV.

[0055] Preferably, the molar ratio of the compound shown in Formula III to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0056] Preferably, the compound shown in Formula III reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 0–10°C.

[0057] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0058] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0059] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0060] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide; preferably sodium carbonate or potassium carbonate.

[0061] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof; preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0062] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0063] According to another embodiment of the present invention, the use of the compound shown in Formula III-a is provided for the preparation of the compound shown in Formula IV-a:

[0064]

[0065] Where R is selected from

[0066] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0067] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0068] In one embodiment, the compound of formula III-a, its salt or solvate thereof, reacts with hydroxylamine to give the compound of formula IV-a;

[0069] Specifically, in the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III-a, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours, and a solid is precipitated. The solid is filtered, washed, and dried to obtain the compound of formula IV-a.

[0070] Preferably, the molar ratio of the compound shown in Formula III-a to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0071] Preferably, the compound shown in Formula III-a reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 5–10°C.

[0072] The hydroxylamine mentioned above includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0073] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0074] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0075] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0076] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0077] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0078] According to another embodiment of the present invention, a use is provided for the compound of Formula III in preparing the compound of Formula V:

[0079]

[0080] Where R is selected from

[0081] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0082] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0083] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0084] R2 is selected from acyl-C(=O)R3, sulfonyl-SO2R4, alkoxycarbonyl-C(=O)-OR5, alkylaminecarbonyl-C(=O)-NR6R7, or alkoxyphosphoryl-P(=O)(OR8)2; wherein R3 is a substituted or unsubstituted C1-C20 straight-chain or branched alkyl group, or a C3-C20 cyclic alkyl group, a substituted or unsubstituted C1-C20 straight-chain or branched alkenyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted C6-C20 aryl group; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl group, or C3-C20 Cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy; wherein R4 to R8 are each independently substituted or unsubstituted C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, substituted or unsubstituted C1-C20 straight-chain or branched alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C6-C20 aryl; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy;

[0085] Wherein, the salt of the compound shown in Formula III is selected from inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate.

[0086] Solvates of compounds represented by Formula III, such as hydrates, alcohols, dichloromethane compounds, tertiary methyl ether compounds, and toluene compounds;

[0087] Step A:

[0088] In one embodiment, the compound of formula III, its salt or solvate thereof, reacts with hydroxylamine in the presence of a base to give the compound of formula IV.

[0089] Specifically, in the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours, and a solid is precipitated. The solid is filtered, washed, and dried to obtain the compound of formula IV.

[0090] Preferably, the molar ratio of the compound shown in Formula III to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0091] Preferably, the compound shown in Formula III reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 0–15°C.

[0092] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0093] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0094] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0095] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0096] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0097] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0098] Step B:

[0099] In another embodiment, the compound of formula IV is reacted with an acylation agent in the presence of a base and a solvent to give the compound of formula V.

[0100] Specifically, in the range of -20 to 30°C, the compound of formula IV, a base, and an acylation reagent are added to the solvent; after the addition is complete, the reaction continues for 1 to 13 hours, an appropriate amount of hydrochloric acid is added to neutralize the reaction system, the organic phase is separated, and the compound of formula V is concentrated.

[0101] Preferably, the molar ratio of the compound shown in Formula IV to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0102] Preferably, the compound shown in Formula IV reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0103] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0104] The base is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0105] The solvent is selected from one or a combination of dichloromethane, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, anisole, or water; preferably dichloromethane, toluene, methyl tert-butyl ether, chlorobenzene, or acetonitrile.

[0106] Steps A and B above can be implemented separately or in a single batch.

[0107] The compound shown in Formula III, its salt or its solvate, reacts with hydroxylamine in the presence of a base to give the compound shown in Formula IV, and then reacts with an acylation reagent to give the compound shown in Formula V.

[0108] Specifically, within the temperature range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III, its salt, or its solvate is added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours to obtain compound IV for later use. An acylation reagent is added to the above reaction solution, and after the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added to neutralize the reaction system, the organic phase is separated, and the mixture is concentrated to obtain compound V.

[0109] Preferably, the molar ratio of the compound shown in Formula III to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0110] Preferably, the compound shown in Formula III reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 5–10°C.

[0111] Preferably, the molar ratio of the compound shown in Formula IV to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0112] Preferably, the compound shown in Formula IV reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0113] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0114] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0115] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0116] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0117] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0118] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0119] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0120] According to another embodiment of the present invention, the use of a compound of formula III-a, its salt, or a solvate thereof is provided for the preparation of a compound of formula Va:

[0121]

[0122] Where R is selected from

[0123] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0124] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0125] R2 is selected from acyl-C(=O)R3, sulfonyl-SO2R4, alkoxycarbonyl-C(=O)-OR5, alkylaminecarbonyl-C(=O)-NR6R7, or alkoxyphosphoryl-P(=O)(OR8)2; wherein R3 is a substituted or unsubstituted C1-C20 straight-chain or branched alkyl group, or a C3-C20 cyclic alkyl group, a substituted or unsubstituted C1-C20 straight-chain or branched alkenyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted C6-C20 aryl group; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl group, or C3-C20 Cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy; wherein R4 to R8 are each independently substituted or unsubstituted C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, substituted or unsubstituted C1-C20 straight-chain or branched alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C6-C20 aryl; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy;

[0126] Wherein, the salt of the compound shown in Formula III is selected from inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate;

[0127] Solvates of compounds represented by Formula III, such as hydrates, alcohols, dichloromethane compounds, tertiary methyl ether compounds, and toluene compounds;

[0128] Step A:

[0129] In one embodiment, the compound shown in Formula III-a, its salt, or its solvate, reacts with hydroxylamine in the presence of a base to give the compound shown in Formula IV-a;

[0130] Specifically, in the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III-a, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours, and a solid is precipitated. The solid is filtered, washed, and dried to obtain the compound of formula IV-a.

[0131] Preferably, the molar ratio of the compound shown in Formula III-a to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0132] Preferably, the compound shown in Formula III-a reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 5–10°C.

[0133] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0134] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0135] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0136] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0137] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0138] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0139] Step B:

[0140] In another embodiment, the compound of formula IV-a is reacted with an acylation agent in the presence of a base and a solvent to give the compound of formula Va;

[0141] Specifically, in the range of -20 to 30°C, the compound shown in formula IV-a, a base, and an acylation reagent are added to the solvent; after the addition is complete, the reaction continues for 1 to 13 hours, an appropriate amount of hydrochloric acid is added to neutralize the reaction system, the organic phase is separated, and the compound of formula Va is concentrated.

[0142] Preferably, the molar ratio of the compound shown in formula IV-a to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0143] Preferably, the compound shown in formula IV-a reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0144] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0145] The base is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0146] The solvent is selected from one or a combination of dichloromethane, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, anisole, or water; preferably dichloromethane, toluene, methyl tert-butyl ether, chlorobenzene, or acetonitrile.

[0147] In one implementation scheme, steps A and B may be performed using a "one-pot" method:

[0148] The compound shown in Formula III-a, its salt or its solvate, reacts with hydroxylamine in the presence of a base to give the compound shown in Formula IV-a, and then reacts with an acylation reagent to give the compound shown in Formula Va.

[0149] Specifically, within the temperature range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III-a, its salt, or its solvate is added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours to obtain compound IV-a for later use. An acylation reagent is added to the above reaction solution, and after the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added to neutralize the reaction system, the organic phase is separated, and the concentration yields compound Va.

[0150] Preferably, the molar ratio of the compound shown in Formula III-a to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0151] Preferably, the compound shown in formula III-a reacts with hydroxylamine in the range of 0 to 30°C, more preferably in the range of 5 to 10°C;

[0152] Preferably, the molar ratio of the compound shown in formula IV-a to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0153] Preferably, the compound shown in formula IV-a reacts with the acylation agent in the range of 0–30°C, more preferably in the range of 10–25°C;

[0154] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0155] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0156] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0157] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0158] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0159] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0160] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0161] According to another embodiment of the present invention, a use is provided for the compound of Formula III for the preparation of the compound of Formula VI:

[0162]

[0163] Where R is selected from

[0164] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0165] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0166] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0167] R2 is selected from acyl-C(=O)R3, sulfonyl-SO2R4, alkoxycarbonyl-C(=O)-OR5, alkylaminecarbonyl-C(=O)-NR6R7, or alkoxyphosphoryl-P(=O)(OR8)2; wherein R3 is a substituted or unsubstituted C1-C20 straight-chain or branched alkyl group, or a C3-C20 cyclic alkyl group, a substituted or unsubstituted C1-C20 straight-chain or branched alkenyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted C6-C20 aryl group; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl group, or C3-C20 Cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy; wherein R4 to R8 are each independently substituted or unsubstituted C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, substituted or unsubstituted C1-C20 straight-chain or branched alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C6-C20 aryl; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy;

[0168] Wherein, the salt of the compound shown in Formula III is selected from inorganic acid salts and organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate;

[0169] Solvates of compounds represented by Formula III, such as hydrates, alcohols, dichloromethane compounds, tertiary methyl ether compounds, and toluene compounds;

[0170] Step A:

[0171] In one embodiment, the compound of formula III, its salt or solvate thereof, reacts with hydroxylamine in the presence of a base to give the compound of formula IV.

[0172] Specifically, in the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours, and a solid is precipitated. The solid is filtered, washed, and dried to obtain the compound of formula IV.

[0173] Preferably, the molar ratio of the compound shown in Formula III to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0174] Preferably, the compound shown in Formula III reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 5–10°C.

[0175] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or an aqueous solution of hydroxylamine;

[0176] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0177] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0178] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0179] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0180] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0181] Step B:

[0182] In another embodiment, the compound of formula IV is reacted with an acylation agent in the presence of a base and a solvent to give the compound of formula V;

[0183] Specifically, in the range of -20 to 30°C, the compound of formula IV, a base, and an acylation reagent are added to the solvent; after the addition is complete, the reaction continues for 1 to 13 hours, an appropriate amount of hydrochloric acid is added to neutralize the reaction system, the organic phase is separated, and the compound of formula V is concentrated.

[0184] Preferably, the molar ratio of the compound of formula IV to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0185] Preferably, the compound shown in Formula IV reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0186] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0187] The base is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0188] The solvent is selected from one or a combination of dichloromethane, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, anisole, or water; preferably dichloromethane, toluene, methyl tert-butyl ether, chlorobenzene, or acetonitrile.

[0189] Step C:

[0190] In another embodiment, the compound of formula V undergoes a cyclization reaction in the presence of a base to obtain the compound of formula VI.

[0191] Specifically, in the range of -20 to 50°C, the compound shown in formula V and a base are added to the solvent. After the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added to neutralize the reaction system, and a solid is precipitated. The solid is filtered and dried to obtain the compound of formula VI.

[0192] Preferably, the molar ratio of the compound shown in Formula V to the base is 1:0.8-1:10, more preferably 1:1-1:5;

[0193] Preferably, the compound shown in Formula V reacts with a base in the range of 10–40°C, more preferably in the range of 20–30°C.

[0194] The alkali is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or combinations thereof, preferably sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, or potassium hydroxide;

[0195] The solvent is selected from water, methanol, ethanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, phenyl methyl ether, ethanol, isopropanol, or water, or a combination thereof; preferably toluene, acetonitrile, phenyl methyl ether, ethanol, isopropanol, or water.

[0196] In one implementation scheme, steps A, B, and C may be performed using a "one-pot" method:

[0197] The compound shown in Formula III, its salt or its solvate, reacts with hydroxylamine in the presence of a base to give the compound shown in Formula IV. Then, an acylation reagent is added to react with it to give the compound shown in Formula V. Finally, a base is added and a cyclization reaction is carried out to give the compound shown in Formula VI.

[0198] Specifically, within the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours to obtain compound IV for later use. An acylation reagent is added to the above reaction solution, and after the addition is complete, the reaction continues for 1 to 13 hours. Then, a base is added and the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added to neutralize the reaction system, and a solid precipitates. The solid is then filtered to obtain compound VI.

[0199] Preferably, the molar ratio of the compound shown in Formula III to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0200] Preferably, the compound shown in Formula III reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 5–10°C.

[0201] Preferably, the molar ratio of the compound of formula IV to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0202] Preferably, the compound shown in Formula IV reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0203] Preferably, the molar ratio of the compound shown in Formula V to the base is 1:0.8-1:10, more preferably 1:1-1:5;

[0204] Preferably, the compound shown in Formula V reacts with a base in the range of 10–40°C, more preferably in the range of 20–30°C.

[0205] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0206] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0207] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0208] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0209] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0210] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0211] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0212] According to another embodiment of the present invention, the use of the compound shown in Formula III-a is provided for the preparation of the compound shown in Formula VI-a:

[0213]

[0214] Where R is selected from

[0215] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0216] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0217] R2 is selected from acyl-C(=O)R3, sulfonyl-SO2R4, alkoxycarbonyl-C(=O)-OR5, alkylaminecarbonyl-C(=O)-NR6R7, or alkoxyphosphoryl-P(=O)(OR8)2; wherein R3 is a substituted or unsubstituted C1-C20 straight-chain or branched alkyl group, or a C3-C20 cyclic alkyl group, a substituted or unsubstituted C1-C20 straight-chain or branched alkenyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted C6-C20 aryl group; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl group, or C3-C20 Cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy; wherein R4 to R8 are each independently substituted or unsubstituted C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, substituted or unsubstituted C1-C20 straight-chain or branched alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C6-C20 aryl; the substituent is selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C1-C20 straight-chain or branched alkyl, or C3-C20 cyclic alkyl, C1-C20 straight-chain or branched alkenyl, C1-C20 straight-chain or branched alkoxy;

[0218] Wherein, the salt of the compound shown in Formula III-a is selected from inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate;

[0219] The solvate forms of the compounds shown in Formula III-a, such as hydrates, alcohols, dichloromethane compounds, tertiary methyl ether compounds, and toluene compounds;

[0220] Step A:

[0221] In one embodiment, the compound shown in Formula III-a, its salt, or its solvate, reacts with hydroxylamine in the presence of a base to give the compound shown in Formula IV-a;

[0222] Specifically, in the range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in III-a, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours, and a solid is precipitated. The solid is filtered, washed, and dried to obtain compound of formula IV.

[0223] Preferably, the molar ratio of the compound shown in Formula III-a to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0224] Preferably, the compound shown in Formula III-a reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 0–15°C.

[0225] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or an aqueous solution of hydroxylamine;

[0226] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0227] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0228] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0229] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0230] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0231] Step B:

[0232] In another embodiment, the compound of formula IV-a is reacted with an acylation agent in the presence of a base and a solvent to give the compound of formula Va.

[0233] Specifically, in the range of -20 to 30°C, the compound shown in formula IV-a, a base, and an acylation reagent are added to the solvent; after the addition is complete, the reaction continues for 1 to 13 hours, an appropriate amount of hydrochloric acid is added to neutralize the reaction system, the organic phase is separated, and the compound of formula Va is concentrated.

[0234] Preferably, the molar ratio of the compound shown in formula IV-a to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0235] Preferably, the compound shown in formula IV-a reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0236] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0237] The base is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0238] The solvent is selected from one or a combination of dichloromethane, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, anisole, or water; preferably dichloromethane, toluene, methyl tert-butyl ether, chlorobenzene, or acetonitrile.

[0239] Step C:

[0240] In another embodiment, the compound of formula Va undergoes a cyclization reaction in the presence of a base to give the compound of formula VI-a.

[0241] In the range of -20 to 50°C, the base of the compound shown in formula Va is added to the solvent. After the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added to neutralize the reaction system, and a solid is precipitated. The solid is filtered and dried to obtain the compound of formula VI-a.

[0242] Preferably, the molar ratio of the compound represented by formula Va to the base is 1:0.8-1:10, more preferably 1:1-1:5;

[0243] Preferably, the compound represented by formula Va reacts with the base in the range of 10–40°C, more preferably in the range of 20–30°C.

[0244] The alkali is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or combinations thereof, preferably sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, or potassium hydroxide;

[0245] The solvent is selected from water, methanol, ethanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, phenyl methyl ether, ethanol, isopropanol, or water, or a combination thereof; preferably toluene, acetonitrile, phenyl methyl ether, ethanol, isopropanol, or water.

[0246] In one implementation scheme, steps A, B, and C are specifically implemented using a "one-pot" method:

[0247] The compound shown in Formula III-a, its salt or its solvate, reacts with hydroxylamine in the presence of a base to give the compound shown in Formula IV-a. Then, an acylation reagent is added to react with it to give the compound shown in Formula Va. Finally, a base is added, and the compound is cyclized to give the compound shown in Formula VI-a.

[0248] Specifically, within the temperature range of -20 to 50°C, hydroxylamine and a base are added to a solvent and reacted for 0.1 to 2 hours. Then, the compound shown in formula III-a, its salt, or its solvate are added to the above reaction solution. After the addition is complete, the reaction continues for 1 to 13 hours to obtain compound IV-a for later use. An acylation reagent is added to the above reaction solution, and after the addition is complete, the reaction continues for 1 to 13 hours. Then, a base is added and the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added to neutralize the reaction system, and a solid precipitates. The solid is then filtered to obtain the compound shown in formula VI-a.

[0249] Preferably, the molar ratio of the compound shown in Formula III-a to hydroxylamine is 1:0.8-1:10, more preferably 1:1-1:2.5;

[0250] Preferably, the compound shown in Formula III-a reacts with hydroxylamine in the range of 0–30°C, more preferably in the range of 5–10°C.

[0251] Preferably, the molar ratio of the compound shown in formula IV-a to the acylation reagent is 1:0.8-1:10, more preferably 1:1-1:2.0;

[0252] Preferably, the compound shown in formula IV-a reacts with the acylation reagent in the range of 0–30°C, more preferably in the range of 10–25°C.

[0253] Preferably, the molar ratio of the compound represented by formula Va to the base is 1:0.8-1:10, more preferably 1:1-1:5;

[0254] Preferably, the compound represented by formula Va reacts with the base in the range of 0 to 50°C, more preferably in the range of 10 to 30°C.

[0255] The hydroxylamine includes basic hydroxylamine or its salt, preferably hydroxylamine hydrochloride, hydroxylamine sulfate or hydroxylamine solution;

[0256] The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metallic organic alkalis.

[0257] The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine.

[0258] The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide, preferably sodium carbonate or potassium carbonate.

[0259] The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or combinations thereof, preferably sodium acetate, potassium acetate, sodium methoxide, or sodium ethoxide.

[0260] The solvent is selected from water, C1-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, and isoamyl alcohol; or aromatic hydrocarbons such as toluene, xylene, and chlorobenzene; or esters such as isopropyl acetate, n-butyl acetate, and ethyl acetate; or ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and anisole; or other solvents such as acetonitrile, dichloromethane, etc.; or combinations of the above solvents; preferably water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; more preferably water, methanol, ethanol, isopropanol, and acetonitrile;

[0261] The acyl chloride or anhydride reagent is an acyl chloride or anhydride containing a substituent R2, preferably one or a combination of acetyl chloride, trifluoroacetyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-methylbenzenesulfonyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoic anhydride, p-nitrobenzoic anhydride, p-chlorobenzoic anhydride, methanesulfonyl anhydride, trifluoromethanesulfonyl anhydride, p-methylbenzenesulfonyl anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, ditert-butyl dicarbonate, N,N-dimethylchloroformamide, or diethoxyphosphoryl chloride.

[0262] According to another embodiment of the present invention, a use is provided for the compound of formula III to prepare the compound of formula VII:

[0263]

[0264] Where R is selected from

[0265] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0266] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0267] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0268] In one embodiment, the compound of formula III is reacted with ammonia in a solvent to give the compound of formula VII.

[0269] Specifically, in the range of 0–120°C, the compound shown in Formula III and ammonia are added to a solvent and reacted for 1–13 hours. The reaction system is neutralized with an appropriate amount of hydrochloric acid, a solid is precipitated, filtered, and dried to obtain the compound of Formula VII.

[0270] Preferably, the molar ratio of the compound represented by Formula III to ammonia is 1:0.8-1:10, more preferably 1:1-1:5;

[0271] Preferably, the compound shown in Formula III reacts with ammonia in the range of 50–100°C, more preferably in the range of 60–80°C.

[0272] The ammonia is selected from liquid ammonia, aqueous solutions of ammonia, and other solutions of ammonia; wherein, other solutions include methanol solutions of ammonia, ethanol solutions of ammonia, toluene solutions of ammonia, tetrahydrofuran solutions of ammonia, and methyltetrahydrofuran solutions of ammonia.

[0273] The solvent is selected from one or a combination thereof, including acetonitrile, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, isopropanol, or water.

[0274] According to another embodiment of the present invention, the use of the compound shown in formula III-a for the preparation of the compound shown in formula VII-a is provided:

[0275]

[0276] Where R is selected from

[0277] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0278] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0279] In one embodiment, the compound shown in formula III-a is reacted with ammonia in a solvent to give the compound shown in formula VII-a;

[0280] Specifically, in the range of 0–120°C, the compound shown in formula III-a is added to a solvent and reacted with ammonia for 1–13 hours. The reaction system is neutralized with an appropriate amount of hydrochloric acid, a solid is precipitated, filtered, and dried to obtain the compound of formula VII-a.

[0281] Preferably, the molar ratio of the compound shown in Formula III-a to ammonia is 1:0.8-1:10, more preferably 1:1-1:5;

[0282] Preferably, the compound shown in Formula III-a reacts with ammonia in the range of 50–100°C, more preferably in the range of 60–80°C.

[0283] The ammonia is selected from liquid ammonia, aqueous solutions of ammonia, and other solutions of ammonia; wherein, other solutions include methanol solutions of ammonia, ethanol solutions of ammonia, toluene solutions of ammonia, tetrahydrofuran solutions of ammonia, and methyltetrahydrofuran solutions of ammonia.

[0284] The solvent is selected from one or a combination thereof, including toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, isopropanol, or water.

[0285] According to another embodiment of the present invention, a use is provided for the compound of Formula III for the preparation of the compound of Formula VI:

[0286]

[0287] Where R is selected from

[0288] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0289] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0290] R' is selected from C1-C10 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably n-propyl;

[0291] In one embodiment, the compound of formula III undergoes two steps, D and E, to obtain the compound of formula VI:

[0292] In step D, the compound shown in formula III reacts with ammonia in a solvent to give the compound shown in formula VII.

[0293] Specifically, in the range of 0–120°C, the compound shown in Formula III and ammonia are added to a solvent and reacted for 1–13 hours. The reaction system is neutralized with an appropriate amount of hydrochloric acid, a solid is precipitated, filtered, and dried to obtain the compound of Formula VII.

[0294] Preferably, the molar ratio of the compound represented by Formula III to ammonia is 1:0.8-1:10, more preferably 1:1-1:5;

[0295] Preferably, the compound shown in Formula III reacts with ammonia in the range of 50–100°C, more preferably in the range of 60–80°C.

[0296] The ammonia is selected from liquid ammonia, aqueous solutions of ammonia, and other solutions of ammonia; wherein, other solutions include methanol solutions of ammonia, ethanol solutions of ammonia, toluene solutions of ammonia, tetrahydrofuran solutions of ammonia, and methyltetrahydrofuran solutions of ammonia.

[0297] The solvent is selected from one or a combination thereof, including toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, isopropanol, or water.

[0298] In step E, the compound shown in formula VII undergoes a ring-closing reaction in the presence of a halogenating agent and a base to give the compound shown in formula VI.

[0299] Specifically, in the range of -20 to 50°C, the compound shown in formula VII, the base, and the calcium hypochlorite solution are added to the solvent. After the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added, a solid is precipitated, filtered, and dried to obtain the compound of formula VI.

[0300] Preferably, the molar ratio of the compound shown in Formula VII to the base is 1:0.8-1:10, more preferably 1:1-1:5;

[0301] Preferably, the compound represented by formula VII reacts with a base in the range of 10–40°C, more preferably in the range of 10–25°C.

[0302] The cyclization reaction is carried out in the presence of a halogenating agent and a base, and in a reaction solvent;

[0303] The halogenated reagent is a chlorine, bromine, or iodine reagent, selected from chlorine, sodium hypochlorite, calcium hypochlorite, dichlorohydantoin, N-chlorosuccinimide, cyanuric chloride, bromine, N-bromosuccinimide, dibromohydantoin, elemental iodine, N-iodosuccinimide, or a combination thereof.

[0304] The base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, sodium isopropoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0305] The solvent is selected from one or a combination of water, acetonitrile, methanol, ethanol, isopropanol, toluene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide.

[0306] In another embodiment, steps D and E are specifically implemented using a "one-pot" method;

[0307] Specifically, in the range of -20 to 50°C, ammonia, alkali, calcium hypochlorite solution and compound III are added to the solvent. After the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added, a solid is precipitated, filtered, and dried to obtain compound VI.

[0308] The ammonia is selected from liquid ammonia, aqueous solutions of ammonia, and other solutions of ammonia; wherein, other solutions include methanol solutions of ammonia, ethanol solutions of ammonia, toluene solutions of ammonia, tetrahydrofuran solutions of ammonia, and methyltetrahydrofuran solutions of ammonia.

[0309] The solvent is selected from one or a combination thereof, including acetonitrile, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, isopropanol, or water.

[0310] The cyclization reaction is carried out in the presence of a halogenating agent and a base, and in a reaction solvent;

[0311] The halogenated reagent is a chlorine, bromine, or iodine reagent, selected from chlorine, sodium hypochlorite, calcium hypochlorite, dichlorohydantoin, N-chlorosuccinimide, cyanuric chloride, bromine, N-bromosuccinimide, dibromohydantoin, elemental iodine, N-iodosuccinimide, or a combination thereof.

[0312] The base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, sodium isopropoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0313] According to another embodiment of the present invention, the use of the compound shown in Formula III-a is provided for the preparation of the compound shown in Formula VI-a:

[0314]

[0315] Where R is selected from

[0316] R0 is selected from hydrogen, C1-C4 alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl, and more preferably hydrogen or methyl;

[0317] R1 is selected from C1-C4 alkyl groups, preferably methyl, ethyl, propyl, butyl, and more preferably methyl;

[0318] In one embodiment, the compound of formula III-a undergoes a two-step reaction in steps D and E to obtain the compound of formula VI-a:

[0319] In step D, the compound shown in formula III-a reacts with ammonia in a solvent to give the compound shown in formula VII-a;

[0320] Specifically, in the range of 0–120°C, the compound shown in formula III-a is added to a solvent and reacted with ammonia for 1–13 hours. The reaction system is neutralized with an appropriate amount of hydrochloric acid, a solid is precipitated, filtered, and dried to obtain the compound of formula VII-a.

[0321] Preferably, the molar ratio of the compound shown in Formula III-a to ammonia is 1:0.8-1:10, more preferably 1:1-1:5;

[0322] Preferably, the compound shown in Formula III-a reacts with ammonia in the range of 50–100°C, more preferably in the range of 60–80°C.

[0323] The ammonia is selected from liquid ammonia, aqueous solutions of ammonia, and other solutions of ammonia; wherein, other solutions include methanol solutions of ammonia, ethanol solutions of ammonia, toluene solutions of ammonia, tetrahydrofuran solutions of ammonia, and methyltetrahydrofuran solutions of ammonia.

[0324] The solvent is selected from one or a combination thereof, including toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, isopropanol, or water.

[0325] In step E, the compound shown in formula VII-a undergoes a ring-closing reaction in the presence of a halogenating agent and a base to give the compound shown in formula VI-a.

[0326] Specifically, in the range of -20 to 50°C, the compound shown in VII-a, the base, and the calcium hypochlorite solution are added to the solvent. After the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added, a solid is precipitated, filtered, and dried to obtain the compound of formula VI-a.

[0327] The cyclization reaction is carried out in the presence of a halogenating agent and a base, and in a reaction solvent;

[0328] The halogenated reagent is a chlorine, bromine, or iodine reagent, selected from chlorine, sodium hypochlorite, calcium hypochlorite, dichlorohydantoin, N-chlorosuccinimide, cyanuric chloride, bromine, N-bromosuccinimide, dibromohydantoin, elemental iodine, N-iodosuccinimide, or a combination thereof.

[0329] The base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, sodium isopropoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0330] The solvent is selected from one or a combination of water, acetonitrile, methanol, ethanol, isopropanol, toluene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide.

[0331] In another embodiment, steps D and E are carried out using a one-pot method.

[0332] Specifically, in the range of -20 to 50°C, ammonia, alkali, calcium hypochlorite solution and compound III-a are added to the solvent. After the addition is complete, the reaction continues for 1 to 13 hours. An appropriate amount of hydrochloric acid is added, a solid is precipitated, filtered, and dried to obtain compound VI-a.

[0333] The ammonia is selected from liquid ammonia, aqueous solutions of ammonia, and other solutions of ammonia; wherein, other solutions include methanol solutions of ammonia, ethanol solutions of ammonia, toluene solutions of ammonia, tetrahydrofuran solutions of ammonia, and methyltetrahydrofuran solutions of ammonia.

[0334] The solvent is selected from one or a combination thereof, including acetonitrile, toluene, xylene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, methanol, ethanol, isopropanol, or water.

[0335] The cyclization reaction is carried out in the presence of a halogenating agent and a base, and in a reaction solvent;

[0336] The halogenated reagent is a chlorine, bromine, or iodine reagent, selected from chlorine, sodium hypochlorite, calcium hypochlorite, dichlorohydantoin, N-chlorosuccinimide, cyanuric chloride, bromine, N-bromosuccinimide, dibromohydantoin, elemental iodine, N-iodosuccinimide, or a combination thereof.

[0337] The base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, sodium isopropoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof.

[0338] Synthetic schematic diagrams of N-aryl substituted imine ester compound III and telmisartan intermediate VI are shown below. Figure 1 As shown.

[0339] Beneficial effects

[0340] This invention provides N-aryl substituted imine ester compounds III, their synthesis methods, and uses. When used in the preparation of key intermediates for telmisartan, specifically benzimidazole (VI-2) and bisbenzimidazole (VI-1), this invention avoids the use of nitration and polyphosphoric acid cyclization reactions in existing synthetic routes, thereby fundamentally avoiding the safety issues associated with nitration and the environmental problems related to the disposal of nitration and polyphosphoric acid wastewater.

[0341] This invention can also be used to prepare benzimidazole or arylzimidazole compounds in a broader sense. The synthetic method embodied in this invention has the advantages of good safety, mild conditions, and low pollutant and waste production, making it suitable for development into a green and sustainable production process. Attached Figure Description

[0342] Figure 1 This is a schematic diagram illustrating the synthesis of N-aryl substituted imine ester compound III and telmisartan intermediate VI of the present invention. Detailed Implementation

[0343] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0344] Example 1

[0345] Preparation of compound III-1:

[0346]

[0347] Aniline I-1 (4.74 g, 20 mmol), trimethyl orthobutyrate II-1 (3.5 ml, 22 mmol), and acetic acid (575 μl, 10 mmol) were added to toluene (50 ml), and nitrogen was purged. The reaction was carried out at 50–60 °C for 1 hour. The mixture was then concentrated under reduced pressure to give compound III-1 (6.4 g, 99% yield).

[0348] Characterization data of compound III-1:

[0349] 1H NMR(CDCl3,600MHz)δ:0.85(t,J=7.2Hz,3H),1.53-1.57(m,2H),2.11(t,J=7.2Hz,2H),2.18(s,3H),3.85(s,3H),3.87(s,3H),6.78(d,J= 8.4Hz,1H),7.29-7.31(m,2H),7.37-7.38(m,1H),7.48-7.50(m,1H),7.63(d,J=1.2Hz,1H),7.80-7.82(m,1H).ESI-MS(m / z):322.20(M+H) + .

[0350] Example 2

[0351] Preparation of compound III-1:

[0352]

[0353] Aniline I-1 (2.37 g, 10 mmol), trimethyl orthobutyrate II-1 (1.75 ml, 11 mmol), and acetic acid (300 μl, 5 mmol) were added to acetonitrile (25 ml), and nitrogen gas was purged. The reaction was carried out at 50–60 °C for 1 hour. The mixture was then concentrated under reduced pressure to give compound III-1 (3.2 g, 99% yield). The characterization data of compound III-1 were consistent with those in Example 1.

[0354] Example 3

[0355] Preparation of compound III-1:

[0356]

[0357] Add 5.94 g (20 mmol) of aniline I-1 acetate and 3.5 ml (22 mmol) of trimethyl orthobutyrate II-1 to toluene (50 ml), purge with nitrogen, and react at 50-60 °C for 1 hour. Then concentrate under reduced pressure to give compound III-1 (6.4 g, 99% yield). Characterization data for compound III-1 are consistent with those in Example 1.

[0358] Example 4

[0359] Preparation of compound IV-1:

[0360]

[0361] At -5 to -5°C, hydroxylamine hydrochloride (2.08 g, 30 mmol) and sodium acetate (3.20 g, 40 mmol) were added to anhydrous ethanol (15 mL), and the mixture was stirred at this temperature for 30 minutes. A solution of compound III-1 (6.42 g, 20 mmol) and ethanol (15 mL) was added to the above reaction solution, and the reaction was continued for 2 to 3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45 to 50°C to obtain compound IV-1 (6.08 g, 95% yield).

[0362] Characterization data of compound IV-1:

[0363] 1 H NMR(CDCl3,400MHz)δ:0.88(t,J=8Hz,3H),1.42-1.46(m,2H),2.32(t,J=8Hz,2H),2.39(s,3H),3.91(s,3H),7.02(brs,1H),7.24(d ,J=8Hz,1H),7.32-7.34(m,2H),7.40-7.42(m,1H),7.58(d,J=8Hz,1H),7.72(s,1H),7.82-7.85(m,1H).ESI-MS(m / z):323.20(M+H) + .

[0364] Example 5

[0365] Preparation of compound IV-1:

[0366]

[0367] At -5 to -5°C, hydroxylamine hydrochloride (2.08 g, 30 mmol) and sodium acetate (3.20 g, 40 mmol) were added to acetonitrile (15 mL), and the mixture was stirred at this temperature for 30 minutes. A solution of compound III-1 (6.42 g, 20 mmol) and acetonitrile (15 mL) was added to the above reaction solution, and the reaction was continued for 2 to 3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45 to 50°C to obtain compound IV-1 (6.08 g, 95% yield). The characterization data of compound IV-1 were consistent with those in Example 4.

[0368] Example 6

[0369] Preparation of compound IV-1:

[0370]

[0371] At -5 to -5°C, hydroxylamine hydrochloride (2.77 g, 40 mmol) and sodium carbonate (4.20 g, 40 mmol) were added to anhydrous ethanol (15 mL), and the mixture was stirred at this temperature for 30 minutes. A solution of compound III-1 (6.42 g, 20 mmol) and ethanol (15 mL) was added to the above reaction solution, and the reaction was continued for 2 to 3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45 to 50°C to obtain compound IV-1 (5.5 g, 85% yield). The characterization data of compound IV-1 were consistent with those in Example 4.

[0372] Example 7

[0373] Preparation of compound IV-1:

[0374]

[0375] At -5 to -5°C, hydroxylamine hydrochloride (2.08 g, 30 mmol) and sodium methoxide (2.20 g, 40 mmol) were added to methanol (15 mL), and the mixture was stirred at this temperature for 30 minutes. A solution of compound III-1 (6.42 g, 20 mmol) and methanol (15 mL) was added to the above reaction solution, and the reaction was continued for 2 to 3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45 to 50°C to obtain compound IV-1 (6.0 g, 93% yield). The characterization data of compound IV-1 were consistent with those in Example 4.

[0376] Example 8

[0377] Preparation of compound IV-1:

[0378]

[0379] Add aniline I-1 (4.74 g, 20 mmol), trimethyl orthobutyrate II-1 (3.5 ml, 22 mmol), and acetic acid (575 μl, 10 mmol) to toluene (50 ml), displace nitrogen gas, and react at 50-60 °C for 1 hour. Then cool to 25-30 °C to obtain a toluene solution of compound III-1 for later use.

[0380] At -5 to -5°C, hydroxylamine hydrochloride (2.08 g, 30 mmol) and sodium acetate (3.20 g, 40 mmol) were added to acetonitrile (15 mL), and the mixture was stirred at this temperature for 30 minutes. Then, a toluene solution of compound III-1 from the previous step was added to the reaction mixture, and the reaction was continued for 2-3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, then filtered again. The filter cake was collected and dried at 45-50°C to obtain compound IV-1 (5.6 g, 87% yield). The characterization data of compound IV-1 were consistent with those in Example 4.

[0381] Example 9

[0382] Preparation of compound IV-1:

[0383]

[0384] Add aniline I-1 (2.37 g, 10 mmol), trimethyl orthobutyrate II-1 (1.75 ml, 11 mmol), and acetic acid (300 μl, 5 mmol) to acetonitrile (25 ml), displace nitrogen gas, and react at 50-60 °C for 1 hour. Then cool to 25-30 °C to obtain an acetonitrile solution of compound III-1 for later use.

[0385] At -5 to -5°C, hydroxylamine hydrochloride (1.4 g, 20 mmol) and sodium acetate (1.6 g, 20 mmol) were added to acetonitrile (15 mL), and the mixture was stirred at this temperature for 30 minutes. Then, an acetonitrile solution of compound III-1 from the previous step was added to the above reaction mixture, and the reaction was continued for 2-3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45-50°C to obtain compound IV-1 (2.84 g, 88% yield). The characterization data of compound IV-1 were consistent with those in Example 4.

[0386] Example 10

[0387] Preparation of compound IV-1:

[0388]

[0389] Add aniline I-1 (4.74 g, 20 mmol), trimethyl orthobutyrate II-1 (3.5 ml, 22 mmol), and acetic acid (575 μl, 10 mmol) to ethanol (25 ml), displace nitrogen gas, and react at 50-60 °C for 1 hour. Then cool to 25-30 °C to obtain an ethanol solution of compound III-1 for later use.

[0390] At -5 to -5°C, hydroxylamine hydrochloride (2.77 g, 40 mmol) and sodium acetate (3.20 g, 40 mmol) were added to ethanol (15 mL), and the mixture was stirred at this temperature for 30 minutes. Then, an ethanol solution of compound III-1 from the previous step was added to the above reaction mixture, and the reaction was continued for 2–3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45–50°C to obtain compound IV-1 (6.0 g, 93% yield). The characterization data of compound IV-1 were consistent with those in Example 4.

[0391] Example 11

[0392] Preparation of compound VII-1:

[0393]

[0394] Compound III-1 (6.4 g, 20 mmol) and 28% ammonia (5 mL) were added to methanol (15 mL), and the mixture was heated to 60 °C for 2-3 hours. Heating was stopped, and the mixture was cooled to precipitate a solid. The solid was filtered, and the filter cake was added to 25 mL of water and stirred for 2 hours. The mixture was then filtered, and the filter cake was collected and dried at 45-50 °C to obtain compound VII-1 (5.0 g, 80% yield).

[0395] Characterization data of compound VII-1:

[0396] 1H NMR (CDCl3, 400MHz): 1.10 (m, 3H), 1.82-1.80 (m, 2H), 2.23 (s, 3H), 2.37 (m, 2H), 3.89 (s, 3H), 4.42 (brs, 2H), 6.95 (d, J = 8.0Hz, 1H),7.32-7.31(m,2H),7.42-7.35(m,1H),7.51(d,J=7.8Hz,1H),7.66(s,1H),δ7.85-7.75(m,1H).ESI-MS(m / z):307.20(M+H) + .

[0397] Example 12

[0398] Preparation of compound VII-1:

[0399]

[0400] Compound III-1 (6.4 g, 20 mmol) and 10% ammonia-methanol solution (10 mL) were added to methanol (15 mL), and the mixture was heated to 60 °C for 2–3 hours. Heating was stopped, and the mixture was cooled to precipitate a solid. The solid was filtered, and the filter cake was added to 25 mL of water and stirred for 2 hours. The mixture was then filtered again, and the filter cake was collected and dried at 45–50 °C to obtain compound VII-1 (5.3 g, yield 83%). The characterization data of compound VII-1 were consistent with those in Example 11.

[0401] Example 13

[0402] Preparation of compound III-2:

[0403]

[0404] Aniline I-2 (3.0 g, 20 mmol), trimethyl orthobutyrate II-1 (3.5 ml, 22 mmol), and acetic acid (575 μl, 10 mmol) were added to acetonitrile (50 ml), and nitrogen gas was purged. The reaction was carried out at 50-60 °C for 1 hour. The mixture was then concentrated under reduced pressure to give compound III-2 (4.6 g, 97% yield).

[0405] Characterization data of compound III-2:

[0406] 1 H NMR (CDCl3, 400MHz) δ: 0.87 (t, J = 7.4Hz, 3H), 1.52-1.62 (m, 2H), 2.10 (dd, J = 8.5, 6.7Hz, 2H), 2.18 (s, 3H), 3.8 7(s,3H),6.74(d,J=8.1Hz,1H),7.92(dd,J=8.2,2.0Hz,1H), δ7.97(d,J=1.9Hz,1H); ESI-MS(m / z):234.12(MH) - .

[0407] Example 14

[0408] Preparation of compound III-3:

[0409]

[0410] Aniline I-3 (3.3 g, 20 mmol), trimethyl orthobutyrate II-1 (3.5 ml, 22 mmol), and acetic acid (575 μl, 10 mmol) were added to acetonitrile (50 ml), and nitrogen gas was purged. The reaction was carried out at 50-60 °C for 1 hour. The mixture was then concentrated under reduced pressure to give compound III-3 (4.85 g, 97% yield).

[0411] Characterization data of compound III-3:

[0412] 1 H NMR (CDCl3, 400MHz) δ: 0.84 (t, J = 7.4Hz, 3H), 1.57–1.48 (m, 2H), 2.07 (dd, J = 8.5, 6.7Hz, 2H), 2.14 (s, 3H), 3.84 (s, 3H) ),3.90(s,3H),6.69(d,J=8.1Hz,1H),7.82(dd,J=8.1,2.0Hz,1H),δ7.88(d,J=1.9Hz,1H); ESI-MS(m / z):250.15(M+H) + .

[0413] Example 15

[0414] Preparation of compound IV-2:

[0415]

[0416] At -5 to -5°C, hydroxylamine hydrochloride (2.77 g, 40 mmol) and sodium acetate (3.20 g, 40 mmol) were added to ethanol (15 mL), and the mixture was stirred at this temperature for 30 minutes. A solution of compound III-2 (4.6 g, 20 mmol) and ethanol (15 mL) was added to the above reaction solution, and the reaction was continued for 2 to 3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45 to 50°C to obtain compound IV-2 (4.2 g, 90% yield).

[0417] Example 16

[0418] Preparation of compound IV-3:

[0419]

[0420] At -5 to -5°C, hydroxylamine hydrochloride (2.77 g, 40 mmol) and sodium acetate (3.20 g, 40 mmol) were added to ethanol (15 mL), and the mixture was stirred at this temperature for 30 minutes. A solution of compound III-3 (4.9 g, 20 mmol) and ethanol (15 mL) was added to the above reaction solution, and the reaction was continued for 2 to 3 hours. A solid precipitated, which was filtered. The filter cake was added to 25 mL of water and stirred for 2 hours, filtered again, and the filter cake was collected and dried at 45 to 50°C to obtain compound IV-2 (4.6 g, 97% yield).

[0421] Characterization data of compound IV-3: 1H NMR (DMSO-d6, 500MHz)0.79(t,J=7.4Hz,3H),1.28(dt,J=14.7,7.4Hz,2H),2.30–2.21(m,5H),3.82(s,3H),7.08(d,J =8.3Hz,1H),7.46(s,1H),7.74(dd,J=8.3,2.1Hz,1H),7.79(d,J=2.1Hz,1H),9.86(s,1H).ESI-MS(m / z):251.13(M+H) + .

[0422] Example 17

[0423] Preparation of compound IV-2:

[0424]

[0425] Compound III-2 (2.35 g, 10 mmol) and 10% ammonia-methanol solution (10 mL) were added to methanol (15 mL), and the mixture was heated to 60 °C for 2-3 hours. Heating was stopped, the mixture was cooled, and an appropriate amount of hydrochloric acid was added. A solid precipitated, which was filtered. The filter cake was added to 6 mL of water and stirred for 2 hours. The mixture was filtered again, and the filter cake was collected and dried at 45-50 °C to obtain compound VII-2 (2.0 g, 90% yield).

[0426] Example 18

[0427] Preparation of compound IV-3:

[0428]

[0429] Compound III-3 (5.0 g, 20 mmol) and 10% ammonia-methanol solution (20 mL) were added to methanol (30 mL), and the mixture was heated to 60 °C for 2-3 hours. Heating was stopped, the mixture was cooled, and a solid precipitated. The solid was filtered, and the filter cake was added to 20 mL of water and stirred for 2 hours. The mixture was then filtered, and the filter cake was collected and dried at 45-50 °C to obtain compound VII-3 (4.2 g, 90% yield).

[0430] Example 19

[0431] Preparation of bisbenzimidazole compound VI-1:

[0432]

[0433] Compound IV-1 (1 g, 3 mmol) from any of the above examples was suspended in dichloromethane (10 ml), then sodium carbonate (318 mg, 3 mmol) was added and the temperature was lowered to 0-10 °C. Acetyl chloride (0.24 g, 3 mmol) was added, and the reaction was continued for 5 hours. The mixture was separated and the organic phase was concentrated to obtain V-1 (1.1 g, 97% yield), which was used directly for the next reaction.

[0434]

[0435] At 0-10°C, V-1 (365 mg, 1 mmol) and 30% sodium hydroxide aqueous solution (133 mg, 4 mmol) prepared in the previous step were added to dichloromethane (5 ml), and the mixture was then heated to 25°C and reacted for 5 hours. Water (5 mL) was added to the reaction mixture, the mixture was separated, and the organic phase was concentrated to dryness to obtain VI-1 (307 mg, yield 96%).

[0436] Characterization data of compound VI-1:

[0437] 1 H NMR (CDCl3, 400MHz) δ: 0.79 (t, J = 8Hz, 3H), 1.68 (m, 2H), 2.47 (s, 3H), 2.70 (t, J = 8Hz, 2H), 3.85 (s ,3H),7.26(s,1H),7.30-7.42(m,3H),7.68(s,1H),7.74-7.77(m,1H).ESI-MS(m / z):305.18(M+H) + .

[0438] Example 20

[0439] Preparation of bisbenzimidazole compound VI-1:

[0440]

[0441] Compound VII-1 (3.06 g, 10 mmol) prepared in Example 12 was suspended in acetonitrile (100 ml) at 20-30 °C. Sodium hydroxide (800 mg, 20 mmol) and a 3% calcium hypochlorite aqueous solution (50 g, 10 mmol) were added, and the reaction was carried out at this temperature for 1-2 hours. A solid precipitated out, which was filtered, and the filter cake was collected and dried at 45-50 °C to obtain compound VI-1 (2.94 g, 96% yield). The characterization data of compound VI-1 were consistent with those of Example 19.

[0442] Example 21

[0443] Preparation of benzimidazole compound VI-2:

[0444]

[0445] Compound IV-2 (2.36 g, 10 mmol) prepared in Example 15 was suspended in dichloromethane (50 mL), and then sodium carbonate (1.06 g, 10 mmol) was added. Acetyl chloride (785 mg, 10 mmol) was added at a controlled temperature of 0-10 °C and reacted for 2-3 hours. The reaction system was neutralized with an appropriate amount of hydrochloric acid, separated, and the organic layer was concentrated to dryness to obtain V-2 (2.8 g), with a molar yield of 97%. This was used directly in the next reaction.

[0446]

[0447] At 20-30°C, V-2 (2.78 g, 10 mmol) and 30% sodium hydroxide aqueous solution (1.33 g, 40 mmol) prepared in the previous step were added to dichloromethane (50 ml). After the addition was complete, the temperature was raised to 25°C and the reaction was continued for 5 hours. An appropriate amount of hydrochloric acid was added to neutralize the reaction system. The mixture was separated, and the organic phase was concentrated to dryness to obtain VI-2 (2.0 g, yield 90%).

[0448] Characterization data of compound VI-2:

[0449] 1 H NMR (CDCl3, 400MHz) δ: 0.99 (t, J = 7.4, 3H), 1.86 (q, J = 7.3, 2H), 2.05 (s, 3H), 2.80 ( t,J=7.4,2H),3.89(s,3H),7.2-7.7(m,6H),7.8(s,1H).ESI-MS(m / z):219.11(M+H) + .

[0450] Example 22

[0451] Preparation of benzimidazole compound VI-3:

[0452]

[0453] Compound IV-3 (2.5 g, 10 mmol) prepared in Example 16 was suspended in dichloromethane (50 mL), and then sodium carbonate (1.06 g, 10 mmol) was added. Acetyl chloride (785 mg, 10 mmol) was added at a controlled temperature of 0-10 °C and reacted for 2-3 hours. The reaction system was neutralized with an appropriate amount of hydrochloric acid, separated, and the organic layer was concentrated to dryness to obtain V-3 (2.9 g), with a molar yield of 97%. This was used directly in the next reaction.

[0454]

[0455] At 20-30°C, V-3 (2.9 g, 10 mmol) and 30% sodium hydroxide aqueous solution (1.33 g, 40 mmol) prepared in the previous step were added to dichloromethane (50 ml). After the addition was complete, the temperature was raised to 25°C and the reaction was continued for 5 hours. An appropriate amount of hydrochloric acid was added to neutralize the reaction system. The mixture was separated, and the organic phase was concentrated to dryness to obtain VI-3 (2.0 g, yield 90%).

[0456] Characterization data of compound VI-2:

[0457] 1 H NMR (CDCl3, 400MHz) δ: 1.0 (t, J = 8.0, 3H), 1.9 (m, 2H), 2.4 (s, 3H), 2.9 (t, J = 8.0, 2H), 3.9 (s, 3H), 7.8 (s, 1H), 8.1 (s, 1H). ESI-MS (m / z): 233.12 (M+H) + .

[0458] Example 23

[0459] Preparation of benzimidazole compound VI-2:

[0460]

[0461] Compound VII-2 (1.1 g, 5 mmol) prepared in Example 17 was suspended in acetonitrile (50 mL). Sodium hydroxide (400 mg, 10 mmol) and a 3% calcium hypochlorite aqueous solution (50 mL, 10 mmol) were added at 20-30 °C, and the mixture was reacted for 5-6 hours. An appropriate amount of hydrochloric acid was added to neutralize the reaction system, and a solid precipitated. The solid was filtered, and the filter cake was dried at 45-50 °C to obtain VI-2 (1.0 g, 90% yield). The characterization data of compound VI-2 were consistent with those of Example 21.

[0462] Example 24

[0463] Preparation of benzimidazole compound VI-3:

[0464]

[0465] Compound VII-3 (2.34 g, 10 mmol) prepared in Example 18 was suspended in acetonitrile (100 mL). Sodium hydroxide (400 mg, 10 mmol) and a 3% calcium chlorate aqueous solution (50 mL, 10 mmol) were added at 20-30 °C, and the mixture was reacted for 5-6 hours. A solid precipitated out. The mixture was filtered, and the filter cake was dried at 45-50 °C under normal pressure to obtain solid product VI-3 (2.1 g, 90% yield). The characterization data of compound VI-3 were consistent with those of Example 22.

[0466] Example 25

[0467] Preparation of bisbenzimidazole compound VI-1

[0468]

[0469] One-pot method: At 5-10℃, add 28% ammonia water (5mL), sodium hydroxide (800mg, 20mmol), and 14% calcium hypochlorite aqueous solution (20mL, 20mmol) to acetonitrile (100mL). Then add III-1 (3.21g, 10mmol) and acetonitrile (10mL) solution to the above reaction solution. After the addition is complete, heat to 20-30℃ and react for 5-6 hours. A solid precipitates out. Filter, collect the filter cake, and dry at 45-50℃ to obtain VI-1 (2.1g, yield 70%).

[0470] The characterization data for compound VI-1 are consistent with those in Example 19.

[0471] Example 26

[0472] Preparation of benzimidazole compound VI-2:

[0473]

[0474] One-pot method: At 5-10℃, add 28% ammonia (5mL), sodium hydroxide (800mg, 20mmol), and 14% calcium hypochlorite aqueous solution (20mL, 20mmol) to acetonitrile (100mL). Then add III-2 (1.18g, 5mmol) and acetonitrile (10mL) solution to the above reaction solution. After the addition is complete, heat to 20-30℃ and react for 5-6 hours. Add an appropriate amount of hydrochloric acid to neutralize the reaction system. A solid precipitates out. Filter, collect the filter cake, and dry at 45-50℃ to obtain VI-2 (0.61g, yield 60%).

[0475] The characterization data for compound VI-2 are consistent with those of Example 21.

[0476] Example 27

[0477] Preparation of benzimidazole compound VI-3:

[0478]

[0479] One-pot method: Add 100 mL of acetonitrile to a 250 mL reaction flask, and add ammonia (4 mL), sodium hydroxide (400 mg, 10 mmol), and 14% calcium hypochlorite aqueous solution (15 mL, 15 mmol) while controlling the temperature at 5-10 °C. Then add a solution of III-3 (1.0 g, 4 mmol) and acetonitrile (10 mL) to the above reaction solution. After the addition is complete, raise the temperature to 20-30 °C and react. A solid precipitates out. TLC shows that the starting material has basically reacted completely and converted into the product. Filter and dry the filter cake at 45-50 °C under normal pressure to obtain solid product VI-3 (0.62 g, yield 60%).

[0480] The characterization data for compound VI-3 are consistent with those in Example 22.

[0481] Example 28

[0482] Preparation of the bisbenzimidazole intermediate compound VI-1:

[0483]

[0484] One-pot reaction: Aniline I-1 (4.74 g, 20 mmol), trimethyl orthobutyrate II-1 (3.5 mL, 22 mmol), and acetic acid (580 μl, 10 mmol) were added to acetonitrile (25 mL), and nitrogen was introduced to replace the nitrogen atmosphere. The reaction was carried out at 50-60 °C for 1 hour. The temperature was lowered to -5 to 0 °C, and sodium acetate (4.0 g, 50 mmol) and hydroxylamine hydrochloride (3.46 g, 50 mmol) were added to the reaction solution. The mixture was stirred at this temperature for 3-5 hours, and then acetyl chloride (1.57 g, 20 mmol) was added dropwise. After reacting for 1-2 hours, 30% sodium hydroxide solution (10.7 g, 80 mmol) was added, and the reaction was carried out for 5-6 hours. The mixture was filtered, and the filter cake was added to 25 mL of purified water and stirred at 25-30 °C for 2 hours. The mixture was then filtered, and the filter cake was collected and dried at 45-50 °C to obtain compound VI-1 (5.2 g, 85% yield). The characterization data for compound VI-1 are consistent with those in Example 19.

Claims

1. As shown in Formula III N - Use of aryl-substituted imine esters or their salts for the reaction with hydroxylamine to prepare compounds of formula IV: in, R is selected from , or ; R0 is selected from hydrogen, methyl, ethyl, propyl, or butyl; R1 is selected from methyl, ethyl, propyl, or butyl; R' is n-propyl; The salts of the compounds shown in Formula III are inorganic acid salts or organic acid salts, wherein the inorganic acid salts are selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate; and the organic acid salts are selected from formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate or benzenesulfonate. The hydroxylamine is hydroxylamine hydrochloride, hydroxylamine sulfate, or a hydroxylamine solution; The compound shown in Formula III or its salt reacts with hydroxylamine in the presence of a base and in a solvent to give the compound shown in Formula IV; The alkali is selected from one or a combination of non-metallic organic alkalis, inorganic alkalis, and metal organic alkalis. The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine. The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide. The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof. The solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof.

2. The use according to claim 1, wherein, R0 is hydrogen or methyl; R1 is a methyl group.

3. The use according to claim 1, wherein, The inorganic base is selected from sodium carbonate and potassium carbonate; The organometallic base is selected from sodium acetate, potassium acetate, sodium methoxide, and sodium ethoxide; The solvent is selected from water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole.

4. The use according to claim 1, wherein, The solvent is water, methanol, ethanol, isopropanol, acetonitrile, or a combination thereof.

5. Equation III N - Use of aryl-substituted imine esters or their salts for the preparation of compounds of formula V: in, The definitions of R, R1, R' and salts of the compounds shown in Formula III are consistent with those in claim 1; In step A, the compound shown in formula III or its salt is reacted with hydroxylamine in the presence of a base and a solvent to obtain the compound shown in formula IV. The hydroxylamine is hydroxylamine hydrochloride or hydroxylamine sulfate; The alkali mentioned in step A is selected from non-metallic organic alkalis, inorganic alkalis, metal organic alkalis, or combinations thereof; The non-metallic organic base is selected from one or a combination of ammonia, imidazole, triazole, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine. The inorganic base is selected from one or a combination of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, or magnesium oxide. The organometallic base is selected from lithium acetate, sodium acetate, potassium acetate, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, or magnesium tert-butoxide, or a combination thereof. The solvent mentioned in step A is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, isobutanol, isoamyl alcohol, toluene, xylene, chlorobenzene, isopropyl acetate, n-butyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, anisole, acetonitrile, dichloromethane, or combinations thereof. In step B, the compound shown in formula IV reacts with an acylation reagent in the presence of a base and a solvent to give the compound shown in formula V. The acylation reagent mentioned in step B is one of acetyl chloride, trifluoroacetyl chloride, acetic anhydride, or a combination thereof; The base mentioned in step B is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof. The solvent mentioned in step B is selected from one or a combination thereof, including dichloromethane, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, anisole, or water. Steps A and B can be implemented separately or in one batch.

6. The use according to claim 5, wherein, The inorganic base mentioned in step A is selected from sodium carbonate and potassium carbonate; The organometallic base mentioned in step A is selected from sodium acetate, potassium acetate, sodium methoxide, and sodium ethoxide; The solvent mentioned in step A is selected from water, methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and anisole; The solvent mentioned in step B is selected from dichloromethane, toluene, methyl tert-butyl ether, chlorobenzene, or acetonitrile.

7. The use according to claim 5, wherein, The solvent mentioned in step A is selected from water, methanol, ethanol, isopropanol, acetonitrile, or combinations thereof.

8. Equation III N - Use of aryl-substituted imine esters or their salts for the preparation of compounds of formula VI: in, The definitions of R, R1, R' and the salts of the compounds shown in Formula III are consistent with those in claim 1; the definition of substituent R2 is consistent with that in claim 5. The reagents and conditions used in steps A and B are the same as those used in claim 5. In step C, the compound of formula V reacts with a base in a solvent to give the compound of formula VI. The base mentioned in step C is selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, or 2,2,6,6-tetramethylpiperidine, or a combination thereof. The solvent mentioned in step C is selected from one or a combination of methanol, ethanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl acetate, n-butyl acetate, phenyl methyl ether, or water. Steps A, B, and C can be implemented separately or in one batch.

9. The use according to claim 8, wherein, The alkali mentioned in step C is selected from sodium carbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, or potassium hydroxide; The solvent mentioned in step C is selected from toluene, acetonitrile, phenyl methyl ether, ethanol, isopropanol or water.

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