CN112441984B - Benzimidazole-substituted phenyl n-butyramide-based compound and preparation method thereof - Google Patents

Benzimidazole-substituted phenyl n-butyramide-based compound and preparation method thereof Download PDF

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CN112441984B
CN112441984B CN202010863046.1A CN202010863046A CN112441984B CN 112441984 B CN112441984 B CN 112441984B CN 202010863046 A CN202010863046 A CN 202010863046A CN 112441984 B CN112441984 B CN 112441984B
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sodium
potassium
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CN112441984A (en
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沈敬山
孙长亮
朱富强
张骏驰
李锐
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Shandong Fuchang Pharmaceutical Co ltd
Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Shandong Fuchang Pharmaceutical Co ltd
Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Priority to US17/637,637 priority patent/US20220289684A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present disclosure relates to benzimidazole-substituted phenyl n-butyramide-based compounds and methods of preparing the same. The method avoids nitration and polyphosphoric acid cyclization reaction, and avoids the generation of a large amount of waste acid reaction liquid from the source. The synthesis method has the advantages of simplicity, high efficiency, mild condition, few pollutants and the like, and is suitable for development into a green sustainable production process.

Description

Benzimidazole-substituted phenyl n-butyramide-based compound and preparation method thereof
The present disclosure claims priority from patent application number 2019108072922 filed on 2019, 8, 29.
Technical Field
The present disclosure relates to a pharmaceutical compound and a method of preparing the same. In particular, the present disclosure relates to benzimidazole-substituted phenyl n-butyramide-based compounds and methods of preparing the same.
Background
Telmisartan (TELMISARTAN) is a novel non-peptide angiotensin II (ATII type) receptor antagonist, and is a novel antihypertensive drug for clinical treatment. Telmisartan was first developed by the bringen john pharmaceutical company (Boehringer Ingelheim) and was first marketed in the united states in 3 months 1999 and subsequently in many other countries around the world. Telmisartan has the chemical name 4'- [ (1, 4' -dimethyl-2 '-propyl [2,6' -di-1H-benzoimidazole ] -1 '-yl) methyl ] - [1,1' -biphenyl ] -2-carboxylic acid, and the structure is as follows:
The telmisartan molecular structure contains two connected benzimidazole rings, and the construction of the bisbenzimidazole ring structure is the important strategy for synthesizing the telmisartan molecules. Of the many bis-benzimidazole intermediate compounds, 2-n-propyl-4-methyl-6- (1' -methylbenzo [ d ] imidazol-2-yl) benzimidazole, the most involved intermediate compound in the known telmisartan synthesis route, is the most typical.
In the currently known synthetic method route, a synthetic strategy of constructing a benzimidazole ring in the middle of a structure and then constructing another benzimidazole ring in the terminal position of the structure is mainly adopted. For the construction of benzimidazole ring in the middle of the structure, substituted n-butyrylaniline is generally used as a raw material, and the steps of introducing nitro group through ortho-nitration of the aromatic ring of n-butyrylamino, reducing the nitro group into amino group, condensing and closing the ring and the like are carried out. There are still many problems in the synthetic route under this strategy, such as the problem of safety in the nitration reaction and the problem of disposal of the nitration waste liquid, the problem of disposal of a large amount of waste acid liquid and waste acid neutralization waste liquid generated by forming the second imidazole ring in polyphosphoric acid or strong acid, and the like.
Therefore, it is important to find and develop a new synthesis route and process condition of telmisartan bisbenzimidazole intermediate compound which is safer, more environment-friendly, simpler, more efficient, mild in condition and low in cost and is suitable for industrial production. Meanwhile, the new method also meets the requirements of an ESH management system, accords with the higher pursuit and concept of safe and environment-friendly green synthesis, and is suitable for development into a green sustainable production process.
Disclosure of Invention
It is an object of the present disclosure to provide benzimidazole-substituted phenyl-n-butyramide-based compounds or salts thereof.
It is an object of the present disclosure to provide a process for preparing benzimidazole-substituted phenyl-n-butyramide-based compounds.
According to one embodiment of the present disclosure, there is provided a benzimidazole-substituted phenyl-n-butyramide-based compound represented by formula III:
In particular, the salt is a salt III.HX formed by a compound shown in formula III and an acid, wherein HX is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid and acetic acid.
According to one embodiment of the present disclosure, there is provided a process for preparing a benzimidazole-substituted phenyl-n-butyramide-based compound represented by formula III, which is one of the following processes:
the method comprises the following steps: is prepared by reacting a compound shown in a formula IV with a methylating agent,
In particular, the methylating agent is selected from methyl iodide, dimethyl sulfate and dimethyl carbonate;
in particular, the reaction is carried out in a solvent under an alkaline reagent,
In particular, the alkaline reagent is one or a mixture of several selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, the solvent is one or a mixture of more selected from tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
the second method is as follows: prepared from a compound represented by formula V-1,
Step (1), 3-methyl-4-n-butyrylaminobenzoic acid is taken as a starting material, and a compound shown as a 3-methyl-4-n-butyrylaminobenzoyl chloride formula V-2 is prepared through a chlorination reaction;
Step (2), reacting a compound shown in a formula V-2 with N-methyl o-phenylenediamine to obtain compounds shown in formulas V-3 and V-4;
step (3), the compounds shown in the formulas V-3 and V-4 undergo condensation reaction in the presence of an acidic reagent, an alkaline reagent or a condensation reagent to obtain a compound shown in the formula III;
In particular, in the step (1), the chlorinating agent used in the chlorination reaction is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate (triphosgene);
In particular, in step (1), the chlorination is carried out in a solvent, in particular, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether, preferably dichloromethane;
in particular, in step (2), an alkaline agent is used as an acid-binding agent, in particular, the alkaline agent is one or a mixture of several selected from 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, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, step (2) is carried out in a solvent, in particular, the solvent used is selected from one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene chloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water;
In particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-2 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation;
In particular, in the step (3), the acidic reagent used is one or a mixture of several selected from conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (3), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (3), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in the step (3), the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
And a third method: prepared from a compound represented by formula V-1,
Step (1), reacting 3-methyl-4-N-butyrylaminobenzoic acid with N-methyl-o-phenylenediamine in the presence of an acidic reagent or a condensation reagent to obtain compounds shown as formulas V-3 and V-4;
Step (2), the compounds shown in the formulas V-3 and V-4 are reacted under the conditions of the acidic reagent, the condensation reagent or the alkaline reagent in the step (1) to obtain the compound shown in the formula III;
In particular, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compounds shown in the formulas V-3 and V-4 prepared by the step (1) are not separated under the condition of an acid reagent or a condensation reagent, and the compound shown in the formula III is continuously prepared under the reaction condition of the step (1);
In particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in particular, in step (1), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in step (2), the acidic reagent or condensing reagent used is as defined in step (1).
In particular, in step (2), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in the step (1) and the step (2), the solvent used is one or a mixture of several selected from methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
The method four: prepared from a compound represented by the formula V-6 or V-7,
Step (1), 3-methyl-4-N-butyrylaminobenzoic acid methyl ester or 3-methyl-4-N-butyrylaminobenzoic acid ethyl ester reacts with N-methyl o-phenylenediamine in the presence of an acidic reagent or an alkaline reagent to obtain compounds shown in the formulas V-3 and V-4;
Step (2), reacting the compounds shown in the formulas V-3 and V-4 under the conditions of the acidic reagent, the alkaline reagent or the condensing reagent in the step (1) to obtain a compound shown in the formula III;
In particular, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compounds shown in the formulas V-3 and V-4 prepared by the step (1) are not separated under the condition of an acidic reagent or an alkaline reagent, and the compound shown in the formula III is continuously prepared under the reaction condition of the step (1);
In particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (1), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (2), the acidic reagent or basic reagent used is as defined in step (1).
In particular, in step (2), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in step (1) and step (2), the solvent used is one or a mixture of several selected from methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
And a fifth method: prepared from a compound of formula VI,
2-Methyl-4- (1-methyl-1H-benzo [ d ] imidazol-2-yl) aniline reacts with a compound shown in a general formula VII to obtain a compound shown in a formula III;
The method six: prepared from a compound represented by formula VIII,
Wherein Y is chlorine (Cl), bromine (Br) or iodine (I),
Reacting a compound shown in a general formula VIII with N-methylbenzimidazole in the presence of an alkaline reagent to obtain a compound shown in a general formula III,
In particular, the alkaline reagent is one or a mixture of several selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, sodium acetate, potassium acetate, magnesium acetate, sodium pivalate, potassium pivalate, magnesium pivalate, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, the reaction is carried out in the presence of a transition metal compound which is one or a mixture of several selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cupric chloride, cupric bromide, cupric oxide, cupric acetate, cupric sulfate, cupric nitrate, palladium chloride, palladium acetate, palladium trifluoroacetate, palladium triflate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, nickel dichloride, nickel acetate, bis (acetylacetonate) nickel, nickel trifluoroacetate, nickel triflate, bis (1, 5-cyclooctadiene) nickel; the ligand used in the transition metal compound is selected from ethylenediamine, N-methylethylenediamine, N-butylethylenediamine, N '-dimethylethylenediamine, N-dimethylethylenediamine, trimethylethylenediamine, tetramethylethylenediamine, (cis) -1, 2-cyclohexanediamine, (trans) -1, 2-cyclohexanediamine, 1, 2-cyclohexanediamine racemate, (trans) -N, N' -dimethyl-1, 2-cyclohexanediamine, (trans) -N, N '-diethyl-1, 2-cyclohexanediamine, (trans) -N, N' -diisopropyl-1, 2-cyclohexanediamine, 2 '-bipyridine, 1, 10-phenanthroline, 2, 9-dimethyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, tri-t-butylphosphine, 1, 2-bis (diphenyl) ethane, 1, 2-bis (diphenyl) propane, 1, 2' -diphenyl phosphine, 1, 9 '-diphenyl phosphine, 1' -bis (diphenyl) diphenyl phosphine, 9-diphenyl phosphine or a mixture thereof,
In particular, the reaction is carried out in a solvent which is one or a mixture of more selected from dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, acetonitrile, acetone, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, pyridine, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water.
According to one embodiment of the present disclosure, in method five, the compound of formula VI is prepared by the following method:
Step (1), obtaining a compound shown in a formula VI-2 under a reducing condition by using the compound shown in the formula VI-1;
Step (2), obtaining a compound shown in a formula VI-2 under the conditions of an acidic reagent, an alkaline reagent or a condensation reagent;
or the compound VI-1 is added with an acidic reagent or an alkaline reagent in the reduction system in the step (1) at the same time to directly obtain the compound of the formula VI; in particular the acidic or basic reagent used in the course of the reaction is as defined above for step four (1) of the process;
In particular, in step (1), the reducing agent used in the reducing conditions is a nitro reducing agent selected from hydrogen, metal reducing agents, metal chlorides, complex hydrides, sulfur-containing reducing agents, etc., wherein the hydrogen reduction is carried out with the addition of a catalyst selected from Cu, ni, pd, pt, ru, rh and oxides, hydroxides, chlorides, complexes with carbon or corresponding organometallic complexes thereof; the metal reducing agent is selected from iron powder and zinc powder; the metal chloride is selected from stannous chloride dihydrate and titanium trichloride; the complex hydride is selected from lithium aluminum hydride; the sulfur-containing reducing agent is selected from sodium hydrosulfide, sodium sulfide, ammonium sulfide, sodium sulfite, sodium bisulfite, and sodium hydrosulfite;
In particular, step (1) is carried out in a solvent which is one or a mixture of several selected from methanol, ethanol, propanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, acetone, ethyl acetate, N-butyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, formic acid, acetic acid, hydrochloric acid, sulfuric acid, water;
in particular, the acidic reagent, basic reagent, or condensation reagent described in step (2) is as defined in step (2) of method four;
In particular, the solvent used in the step (2) is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or a solvent-free reaction condition is used.
According to one embodiment of the present disclosure, method five is performed according to one of three methods:
In the method (a), when R 3 is chlorine, bromine or n-butyryloxy, the compound shown in the formula VI is reacted with n-butyryl chloride, n-butyryl bromide or n-butyric anhydride to prepare a compound shown in the formula III,
In particular, the process (a) is carried out in the presence of an alkaline reagent selected from the group consisting 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, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, aqueous ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine,
In particular, the process (a) is carried out in a solvent, in particular, the solvent used is one or a mixture of several selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene chloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water;
In the method (b), when R 3 is methoxy or ethoxy, the compound shown in the formula VI is reacted with methyl n-butyrate or ethyl n-butyrate to prepare the compound shown in the formula III,
In particular, the process (b) is carried out in the presence of an acidic or basic reagent,
In particular, in the process (b), the acidic reagent used is one or a mixture of several selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride,
In particular, in the process (b), when an acidic reagent is used, the reaction is carried out in a solvent or using solvent-free reaction conditions, and in particular, when an acidic reagent is used, the solvent used is one or a mixture of several of dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethylene glycol,
In particular, in the process (b), the alkaline reagent used is one or a mixture of several selected from the group consisting of 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, preferably sodium methoxide,
In particular, in the method (b), when an alkaline reagent is used, the reaction is carried out in a solvent, and in particular, when an alkaline reagent is used, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone;
In the method (c), when R 3 is hydroxyl, the compound shown in the formula VI reacts with n-butyric acid in the presence of an acidic reagent or a condensation reagent to prepare a compound shown in the formula III,
In particular, in the process (c), the acidic reagent used is one or a mixture of several selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride,
In particular, in the process (c), when an acidic reagent is used, the reaction is carried out in a solvent or using solvent-free reaction conditions, in particular, when an acidic reagent is used, the solvent is one or a mixture of several of dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethylene glycol,
In particular, in process (c), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate,
In particular, in the method (c), when a condensing agent is used, the reaction is carried out in a solvent, and in particular, when a condensing agent is used, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
According to one embodiment of the present disclosure, wherein the compound of formula IV is prepared by one of the following methods:
method I: is prepared from a compound shown as a formula V-1,
Step (1), 3-methyl-4-n-butyrylaminobenzaldehyde is prepared by taking 3-methyl-4-n-butyrylaminobenzaldehyde as a starting material through chlorination reaction,
Step (2), the prepared compound shown in the formula V-2 reacts with o-phenylenediamine to obtain a compound shown in the formula V-5;
Step (3), the compound shown in the formula V-5 undergoes condensation reaction in the presence of an acidic reagent, an alkaline reagent or a condensation reagent to obtain a compound shown in the formula IV;
In particular, in the step (1), the chlorinating agent used in the chlorination reaction is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate (triphosgene);
In particular, in step (1), the chlorination is carried out in a solvent, in particular, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether, preferably dichloromethane;
in particular, in step (2), an alkaline agent is used as an acid-binding agent, in particular, the alkaline agent is one or a mixture of several selected from 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, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, step (2) is carried out in a solvent, in particular, the solvent used is selected from one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene chloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water;
In particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-2 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation;
In particular, in the step (3), the acidic reagent used is one or a mixture of several selected from conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (3), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (3), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in the step (3), the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
Method II: is prepared from a compound shown as a formula V-1,
Step (1), 3-methyl-4-n-butyrylaminobenzoic acid reacts with o-phenylenediamine in the presence of an acidic reagent or a condensation reagent to obtain a compound shown as a formula V-5;
Step (2), reacting the compound shown in the formula V-5 under the conditions of the acidic reagent, the condensation reagent or the alkaline reagent in the step (1) to obtain a compound shown in the formula IV;
In particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-5 prepared in the step (1) is not separated, and the compound shown in the formula IV is continuously prepared under the reaction condition of the step (1);
In particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in particular, in step (1), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in step (2), the acidic reagent or condensing reagent used is as defined in step (1).
In particular, in step (2), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in the step (1) and the step (2), the solvent used is one or a mixture of several selected from methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
Method III:
step (1), 3-methyl-4-n-butyrylaminobenzoic acid methyl ester or 3-methyl-4-n-butyrylaminobenzoic acid ethyl ester reacts with o-phenylenediamine in the presence of an acidic reagent or an alkaline reagent to obtain a compound shown in a formula V-5;
Step (2), reacting the compound shown in the formula V-5 under the conditions of the acidic reagent, the condensation reagent or the alkaline reagent in the step (1) to obtain a compound shown in the formula IV;
In particular, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compound shown in the formula V-5 prepared in the step (1) is not separated under the condition of an acidic reagent or an alkaline reagent, and the compound shown in the formula IV is continuously prepared under the reaction condition of the step (1);
In particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (1), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably 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, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (2), the acidic reagent or basic reagent used is as defined in step (1).
In particular, in step (2), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in the step (1) and the step (2), the solvent used is one or a mixture of several selected from methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
According to one embodiment of the present disclosure, wherein the compound of formula VI-1 is prepared by one of the following methods:
Method IV:
The method comprises the following steps of (1) reacting o-nitrochlorobenzene in aqueous solution of methylamine under heating condition to obtain o-nitroaniline;
step (2), preparing a compound shown in a formula V-9 by a chlorination reaction of the compound shown in the formula V-8;
step (3), reacting a compound shown in a formula V-9 with o-nitroaniline to obtain a compound shown in a formula VI-1;
In particular, in step (1), the aqueous methylamine solution has a concentration of 20 to 30% and the reaction is carried out at 100 to 150 ℃ and 3 to 10 atm;
In particular, step (2) and step (3) are carried out in a solvent;
in particular, the step (2) and the step (3) are carried out by a one-pot method, namely, the compound shown in the formula V-9 prepared in the step (2) is directly subjected to the reaction of the step (3) without separation;
Wherein the chlorinating agent, the alkaline agent and the solvent used in the chlorinating reaction in the step (2) and the step (3) of the reaction process are the same as the chlorinating agent, the alkaline agent and the solvent used in the chlorinating reaction in the step (1) and the step (2) of the above-mentioned method I;
Method V:
Reacting a compound shown in a formula V-8 with o-nitroaniline in the presence of an acidic reagent or a condensation reagent and in a solvent to obtain a compound shown in a formula VI-1;
In particular, the acidic reagents, condensing reagents and solvents in this reaction process are as defined above for acidic reagents, condensing reagents and solvents in step (1) of method II;
Method VI:
reacting a compound shown in a formula V-10 or a compound shown in a formula V-11 with o-nitroaniline in the presence of an acidic reagent or an alkaline reagent and in a solvent to obtain a compound shown in a formula VI-1;
In particular, the acidic reagent, basic reagent and solvent in the reaction process are as defined above for acidic reagent, basic reagent and solvent in step (1) of method III;
Method VII:
reacting a compound shown in a formula V-12 with o-nitrochlorobenzene in the presence of an alkaline reagent, a transition metal compound and a complex thereof in a solvent to obtain a compound shown in a formula VI-1;
In particular, the basic reagents, transition metal compounds and complexes and solvents in this reaction are as defined above for the basic reagents, transition metal compounds and complexes and solvents in method six.
Method VIII:
Step (1), 3-methyl-4-nitrobenzoyl chloride is prepared by taking 3-methyl-4-nitrobenzoic acid as a starting material through chlorination reaction;
step (2), the prepared compound shown in the formula V-9 reacts with o-nitroaniline in the presence of an alkaline reagent to obtain a compound shown in the formula V-13;
step (3), the compound shown in the formula V-13 reacts with a methylation reagent to prepare a compound shown in the formula VI-1;
in particular, step (1) and step (2) are carried out in a solvent;
In particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-13 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation;
Wherein the chlorinating agent, the alkaline agent and the solvent used in the chlorinating reaction in the step (1) and the step (2) of the reaction process are the same as the chlorinating agent, the alkaline agent and the solvent used in the chlorinating reaction in the step (1) and the step (2) of the above-mentioned method I;
In particular, in step (3), the methylating agent is selected from methyl iodide, dimethyl sulfate and dimethyl carbonate;
In particular, in step (3), the reaction is carried out under an alkaline reagent and in a solvent,
In particular, in step (3), the alkaline reagent is one or a mixture of several selected from 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, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, in the step (3), the solvent is one or a mixture of more selected from tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
According to one embodiment of the present disclosure, there is provided an intermediate for preparing a benzimidazole-substituted phenyl-n-butyramide-based compound represented by formula III, or a salt thereof, the intermediate being selected from the group consisting of compounds represented by formulas IV, V-3, V-4, V-5, VI-1:
According to one embodiment of the present disclosure, there is provided a method for preparing a compound represented by formula II, the method comprising:
Step (1), the compound shown in the formula III reacts with a chlorinating reagent,
Step (2), reacting the chlorination reaction mixture obtained in the step (1) with a hydroxylamine reagent to obtain a compound shown in a formula IX;
step (3), reacting the compound shown in the formula IX with an acyl chloride or anhydride reagent to obtain a compound shown in the general formula X;
step (4), the compound shown in the general formula X reacts in the presence of an alkaline reagent to obtain a compound shown in the formula II,
In particular, in the step (1), the chlorinating agent is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and di (trichloromethyl) carbonate (triphosgene), the solvent is one or a mixture of more selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether and methyl tertiary butyl ether,
In particular, in step (2), the hydroxylamine reagent used is selected from basic free hydroxylamine, hydroxylamine hydrochloride, or a salt of hydroxylamine,
In particular, in the compound represented by the general formula X in step (3), R 4 is a carboxylic acid acyl-C (=o) R 5, sulfonyl-SO 2R6, alkoxycarbonyl-C (=o) -OR 7, alkylaminocarbonyl-C (=o) -NR 8R9, OR alkoxyphosphoryl-P (=o) (OR 10)2;
Wherein R 5 to R 10 are each independently hydrogen, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkyl, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 6-C20 aryl; in the case where R 5 to R 10 are substituted C 1-C20 linear or branched or cyclic alkyl, substituted C 1-C20 linear or branched or cyclic alkenyl, substituted benzyl, or substituted C 6-C20 aryl, the substituents are selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C 1-C20 linear or branched or cyclic alkyl, C 1-C20 linear or branched or cyclic alkenyl, C 1-C20 linear or branched or cyclic alkoxy,
In particular, in step (3), the acid chloride or anhydride reagent used is an acid chloride or anhydride corresponding to R 4, preferably one or more 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, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-methylbenzenesulfonic anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, di-t-butyl dicarbonate, N-dimethylchloroformamide, diethoxyphosphoryl chloride and the like,
In particular, in step (3), the reaction is carried out in an alkaline reagent which is one or a mixture of several 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, 2, 6-tetramethylpiperidine,
In particular, in the step (3), the reaction is carried out in a solvent, wherein the solvent is selected from one or a mixture of more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether and water,
In particular, in the step (4), the alkaline reagent used is one or a mixture of several selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium hydrogencarbonate, 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, 2, 6-tetramethylpiperidine,
In particular, in the step (4), the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether and water.
According to one embodiment of the present disclosure, wherein the step (3) and the step (4) are performed using a one-pot process.
According to one embodiment of the present disclosure, wherein the steps (1) to (4) are performed using a one-pot method.
According to one embodiment of the present disclosure, there is provided an intermediate for preparing a compound represented by formula II or a salt thereof, the intermediate being selected from compounds represented by formulas IX, X or a salt thereof:
Wherein R 4 in the compound of the formula X is defined as -C(＝O)R5、-SO2R6、-C(＝O)-OR7、-C(＝O)-NR8R9、-P(＝O)(OR10)2,
Wherein R 5 to R 10 are each independently hydrogen, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkyl, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 6-C20 aryl; in the case where R 5 to R 10 are substituted C 1-C20 linear or branched or cyclic alkyl, substituted C 1-C20 linear or branched or cyclic alkenyl, substituted benzyl, or substituted C 6-C20 aryl, the substituents are selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C 1-C20 linear or branched or cyclic alkyl, C 1-C20 linear or branched or cyclic alkenyl, C 1-C20 linear or branched or cyclic alkoxy.
Advantageous effects
The invention provides a plurality of preparation methods and applications of benzimidazole-substituted phenyl n-butanamide, and one of the uses thereof is to prepare a bisbenzimidazole intermediate compound of telmisartan (TELMISARTAN) which is an antihypertensive preparation drug. The method avoids nitration and polyphosphoric acid cyclization reaction, and avoids the generation of a large amount of waste acid reaction liquid from the source. The synthesis method has the advantages of simplicity, high efficiency, mild condition, few pollutants and the like, and is suitable for development into a green sustainable production process.
Detailed Description
So that those having ordinary skill in the art can appreciate the features and effects of the present invention, the following general description and definitions apply to the terms and expressions set forth in the specification and claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, in the event of a conflict, the present specification shall control.
As used herein, the terms "comprising," "including," "having," "containing," or any other similar language, are intended to cover a non-exclusive inclusion, as an open-ended linking word (open-ended transitional phrase). For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed, and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….
All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X 1、X2 and X 3," it is also meant that the claims for X 1 and the claims for X 1 and/or X 2 have been fully described. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X 1、X2 and X 3" and Y is described as "selected from the group consisting of Y 1、Y2 and Y 3", then it is meant that the claims of X being X 1 or X 2 or X 3 and Y being Y 1 or Y 2 or Y 3 have been fully described.
The following detailed description is merely exemplary in nature and is not intended to limit the invention and its uses. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or summary or the following detailed description or examples.
Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that the embodiments of the present invention are not limited to the specific details set forth in the following examples, since other variations will be known and apparent to those of ordinary skill in the art in view of the present disclosure, and are intended to be included herein.
Example 1
A method for preparing an intermediate IV from 3-methyl-4-n-butyrylaminobenzoic acid (V-1) through intermediates V-2 and V-5.
1) Preparation of intermediate compound V-5
3-Methyl-4-n-butyrylaminobenzoic acid (22.1 g,100 mmol), triphosgene (10.4 g,35mmol,0.35 eq) and tetrahydrofuran (70 mL) were added to the flask, heated to 40-45℃and stirred well. Then adding N, N-dimethylformamide (365 mg,5mmol,0.05 eq), heating and stirring for 5-6 hours at 40-45 ℃, cooling and transferring to a constant pressure funnel for standby. O-phenylenediamine (11.9 g,110mmol,1.1 eq), acetonitrile (95 mL) and aqueous sodium hydroxide solution (8 g,200mmol,2eq in 200mL water) were added to the other three-necked flask and stirred well in an ice bath at 0-5 ℃. Slowly dripping the prepared acyl chloride into the reaction from a constant pressure funnel under the ice bath stirring at the temperature of 0-5 ℃, and stirring for 1 hour after the dripping is completed, and heating to room temperature. The reaction was concentrated to remove about half the volume of the organic solvent by heating, then water (100 mL) was added and stirred well. The precipitated solid was collected and dried sufficiently to give 28.1g of pale yellow solid in 85% yield.
Characterization data for compound V-5:
1H NMR(d6-DMSO 400MHz)δ:0.96(t,J＝8Hz,3H),1.61-1.65(m,2H),2.30(s,3H),2.38-2.39(m,2H),4.89(s,2H),6.59-6.62(m,1H),6.79(d,J＝8Hz,1H),6.97(t,J＝8Hz,1H),7.18(d,J＝8Hz,1H),7.63(d,J＝8Hz,1H),7.79-7.81(m,1H),7.86(s,1H),9.37(s,1H),9.61(s,1H).
LR-MS(ESI)m/z:312(M+H)+.
2) Preparation of intermediate compound IV
Intermediate compound V-5 (2.0 g,6.5 mmol) and p-toluenesulfonic acid monohydrate (120 mg,0.6mmol,0.1 eq) were added to toluene (20 mL) and stirred well. The reaction was heated to reflux and water was separated overnight, and after cooling, a solid was precipitated. Concentrating to remove most of the solvent, adding sodium hydroxide aqueous solution (with concentration of about 10%), adjusting pH to 11-12, stirring thoroughly, collecting precipitated solid, and drying thoroughly to obtain off-white solid 1.5g with yield of 80%.
Compound IV characterization data:
1H NMR(d6-DMSO 400MHz)δ:0.94(t,J＝8Hz,3H),1.62-1.70(m,2H),2.31(s,3H),2.37(t,J＝8Hz,2H),7.17-7.19(m,2H),7.57-7.80(m,4H),7.95(d,J＝8Hz,1H),8.04(s,1H),9.32(s,1H).
LR-MS(ESI)m/z:294(M+H)+.
Example 2
A process for preparing intermediate compound VI-1 starting from intermediate compound V-8.
Compound V-8 (10 g,55.2 mmol) was poorly soluble in dry 50ml acetonitrile, DMF (400 mg,5.5 mmol), triphosgene (6.5 g,22 mmol), N 2 protection, acetonitrile reflux for 2h, solvent clear, TLC indicated complete reaction of starting material. In another round bottom flask, o-nitroaniline (8.4 g,55.2 mmol) was dissolved in 50ml of dry acetonitrile, potassium carbonate (22.9 g,165.6 mmol) was added, the acid chloride reaction solution was added dropwise to the reaction solution of o-nitroaniline 2 under ice bath, N 2 was protected, acetonitrile was refluxed for 2h, the reaction solution was concentrated, 150ml of water was added to the residue, 150ml of EA was extracted, the organic phase was washed with saturated sodium chloride, dried, spin-dried, and column chromatographed to give compound VI-1 as a pale yellow solid, 14.5g, yield 83.3%.
Characterization data for compound VI-1:
1H NMR(400MHz,MeOD):7.92(dd,J＝8.3,1.5Hz,1H),7.64–7.76(m,3H),7.48–7.55(m,1H),7.32(d,J＝1.9Hz,1H),7.24(dd,J＝8.3,1.9Hz,1H),3.47(s,3H),2.41(s,3H).
LR-MS(ESI)m/z:316.6(M+H)+.
example 3
1) Preparation of Compound V-12:
25ml of acetonitrile was added to compound V-8 (5 g,27.6 mmol), DMF (200 mg,2.76 mmol) and triphosgene (3.27 g,11.0 mmol) were added sequentially, N 2 was used for protection, acetonitrile was refluxed for 2h, 30ml of methylamine alcohol solution was added to the other round bottom flask, acyl chloride solution was added dropwise under ice bath, 100ml of EA was added, and the organic phase was saturated with saline water for 2 times, dried and spun dry to give compound V-12 as a yellow solid, 5g, yield 93.3%. Characterization data for compound V-12:
1H NMR(400MHz,CDCl3):δ7.94(dd,J＝8.4,1.7Hz,1H),7.75(d,J＝1.9Hz,1H),7.67(dd,J＝8.4,1.9Hz,1H),6.62(s,1H),3.00(d,J＝4.8Hz,3H),2.59(s,3H).
LR-MS(ESI)m/z:195.4(M+H)+.
2) Preparation of Compound VI-1
Compound V-12 (3838 mg,2 mmol), o-nitrochlorobenzene (349 mg,2.2 mmol), pd (dppf) Cl 2(73mg,0.1mmol),Cs2CO3 (1.95 g,6 mmol) were added to 10ml toluene, N 2 protected, heated at 110℃for 10h, filtered, filtrate 20ml EA diluted, organic phase saturated brine wash, dried, spin-dried, column chromatographed to give compound VI-1 as a pale yellow solid 530mg, yield 84.0%.
Characterization data for compound VI-1:
1H NMR(400MHz,MeOD):7.92(dd,J＝8.3,1.5Hz,1H),7.64–7.76(m,3H),7.48–7.55(m,1H),7.32(d,J＝1.9Hz,1H),7.24(dd,J＝8.3,1.9Hz,1H),3.47(s,3H),2.41(s,3H).
LR-MS(ESI)m/z:316.6(M+H)+.
Example 4
A process for preparing intermediate compound III starting from intermediate compound IV.
Compound IV (586 mg,2 mmol), dimethyl sulfate (277 mg,2.2mmol,1.1 eq), potassium carbonate (414 mg,3.0mmol,1.5 eq) were added to acetone (10 mL) at room temperature and stirred well. The reaction was heated under reflux for 2 hours, and after the solvent was mostly removed by concentration, the reaction was purified by column chromatography to give 567mg of an off-white solid with a yield of 92%.
Compound III characterization data:
1H NMR(d6-DMSO 400MHz)δ:1.02(t,J＝8Hz,3H),1.76-1.83(m,2H),2.28(s,3H),2.44(t,J＝8Hz,2H),3.83(s,3H),7.31-7.34(m,2H),7.38-7.40(m,1H),7.45(d,J＝8Hz,1H),7.54(s,1H),7.80-7.93(m,1H).
LR-MS(ESI)m/z:308(M+H)+.
example 5
A process for preparing intermediate compound IV starting from compound V-1.
To a three-necked flask, compound V-1 (4.4 g,20 mmol), p-toluenesulfonic acid monohydrate (380 mg,2mmol,0.1 eq), and o-phenylenediamine (2.2 g,21mmol,1.05 eq) were added to toluene (40 mL) and stirred well. The reaction was heated to reflux and water was separated overnight, and after cooling, a solid was precipitated. Concentrating to remove most of the solvent, adding sodium hydroxide aqueous solution (with the concentration of about 10%), adjusting the pH to 11-12, fully stirring, collecting precipitated solid, fully drying to obtain 4.4g of off-white solid, and obtaining the yield of 75%.
Compound IV characterization data:
1H NMR(d6-DMSO 400MHz)δ:0.94(t,J＝8Hz,3H),1.62-1.70(m,2H),2.31(s,3H),2.37(t,J＝8Hz,2H),7.17-7.19(m,2H),7.57-7.80(m,4H),7.95(d,J＝8Hz,1H),8.04(s,1H),9.32(s,1H).
LR-MS(ESI)m/z:294(M+H)+.
the characterization data of the product IV obtained in example 1 are identical.
Example 6
A process for preparing intermediate compound III starting from compound V-6.
To a three-necked flask, compound V-6 (4.7 g,20 mmol), p-toluenesulfonic acid monohydrate (380 mg,2mmol,0.1 eq), and N-methylparaben (2.6 g,21mmol,1.05 eq) were added to toluene (40 mL) and stirred well. The reaction was heated to reflux and water was separated for 30 hours, and after cooling, a solid was precipitated. Concentrating to remove most of the solvent, adding sodium hydroxide aqueous solution (with the concentration of about 10%), adjusting the pH to 11-12, fully stirring, collecting precipitated solid, fully drying to obtain 3.4g of off-white solid, and obtaining the yield of 55%.
Compound III characterization data:
1H NMR(d6-DMSO 400MHz)δ:1.02(t,J＝8Hz,3H),1.76-1.83(m,2H),2.28(s,3H),2.44(t,J＝8Hz,2H),3.83(s,3H),7.31-7.34(m,2H),7.38-7.40(m,1H),7.45(d,J＝8Hz,1H),7.54(s,1H),7.80-7.93(m,1H).
LR-MS(ESI)m/z:308(M+H)+.
the characterization data are identical to those of the product III obtained in example 2.
Example 7
Starting from compound VI-1, a process for preparing intermediate compound III.
1) Preparation of Compound VI
Adding compound VI-1 (10 g,31.7 mmol) into 100ml ethanol, adding acetic acid (7.7 g,128.8 mmol), 5% Pd/C1 g, adding hydrogen under pressure (hydrogen 10 kg pressure), heating at 70 deg.C, filtering the reaction solution after 10h, concentrating filtrate to remove most of solvent, adding saturated NaOH to adjust pH to 10, adding 200ml DCM for extraction, saturated saline washing the organic phase, drying, spinning dry, pulping with a small amount of ethanol to obtain light yellow solid (6.5 g) with yield 86.4％.1H NMR(500MHz,DMSO-d6):δ7.59(d,J＝7.2Hz,1H),7.49–7.55(m,1H),7.46(d,J＝2.1Hz,1H),7.39–7.44(m,1H),7.15–7.26(m,2H),6.75(d,J＝8.2Hz,1H),5.37(s,2H),3.83(s,3H),2.15(s,3H).LR-MS(ESI)m/z:238.2(M+H)+.
2) Preparation of Compound III
In a three-necked flask, compound VI (237 mg,1.0 mmol) was added to acetonitrile (5 mL) and an aqueous sodium hydroxide solution (80 mg,2.0mmol,2.0eq, dissolved in 5mL of water), and stirred well in an ice bath at 0 to 5 ℃. A solution of n-butyryl chloride (106 mg,1.0mmol,1.0 eq) in acetonitrile (3 mL) was slowly added dropwise to the reaction under stirring at 0-5deg.C in an ice bath, and the mixture was stirred at room temperature for half an hour after completion of the dropwise addition. Water (20 mL) was added to the reaction and the mixture was stirred well. The precipitated solid was collected, dissolved by adding a small amount of isopropanol, added with concentrated hydrochloric acid under stirring, precipitated a white precipitate, and the solid was collected and sufficiently dried to give 327mg of a white solid with a yield of 95%.
Compound III (hydrochloride) characterization data:
1H NMR(d6-DMSO 400MHz)δ:0.96(t,J＝8Hz,3H),1.63-1.67(m,2H),2.38(s,3H),2.44(t,J＝8Hz,2H),4.06(s,3H),7.61-7.66(m,2H),7.79-7.92(m,4H),8.03-8.05(m,1H),9.66(s,1H).
LR-MS(ESI)m/z:308(M+H)+.
Example 8
Starting from compound III, a process for preparing compound II.
1) Preparation of Compound IX:
Intermediate compound III (hydrochloride) (6.88 g,20 mmol), triphosgene (2.38 g,8mmol,0.4 eq) and acetonitrile (30 mL) were heated to 80-85℃and stirred well. N, N-dimethylformamide (73 mg,1.0mmol,0.05 eq) was then added thereto and the mixture was heated and stirred at 80 to 85℃for 2 hours. After cooling to room temperature, an acetonitrile solution (990 mg,30mmol,1.5eq; acetonitrile 10 mL) of hydroxylamine was added to the mixture under stirring, and the mixture was kept under stirring at room temperature for 1 hour. After the reaction, adding sodium hydroxide aqueous solution (10%) to adjust the pH value to 10-11, cooling to 0-5 ℃, precipitating off-white precipitate, collecting solid and fully drying to obtain 5.9g of off-white solid with the yield of 92%.
Compound IX characterization data:
1H 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).
LR-MS(ESI)m/z:323(M+H)+.
2) Preparation of Compound X-1:
Compound IX (6.4 g,20 mmol) was dissolved in acetonitrile (20 mL). Triethylamine (2.42 g,24mmol,1.2 eq) was then added to the reaction, followed by slow addition of p-toluenesulfonyl chloride (4.2 g,22mmol,1.1 eq) to the reaction at 0-5℃and reaction at room temperature for 1-2 hours. Ethyl acetate (10 mL) was added for extraction, the aqueous phase was discarded, the organic phase was washed once with aqueous sodium hydroxide (10%, 10 mL), the organic phase was concentrated, solids precipitated, and the precipitated solids were collected and dried sufficiently to give a pale yellow solid product.
3) Preparation of Compound II:
Compound X-1 (9.5 g,20 mmol) was dissolved in acetonitrile (20 mL). Then, an aqueous sodium hydroxide solution (3.2 g,80mmol,4.0eq, 20mL of water) was added to the reaction, and the reaction was completed by heating to room temperature for 3 to 4 hours. . Ethyl acetate (10 mL) was added for extraction, the aqueous phase was discarded, the organic phase was washed once with aqueous sodium hydroxide (10%, 10 mL), the organic phase was concentrated, solids precipitated, and the precipitated solids were collected and dried sufficiently to give 5.5g of pale yellow solid in 90% yield.
Compound II characterization data:
1H NMR(400MHz,CDCl3)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).
LR-MS(ESI)m/z:305(M+H)+.
Example 9
Starting from compound III, a process for preparing compound II by a "one-pot" continuous reaction.
Intermediate compound III (hydrochloride) (6.88 g,20 mmol), triphosgene (2.38 g,8mmol,0.4 eq) and acetonitrile (30 mL) were heated to 80-85℃and stirred well. N, N-dimethylformamide (73 mg,1.0mmol,0.05 eq) was then added thereto and the mixture was heated and stirred at 80 to 85℃for 2 hours. After cooling to room temperature, hydroxylamine (1.0 g,30mmol,1.5 eq) was added with stirring and kept at room temperature for 1 hour with stirring. Triethylamine (8.8 g,80mmol,4.0 eq) was then added to the reaction, followed by slow addition of p-toluenesulfonyl chloride (4.2 g,22mmol,1.1 eq) to the reaction at 0-5℃and reaction at room temperature for 3-4 hours. Ethyl acetate (10 mL) was added for extraction, the aqueous phase was discarded, the organic phase was washed once with aqueous sodium hydroxide (10%, 10 mL), the organic phase was concentrated, solids precipitated, and the precipitated solids were collected and dried sufficiently to give 5.2g of pale yellow solid in 85% yield.
Compound II characterization data:
1H NMR(400MHz,CDCl3)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).
LR-MS(ESI)m/z:305(M+H)+.
Example 10
Starting from compound IX, the process for preparing compound II by a "one-pot" continuous reaction.
Compound IX (6.4 g,20 mmol) was dissolved in acetonitrile (20 mL). Aqueous sodium hydroxide (3.2 g,80mmol,4.0eq, 20mL of water) was added to the reaction, followed by slow addition of p-toluenesulfonyl chloride (4.2 g,22mmol,1.1 eq) to the reaction at 0-5℃and reaction at room temperature for 3-4 hours. Ethyl acetate (10 mL) was added for extraction, the aqueous phase was discarded, the organic phase was washed once with aqueous sodium hydroxide (10%, 10 mL), the organic phase was concentrated, solids precipitated, and the precipitated solids were collected and dried sufficiently to give 5.4g of a pale yellow solid product in 88% yield.
Compound II characterization data:
1H NMR(400MHz,CDCl3)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).
LR-MS(ESI)m/z:305(M+H)+.

Claims (14)

1. A compound of formula III:
The salt is a salt III.HX formed by a compound shown in a formula III and an acid, wherein HX is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid and acetic acid.
2. A process for preparing a compound of formula III, which is one of the following:
the method comprises the following steps: is prepared by reacting a compound shown in a formula IV with a methylating agent,
The methylating agent is selected from methyl iodide, dimethyl sulfate and dimethyl carbonate;
the reaction is carried out under an alkaline reagent and in a solvent,
The alkaline reagent is one or a mixture of more selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
the solvent is one or a mixture of more selected from tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
the second method is as follows: prepared from a compound represented by formula V-1,
Step (1), 3-methyl-4-n-butyrylaminobenzoic acid is taken as a starting material, and a compound shown as a 3-methyl-4-n-butyrylaminobenzoyl chloride formula V-2 is prepared through a chlorination reaction;
Step (2), reacting a compound shown in a formula V-2 with N-methyl o-phenylenediamine to obtain compounds shown in formulas V-3 and V-4;
Step (3), performing condensation reaction on the compounds shown in the formulas V-3 and V-4 in the presence of an acidic reagent to obtain a compound shown in a formula III;
In the step (1), the chlorinating reagent used in the chlorination reaction is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate,
In the step (1), the chlorination reaction is carried out in a solvent, wherein the solvent is selected from one or a mixture of more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether and methyl tertiary butyl ether,
In the step (2), an alkaline reagent is used as an acid-binding agent, wherein the alkaline reagent is one or more selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
The step (2) is carried out in a solvent, wherein the solvent is selected from one or a mixture of more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene dichloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
In the step (3), the acid reagent is one or a mixture of a plurality of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In the step (3), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or a solvent-free reaction condition is used;
And a third method: prepared from a compound represented by formula V-1,
Step (1), reacting 3-methyl-4-N-butyrylaminobenzoic acid with N-methyl-o-phenylenediamine in the presence of an acidic reagent to obtain compounds shown in formulas V-3 and V-4;
Step (2), reacting the compounds shown in the formulas V-3 and V-4 under the acidic reagent in the step (1) to obtain a compound shown in the formula III;
In the step (1), the acid reagent is one or a mixture of a plurality of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in step (2), the acidic reagent used is as defined in step (1);
In the step (1) and the step (2), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or a solvent-free reaction condition is used;
the method four: prepared from a compound represented by the formula V-6 or V-7,
Step (1), 3-methyl-4-N-butyrylaminobenzoic acid methyl ester or 3-methyl-4-N-butyrylaminobenzoic acid ethyl ester reacts with N-methyl o-phenylenediamine in the presence of an acidic reagent to obtain compounds shown in formulas V-3 and V-4;
step (2), reacting the compounds shown in the formulas V-3 and V-4 under the acidic reagent condition in the step (1) to obtain a compound shown in the formula III;
In the step (1), the acid reagent is one or a mixture of a plurality of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in step (2), the acidic reagent used is as defined in step (1);
In the step (1) and the step (2), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or a solvent-free reaction condition is used;
And a fifth method: prepared from a compound of formula VI,
2-Methyl-4- (1-methyl-1H-benzo [ d ] imidazol-2-yl) aniline reacts with a compound shown in a general formula VII to obtain a compound shown in a formula III;
Wherein R 3 is chloro, bromo, n-butyryloxy, methoxy, ethoxy or hydroxy;
The method six: prepared from a compound represented by formula VIII,
Wherein Y is chlorine (Cl), bromine (Br) or iodine (I),
Reacting a compound shown in a general formula VIII with N-methylbenzimidazole in the presence of an alkaline reagent to obtain a compound shown in a general formula III,
The alkaline reagent is one or a mixture of several of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, sodium acetate, potassium acetate, magnesium acetate, sodium pivalate, potassium pivalate, magnesium pivalate, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine and 2, 6-tetramethylpiperidine;
The reaction is carried out in the presence of a transition metal compound and a complex thereof, wherein the transition metal compound is one or a mixture of more selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cupric chloride, cupric bromide, cupric oxide, cupric acetate, cupric sulfate, cupric nitrate, palladium chloride, palladium acetate, palladium trifluoroacetate, palladium triflate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium, nickel dichloride, nickel acetate, bis (acetylacetonate) nickel, nickel trifluoroacetate, nickel triflate and bis (1, 5-cyclooctadiene) nickel; the ligand used in the complex of the transition metal compound is selected from ethylenediamine, N-methylethylenediamine, N-butylethylenediamine, N '-dimethylethylenediamine, N-dimethylethylenediamine, trimethylethylenediamine, tetramethylethylenediamine, (cis) -1, 2-cyclohexanediamine, (trans) -1, 2-cyclohexanediamine, 1, 2-cyclohexanediamine racemate, (trans) -N, N' -dimethyl-1, 2-cyclohexanediamine, (trans) -N, N '-diethyl-1, 2-cyclohexanediamine, (trans) -N, N' -diisopropyl-1, 2-cyclohexanediamine, 2 '-bipyridine, 1, 10-phenanthroline, 2, 9-dimethyl-1, 10-phenanthroline, 3,4,7, 8-tetramethyl-1, 10-phenanthroline, 4, 7-diphenyl-1, 10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 2-bis (diphenylphosphine) propane, 1' -bis (diphenylphosphino) ferrocene, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine,
The reaction is carried out in a solvent, wherein the solvent is one or a mixture of more selected from dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, acetonitrile, acetone, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, pyridine, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water.
3. The method of claim 2, wherein
In the second method, the step (1) and the step (2) are performed by a one-pot method, namely, the compound shown in the formula V-2 prepared in the step (1) is directly subjected to the reaction in the step (2) without separation; and/or
In the third method, the step (1) and the step (2) are performed by a one-pot method, namely, the compounds shown in the formulas V-3 and V-4 prepared by the step (1) are not separated under the condition of an acidic reagent, and the compound shown in the formula III is continuously prepared under the reaction condition of the step (1); and/or
In the fourth method, the step (1) and the step (2) are performed by a one-pot method, namely, the compounds of the formula V-3 and the formula V-4 prepared by the step (1) are not separated under the condition of an acidic reagent, and the compound of the formula III is continuously prepared under the reaction condition of the step (1).
4. The process of claim 2, in process five, the compound of formula VI is prepared by the following process:
Step (1), obtaining a compound shown in a formula VI-2 under a reducing condition by using the compound shown in the formula VI-1;
Step (2), obtaining a compound shown in a formula VI-2 under the condition of an acidic reagent;
Or the compound VI-1 is added with an acidic reagent in the reduction system of the step (1) at the same time to directly obtain the compound of the formula VI; the acidic reagent used in the reaction is as defined in step four (1) of the process of claim 2;
In step (1), the reducing agent used in the reducing conditions is selected from hydrogen, metal reducing agents, metal chlorides, complex hydrides, sulfur-containing reducing agents, wherein the hydrogen reduction is carried out with the addition of a catalyst selected from Cu, ni, pd, pt, ru, rh and oxides, hydroxides, chlorides, complexes with carbon or corresponding organometallic complexes thereof; the metal reducing agent is selected from iron powder and zinc powder; the metal chloride is selected from stannous chloride dihydrate and titanium trichloride; the complex hydride is selected from lithium aluminum hydride; the sulfur-containing reducing agent is selected from sodium hydrosulfide, sodium sulfide, ammonium sulfide, sodium sulfite, sodium bisulfite, and sodium hydrosulfite;
Step (1) is carried out in a solvent, wherein the solvent is one or a mixture of more selected from methanol, ethanol, propanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, acetone, ethyl acetate, N-butyl acetate, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, formic acid, acetic acid, hydrochloric acid, sulfuric acid and water;
The acidic reagent in step (2) is as defined in step (2) of the method of claim 2;
In the step (2), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
5. The method of claim 2, wherein method five is performed according to one of three methods:
In the method (a), when R 3 is chlorine, bromine or n-butyryloxy, the compound shown in the formula VI is reacted with n-butyryl chloride, n-butyryl bromide or n-butyric anhydride to prepare a compound shown in the formula III,
The method (a) is carried out in the presence of an alkaline agent, wherein the alkaline agent is one or more selected from 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, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine,
The method (a) is carried out in a solvent, wherein the solvent is selected from one or a mixture of a plurality of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene dichloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
In the method (b), when R 3 is methoxy or ethoxy, the compound shown in the formula VI is reacted with methyl n-butyrate or ethyl n-butyrate to prepare the compound shown in the formula III,
The process (b) is carried out in the presence of an acidic reagent,
In the method (b), the acidic reagent used is one or a mixture of more selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride,
In the method (b), the reaction is carried out in a solvent or under the condition of solvent-free reaction, wherein the solvent is one or a mixture of more of dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, tertiary butanol and ethylene glycol,
In the method (c), when R 3 is hydroxyl, the compound shown in the formula VI reacts with n-butyric acid in the presence of an acidic reagent to prepare a compound shown in the formula III,
In the method (c), the acidic reagent used is one or a mixture of several selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride,
In the method (c), the reaction is carried out in a solvent or using a solvent-free reaction condition, wherein the solvent is one or a mixture of more of dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, tertiary butanol and ethylene glycol.
6. The method of claim 2, wherein the compound of formula IV is prepared by one of the following methods:
method I: is prepared from a compound shown as a formula V-1,
Step (1), 3-methyl-4-n-butyrylaminobenzaldehyde is prepared by taking 3-methyl-4-n-butyrylaminobenzaldehyde as a starting material through chlorination reaction;
step (2), the prepared compound shown in the formula V-2 reacts with o-phenylenediamine to obtain a compound shown in the formula V-5;
step (3), performing condensation reaction on the compound shown in the formula V-5 in the presence of an acidic reagent to obtain a compound shown in the formula IV;
In the step (1), the chlorinating agent used in the chlorination reaction is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate;
In the step (1), the chlorination reaction is carried out in a solvent, wherein the solvent is one or a mixture of more selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether and methyl tertiary butyl ether;
In the step (2), an alkaline reagent is used as an acid-binding agent, wherein the alkaline reagent is one or more selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
The step (2) is carried out in a solvent, wherein the solvent is selected from one or a mixture of more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene dichloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
In the step (3), the acid reagent is one or a mixture of a plurality of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In the step (3), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or a solvent-free reaction condition is used;
Method II: is prepared from a compound shown as a formula V-1,
Step (1), reacting 3-methyl-4-n-butyrylaminobenzoic acid with o-phenylenediamine in the presence of an acidic reagent to obtain a compound shown in a formula V-5;
Step (2), reacting the compound shown in the formula V-5 under the acidic reagent in the step (1) to obtain a compound shown in the formula IV;
In the step (1), the acid reagent is one or a mixture of a plurality of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in step (2), the acidic reagent used is as defined in step (1);
In the step (1) and the step (2), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, or a solvent-free reaction condition is used;
Method III:
Step (1), 3-methyl-4-n-butyrylaminobenzoic acid methyl ester or 3-methyl-4-n-butyrylaminobenzoic acid ethyl ester reacts with o-phenylenediamine in the presence of an acidic reagent to obtain a compound shown in a formula V-5;
Step (2), reacting the compound shown in the formula V-5 under the acidic reagent in the step (1) to obtain a compound shown in the formula IV;
In the step (1), the acid reagent is one or a mixture of a plurality of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in step (2), the acidic reagent used is as defined in step (1);
In the step (1) and the step (2), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
7. The method of claim 6, wherein
In the method I, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-2 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation; and/or
In the method II, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compound shown in the formula V-5 prepared in the step (1) is not separated, and the compound shown in the formula IV is continuously prepared under the reaction condition of the step (1); and/or
In the method III, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compound shown in the formula V-5 prepared in the step (1) is not separated under the condition of an acid reagent, and the compound shown in the formula IV is continuously prepared under the reaction condition of the step (1).
8. The method of claim 4, wherein the compound of formula VI-1 is prepared by one of the following methods:
Method IV:
The method comprises the following steps of (1) reacting o-nitrochlorobenzene in aqueous solution of methylamine under heating condition to obtain o-nitroaniline;
step (2), preparing a compound shown in a formula V-9 by a chlorination reaction of the compound shown in the formula V-8;
step (3), reacting a compound shown in a formula V-9 with o-nitroaniline to obtain a compound shown in a formula VI-1;
in the step (1), the concentration of the aqueous solution of methylamine is 20-30%, and the reaction is carried out at 100-150 ℃ and 3-10 atm;
Step (2) and step (3) are carried out in a solvent;
Wherein the chlorinated reagent, alkaline reagent and solvent used in step (2) and step (3) of the reaction process are as defined in step (1) and step (2) of the process I of claim 6;
Method V:
reacting a compound shown in a formula V-8 with o-nitroaniline in the presence of an acidic reagent and in a solvent to obtain a compound shown in a formula VI-1;
the acidic reagents and solvents in the course of the reaction are as defined in step (1) of method II of claim 6;
Method VI:
Reacting a compound shown in a formula V-10 or a compound shown in a formula V-11 with o-nitroaniline in the presence of an acidic reagent and in a solvent to obtain a compound shown in a formula VI-1;
The acidic reagent and solvent in the course of the reaction are as defined in step (1) of method III of claim 6;
Method VII:
reacting a compound shown in a formula V-12 with o-nitrochlorobenzene in the presence of an alkaline reagent, a transition metal compound and a complex thereof in a solvent to obtain a compound shown in a formula VI-1;
The definition of the alkaline reagent, the transition metal compound, the complex thereof and the solvent in the reaction process is the same as that of the alkaline reagent, the transition metal compound, the complex thereof and the solvent in the method six of claim 2;
Method VIII:
Step (1), 3-methyl-4-nitrobenzoyl chloride is prepared by taking 3-methyl-4-nitrobenzoic acid as a starting material through chlorination reaction;
step (2), the prepared compound shown in the formula V-9 reacts with o-nitroaniline in the presence of an alkaline reagent to obtain a compound shown in the formula V-13;
step (3), the compound shown in the formula V-13 reacts with a methylation reagent to prepare a compound shown in the formula VI-1;
Step (1) and step (2) are performed in a solvent;
Wherein the chlorinated reagent, alkaline reagent and solvent used in step (1) and step (2) of the reaction process are as defined in step (1) and step (2) of method I of claim 6;
In step (3), the methylating agent is selected from the group consisting of methyl iodide, methyl chloride, dimethyl sulfate and dimethyl carbonate;
in step (3), the reaction is carried out under an alkaline reagent and in a solvent,
In the step (3), the alkaline reagent is one or a mixture of several selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In the step (3), the solvent is one or a mixture of more selected from tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water.
9. The method of claim 8, wherein
In the method IV, the step (2) and the step (3) are carried out by a one-pot method, namely, the compound shown in the formula V-9 prepared in the step (2) is directly subjected to the reaction of the step (3) without separation; and/or
In method VIII, the steps (1) and (2) are carried out using a one-pot method, i.e., the compound of formula V-9 prepared in step (1) is directly subjected to the reaction of step (2) without isolation.
10. An intermediate for the preparation of a compound of formula III or a salt thereof, said intermediate being selected from the group consisting of compounds of formulae IV, V-3, V-4, V-5, VI-1:
11. A process for preparing a compound of formula II, the process comprising:
Step (1), reacting a compound shown in a formula III with a chlorinating reagent;
step (2), reacting the chlorination reaction mixture obtained in the step (1) with a hydroxylamine reagent to obtain a compound shown in a formula IX;
step (3), reacting the compound shown in the formula IX with an acyl chloride or anhydride reagent to obtain a compound shown in the general formula X;
Step (4), reacting a compound shown in a general formula X in the presence of an alkaline reagent to obtain a compound shown in a formula II;
In the step (1), the chlorinating agent is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate, and the solvent is one or a mixture of more selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether and methyl tertiary butyl ether;
In step (2), the hydroxylamine reagent used is selected from hydroxylamine free base, or a salt of hydroxylamine;
In step (3), in the compound represented by the general formula X, R 4 is a carboxylic acid acyl-C (=o) R 5, sulfonyl-SO 2R6, alkoxycarbonyl-C (=o) -OR 7, alkylaminocarbonyl-C (=o) -NR 8R9, OR alkoxyphosphoryl-P (=o) (OR 10)2;
Wherein R 5 to R 10 are each independently hydrogen, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkyl, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 6-C20 aryl; in the case where R 5 to R 10 are substituted C 1-C20 linear or branched or cyclic alkyl, substituted C 1-C20 linear or branched or cyclic alkenyl, substituted benzyl, or substituted C 6-C20 aryl, the substituents are selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C 1-C20 linear or branched or cyclic alkyl, C 1-C20 linear or branched or cyclic alkenyl, C 1-C20 linear or branched or cyclic alkoxy;
In the step (3), the acid chloride or anhydride reagent used is the acid chloride or anhydride corresponding to R 4;
In the step (3), the reaction is carried out in an alkaline reagent, wherein the alkaline reagent is one or a mixture of several 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, 2, 6-tetramethylpiperidine;
in the step (3), the reaction is carried out in a solvent, wherein the solvent is one or a mixture of a plurality of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether and water;
In the step (4), the alkaline reagent used is one or more 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, 2, 6-tetramethylpiperidine;
In the step (4), a solvent is used, and the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether and water.
12. The method of claim 11, wherein
In step (2), the hydroxylamine salt is hydroxylamine hydrochloride;
In step (3), the acid chloride or acid anhydride reagent used is one or a mixture of several selected from 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, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-methylbenzenesulfonic anhydride, methyl chloroformate, ethyl chloroformate, benzyl chloroformate, di-t-butyl dicarbonate, N-dimethylformamide, diethoxyphosphoryl chloride.
13. The method of claim 11, wherein the steps (3) and (4) are performed using a one-pot process, or the steps (1) to (4) are performed using a one-pot process.
14. An intermediate for the preparation of a compound of formula II or a salt thereof, said intermediate being selected from compounds of formula IX, X or a salt thereof:
Wherein R 4 in the compound of the formula IX is as defined in claim 11, is -C(＝O)R5、-SO2R6、-C(＝O)-OR7、-C(＝O)-NR8R9、-P(＝O)(OR10)2;
Wherein R 5 to R 10 are each independently hydrogen, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkyl, substituted or unsubstituted C 1-C20 linear or branched or cyclic alkenyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 6-C20 aryl; in the case where R 5 to R 10 are substituted C 1-C20 linear or branched or cyclic alkyl, substituted C 1-C20 linear or branched or cyclic alkenyl, substituted benzyl, or substituted C 6-C20 aryl, the substituents are selected from cyano, nitro, amino, hydroxy, mercapto, halogen, phenyl, C 1-C20 linear or branched or cyclic alkyl, C 1-C20 linear or branched or cyclic alkenyl, C 1-C20 linear or branched or cyclic alkoxy.
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